Pheochromocytoma is a rare tumor of chromaffin cells most commonly arising from the adrenal medulla. An estimated 800 cases are diagnosed yearly in the United States. The peak incidence is in the third to fifth decades of life. Bilateral disease is present in approximately 10% of patients. Bilaterality is much more common in familial pheochromocytoma, often found in association with the familial multiple endocrine neoplasia syndromes (MEN, types 2A and 2B). In patients with MEN type 2 syndromes, the risk of developing a contralateral tumor following unilateral adrenalectomy is approximately 50%.[1] Other syndromes associated with pheochromocytoma include neurofibromatosis, von Hippel-Lindau disease, cerebellar hemangioblastoma, Sturge-Weber’s syndrome, and tuberous sclerosis. In a series of 82 unselected patients with pheochromocytoma, 23% were found to be carriers of associated familial disorders.[2] Therefore, all patients with pheochromocytomas should be screened for MEN2 and von Hippel-Lindau disease to avert further morbidity and mortality in the patients and their families. Extra-adrenal pheochromocytoma or functional paraganglioma occurs in approximately 10% to 15% of cases and may arise from any extra-adrenal chromaffin tissue in the body associated with sympathetic ganglia.

Extra-adrenal pheochromocytoma is most often located within the abdomen and may have greater malignant potential than adrenal pheochromocytoma.[3,4] Extra-adrenal tumors usually have a poorer prognosis than adrenal tumors.[3,4] However, in one series of 73 patients referred to tertiary care centers, no difference was found in the metastatic potential or the prognosis of extra-adrenal tumors compared to adrenal tumors.[5] Due to the production and release of catecholamines, pheochromocytomas cause hypertension. However, only 0.1% to 0.5% of all hypertension patients will be found to have a pheochromocytoma. The importance of the recognition of this disease is that over 90% of patients properly diagnosed and treated are curable.[4,6-10]

The hypertension caused by pheochromocytoma may be sustained or paroxysmal and is often severe with occasional malignant features of encephalopathy, retinopathy, and proteinuria. Less commonly, severe hypertensive reactions may occur during incidental surgery, following trauma, exercise, or micturition (in the setting of bladder pheochromocytoma) when the diagnosis is unsuspected. Other clinical features of pheochromocytoma include headache, sweating, palpitation, tachycardia, and severe anxiety along with epigastric or chest pain. Orthostatic hypotension is frequently present and is probably due to reduced intravascular volume following chronic adrenergic stimulation.

The diagnosis of pheochromocytoma is established by the demonstration of elevated 24-hour urinary excretion of free catecholamines (norepinephrine and epinephrine) or catecholamine metabolites (vanillylmandelic acid and total metanephrines). The measurement of plasma catecholamines can also be of value in the diagnosis of pheochromocytoma. However, the measurement of plasma catecholamines has limited sensitivity and specificity. Plasma metanephrines have been reported to be more sensitive than plasma catecholamines. When 52 patients with pheochromocytoma were studied, every patient was found to have elevated plasma levels of metanephrines, but 8 had normal levels of plasma catecholamines.[11] Pharmacologic testing with agents such as glucagon or clonidine is rarely required to make the diagnosis.[12,13]

Once the diagnosis is confirmed by biochemical determinations the localization and extent of disease should be determined.[9] Ninety-seven percent are found in the abdomen, 2% to 3% in the thorax, and 1% in the neck. The initial studies should be a chest film and abdominal computed tomographic (CT) scan. I¹³¹meta-iodobenzylguanidine (MIBG) has been found to be useful as a scintigraphic localization agent.[14,15] If the tumor is not adequately localized by these methods then magnetic resonance imaging (MRI), or rarely, vena cava catheterization with selective venous sampling for catecholamines may be indicated.[16] CT and MRI scans are about equally sensitive (98%-100%), while MIBG scanning has a sensitivity of only 80%. However, MIBG scanning has a specificity of 100%, compared to specificity of 70% for CT and MRI.[12] If extra-adrenal or metastatic disease is suspected, additional studies such as bone scan, liver-spleen scan, chest CT scan, or ultrasound may aid in determining the extent of disease.

Surgical resection is the standard curative modality.[17] If the primary tumor is localized to the adrenal gland and is benign, then survival is that of the normal age-matched population. In patients with unresectable, recurrent, or metastatic disease long-term survival is possible; the overall 5-year survival, however, is less than 50%. Pharmacologic treatment of the catecholamine excess is mandatory and surgery, radiation therapy, or chemotherapy may provide palliative benefit.

References

1. Lairmore TC, Ball DW, Baylin SB, et al.: Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217 (6): 595-601; discussion 601-3, 1993.  [PUBMED Abstract]
   
   
2. Neumann HP, Berger DP, Sigmund G, et al.: Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329 (21): 1531-8, 1993.  [PUBMED Abstract]
   
   
3. Sclafani LM, Woodruff JM, Brennan MF: Extraadrenal retroperitoneal paragangliomas: natural history and response to treatment. Surgery 108 (6): 1124-9; discussion 1129-30, 1990.  [PUBMED Abstract]
   
   
4. Whalen RK, Althausen AF, Daniels GH: Extra-adrenal pheochromocytoma. J Urol 147 (1): 1-10, 1992.  [PUBMED Abstract]
   
   
5. Pommier RF, Vetto JT, Billingsly K, et al.: Comparison of adrenal and extraadrenal pheochromocytomas. Surgery 114 (6): 1160-5; discussion 1165-6, 1993.  [PUBMED Abstract]
   
   
6. Manger WM, Gifford RW: Pheochromocytoma. New York: Springer-Verlag, 1977. 
   
   
7. Norton JA, Le HN: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 1770-1787. 
   
   
8. Young JB, Landsberg L: Catecholamines and the adrenal medulla: pheochromocytoma. In: Wilson JD, Foster DW, Kronenberg HM, et al., eds.: Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: W.B. Saunders Company, 1998, pp 705-716. 
   
   
9. Bravo EL, Gifford RW Jr: Current concepts. Pheochromocytoma: diagnosis, localization and management. N Engl J Med 311 (20): 1298-303, 1984.  [PUBMED Abstract]
   
   
10. Remine WH, Chong GC, Van Heerden JA, et al.: Current management of pheochromocytoma. Ann Surg 179 (5): 740-8, 1974.  [PUBMED Abstract]
    
    
11. Lenders JW, Keiser HR, Goldstein DS, et al.: Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 123 (2): 101-9, 1995.  [PUBMED Abstract]
    
    
12. Bravo EL: Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev 15 (3): 356-68, 1994.  [PUBMED Abstract]
    
    
13. Sjoberg RJ, Simcic KJ, Kidd GS: The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls. Arch Intern Med 152 (6): 1193-7, 1992.  [PUBMED Abstract]
    
    
14. McEwan AJ, Shapiro B, Sisson JC, et al.: Radio-iodobenzylguanidine for the scintigraphic location and therapy of adrenergic tumors. Semin Nucl Med 15 (2): 132-53, 1985.  [PUBMED Abstract]
    
    
15. Shapiro B, Copp JE, Sisson JC, et al.: Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med 26 (6): 576-85, 1985.  [PUBMED Abstract]
    
    
16. Fink IJ, Reinig JW, Dwyer AJ, et al.: MR imaging of pheochromocytomas. J Comput Assist Tomogr 9 (3): 454-8, 1985 May-Jun.  [PUBMED Abstract]
    
    
17. Brennan MF, Keiser HR: Persistent and recurrent pheochromocytoma: the role of surgery. World J Surg 6 (4): 397-402, 1982.  [PUBMED Abstract]
    
    

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