Pheochromocytoma And Paraganglioma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Pheochromocytoma and Paraganglioma

Pheochromocytomas and extra-adrenal paragangliomas are rare tumors arising from neural crest tissue that develops into sympathetic and parasympathetic paraganglia throughout the body.

In 2004, the World Health Organization classification used the term pheochromocytoma exclusively for tumors arising from the adrenal medulla, and the term extra-adrenal paraganglioma for similar tumors that arise from other locations.

Incidence and Mortality

The incidence of pheochromocytoma is 2 to 8 per million persons per year.[1,2] Pheochromocytoma is present in 0.1% to 1% of patients with hypertension,[3,4,5] and it is present in approximately 5% of patients with incidentally discovered adrenal masses.[6] The peak incidence occurs in the third to fifth decades of life. The average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases.[7] The incidence is equal between men and women.[8]

Anatomy

Pheochromocytomas and extra-adrenal paragangliomas arise from neural crest tissue. Neural crest tissue develops into sympathetic and parasympathetic paraganglia.

Sympathetic paraganglia include:

• The adrenal medulla.
• The organ of Zuckerkandl near the aortic bifurcation.
• Other paraganglia along the distribution of the sympathetic nervous system.

Parasympathetic paraganglia include:

• The carotid body.
• Other paraganglia along the cervical and thoracic branches of the vagus and glossopharyngeal nerves.

Risk Factors

No known environmental, dietary, or lifestyle risk factors have been linked to the development of pheochromocytoma.

Hereditary Predisposition Syndromes

Of all pheochromocytomas and extra-adrenal paragangliomas, 35% occur in patients with a hereditary cancer syndrome.[7,8,9] Major genetic syndromes that confer an increased risk of pheochromocytoma are included in Table 1.

Pheochromocytomas and extra-adrenal paragangliomas can also occur in two other very rare syndromes:

• The Carney triad of extra-adrenal paraganglioma, gastrointestinal stromal tumor (GIST),[21] and pulmonary chondroma.
• The Carney-Stratakis dyad of paraganglioma and GIST.[22]

Genetic counseling and testing

It has been proposed that all patients diagnosed with a pheochromocytoma or paraganglioma should consider genetic testing because the incidence of a hereditary syndrome in apparently sporadic cases is as high as 25%.[7,8,23] Early identification of a hereditary syndrome allows for early screening for other associated tumors and identification of family members who are at risk. In addition, some patients with a hereditary syndrome are more likely to develop multifocal, malignant, or recurrent disease. Knowledge of the specific genetic variant permits increased vigilance during preoperative localization or postoperative surveillance of such patients.

Certain subgroups of patients are at very low risk of having an inherited syndrome (e.g., <2% in patients diagnosed with apparently sporadic pheochromocytoma after age 50 years).[7] Therefore, genetic testing for all patients diagnosed with a pheochromocytoma or paraganglioma may not be practical or cost effective from a population standpoint. It is recommended that every patient diagnosed with a pheochromocytoma or extra-adrenal paraganglioma should first undergo risk evaluation for a hereditary syndrome by a certified genetic counselor.[24]

Genetic testing is often recommended in the following situations:

• Patients with a personal or family history of clinical features suggestive of a hereditary pheochromocytoma-paraganglioma syndrome.
• Patients with bilateral or multifocal tumors.
• Patients with sympathetic or malignant extra-adrenal paragangliomas.
• Patients diagnosed before age 40 years.

Genetic testing can be considered when a patient has the following features:

• Patient is between the ages of 40 and 50 years.
• Patients has a history of a unilateral pheochromocytoma.
• Patient does not have a personal or family history suggestive of a hereditary cancer syndrome.

If a germline variant is identified, predictive genetic testing may be offered to asymptomatic at-risk family members. For more information, see Genetics of Endocrine and Neuroendocrine Neoplasias.

Genetic testing is not recommended in patients who are older than 50 years.

Clinical Features

Patients with pheochromocytomas and sympathetic extra-adrenal paragangliomas may present with symptoms of excess catecholamine production, including:

• Hypertension.
• Headache.
• Perspiration.
• Forceful palpitations.
• Tremor.
• Facial pallor.

These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma.[25] Episodes of hypertension can be variable in frequency, severity, and duration and are often extremely difficult to manage medically. Hypertensive crisis can lead to cardiac arrhythmias, myocardial infarction, and even death.

Patients are often very symptomatic from excess catecholamine secretion. Symptoms of catecholamine excess can be spontaneous or induced by:

• Strenuous physical exertion.
• Trauma.
• Labor and delivery.
• Anesthesia induction.
• Surgery or other invasive procedures, including direct instrumentation of the tumor (e.g., fine-needle aspiration).
• Eating foods high in tyramine (e.g., red wine, chocolate, and cheese).
• Urination (e.g., bladder wall tumor, which is rare).

Phenoxybenzamine (an alpha-adrenergic receptor blocker) is an effective treatment for catecholamine excess and metyrosine (a catecholamine synthesis antagonist) can be added if needed.

Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines. These tumors usually present as a neck mass with symptoms related to compression or are incidentally discovered on an imaging study performed for an unrelated reason. In addition, approximately half of patients with pheochromocytoma are asymptomatic because their neoplasms are discovered in the presymptomatic state by either abdominal imaging for other reasons (e.g., adrenal incidentalomas) or genetic testing in at-risk family members.[17,26,27,28]

Diagnostics

The diagnosis of pheochromocytoma is usually preceded by the presence of an adrenal mass or is discovered incidentally. Biochemical testing is done to document excess catecholamine secretion. Once the biochemical diagnosis of a catecholamine-secreting tumor is confirmed, localization studies should be performed. Controversy exists as to the optimal single test to make the diagnosis.

Biochemical testing

24-hour urine collection

A 24-hour urine collection for catecholamines (e.g., epinephrine, norepinephrine, and dopamine) and fractionated metanephrines (e.g., metanephrine and normetanephrine) has a relatively low sensitivity (77%–90%) but a high specificity (98%). Pretest probability is also important. The specificity of plasma-free fractionated metanephrines is 82% in patients tested for sporadic pheochromocytoma versus 96% in patients tested for hereditary pheochromocytoma.[29,30]

Plasma-free fractionated metanephrines

Measurement of plasma-free fractionated metanephrines appears to be an ideal case-detection test for patients at higher baseline risk of pheochromocytoma. Examples of these patients might include:

• Patients with an incidentally discovered adrenal mass.
• Patients with a family history of pheochromocytoma.
• Patients with a known inherited predisposition to pheochromocytoma.

The test is associated with a relatively high false-positive rate in patients with a lower baseline risk of pheochromocytoma. Measurement of plasma-free metanephrines (e.g., metanephrine and normetanephrine) has a high sensitivity (97%–99%) but a relatively low specificity (85%).

In general, it is reasonable to use measurement of plasma-free fractionated metanephrines for initial case detection, which is followed by 24-hour measurement of urine-fractionated metanephrines and catecholamines for confirmation. Test results can be difficult to interpret because of the possibility of false-positive results. False-positive results can be caused by:[25,29]

• Common medications (e.g., tricyclic antidepressants).
• Physical or emotional stress.
• Inappropriately low reference ranges based on normal laboratory data rather than clinical data sets.[31]
• Common foods (e.g., caffeine and bananas) that interfere with specific assays and medications.

A mildly elevated catecholamine or metanephrine level is usually the result of assay interference caused by drugs or other factors. Patients with symptomatic pheochromocytoma almost always have increases in catecholamines or metanephrines two to three times higher than the upper limits of reference ranges.[25]

Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.[32]

Imaging studies

Computed tomography (CT) imaging or magnetic resonance imaging (MRI) of the abdomen and pelvis (at least through the level of the aortic bifurcation) are the most commonly used methods for localization.[33] Both have similar sensitivities (90%–100%) and specificities (70%–80%).[33] CT imaging provides superior anatomical detail compared with MRI.

Additional functional imaging may be necessary if CT imaging or MRI fails to localize the tumor. It might also be useful in patients who are at risk for multifocal, malignant, or recurrent disease. Iodine I 123 (123I)-metaiodobenzylguanidine (MIBG) scintigraphy coupled with CT imaging provides anatomical and functional information with good sensitivity (80%–90%) and specificity (95%–100%).[33] 131I-MIBG can be used in the same way, but the image quality is not as high as with 123I-MIBG.[34] Other functional imaging alternatives include gallium Ga 68 (68Ga)-DOTATATE and fluorine F 18-fludeoxyglucose positron emission tomography (PET), both of which can be coupled with CT imaging for improved anatomical detail.[35,36]

It is rare for localization of a catecholamine-secreting tumor to be unsuccessful if currently available imaging methods are used.

Prognosis and Survival

There are no clear data regarding the survival of patients with localized (apparently benign) disease or regional disease. Although patients with localized (apparently benign) disease should experience an overall survival approaching that of age-matched disease-free individuals, 6.5% to 16.5% of these patients will develop a recurrence, usually 5 to 15 years after initial surgery.[37,38,39]

Approximately 15% to 25% of patients with recurrent disease experience distant metastasis. The 5-year overall survival rates in those with metastatic disease range from 50% to 70%.[40,41,42,43] Carriers of SDHB pathogenic variants have an increased risk of developing metastatic disease of approximately 25% to 50%.[44] The most commonly associated gene with metastatic pheochromocytoma and paraganglioma is SDHB (over 40% of cases).[45,46]

Follow-Up Evaluation

Long-term follow-up is essential for all patients with pheochromocytoma or extra-adrenal paraganglioma, even when initial pathology demonstrates no findings that are concerning for malignancy.[5]

• After resection of a solitary sporadic pheochromocytoma, patients should undergo baseline postoperative biochemical testing followed by annual lifelong biochemical testing.
• Patients who have undergone resection of a noncatecholamine-producing tumor should initially undergo annual imaging with CT or MRI and periodic imaging with radiolabeled MIBG or 68Ga-DOTATATE PET/CT to monitor for recurrence or metastasis.
• Patients with a hereditary pheochromocytoma/paraganglioma syndrome who have undergone resection require lifelong annual biochemical screening in addition to routine screening for other component tumors of their specific syndrome.[5]

References:

1. Beard CM, Sheps SG, Kurland LT, et al.: Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 58 (12): 802-4, 1983.
2. Stenström G, Svärdsudd K: Pheochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data. Acta Med Scand 220 (3): 225-32, 1986.
3. Sinclair AM, Isles CG, Brown I, et al.: Secondary hypertension in a blood pressure clinic. Arch Intern Med 147 (7): 1289-93, 1987.
4. Anderson GH, Blakeman N, Streeten DH: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 12 (5): 609-15, 1994.
5. Omura M, Saito J, Yamaguchi K, et al.: Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 27 (3): 193-202, 2004.
6. Young WF: Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 29 (1): 159-85, x, 2000.
7. Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002.
8. Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005.
9. Jiménez C, Cote G, Arnold A, et al.: Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab 91 (8): 2851-8, 2006.
10. Baysal BE, Ferrell RE, Willett-Brozick JE, et al.: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287 (5454): 848-51, 2000.
11. Hao HX, Khalimonchuk O, Schraders M, et al.: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325 (5944): 1139-42, 2009.
12. Niemann S, Müller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26 (3): 268-70, 2000.
13. Astuti D, Latif F, Dallol A, et al.: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69 (1): 49-54, 2001.
14. Burnichon N, Brière JJ, Libé R, et al.: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19 (15): 3011-20, 2010.
15. Eijkelenkamp K, Olderode-Berends MJW, van der Luijt RB, et al.: Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas. Clin Genet 93 (5): 1049-1056, 2018.
16. Abermil N, Guillaud-Bataille M, Burnichon N, et al.: TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. J Clin Endocrinol Metab 97 (5): E805-9, 2012.
17. Else T, Greenberg S, Fishbein L: Hereditary Paraganglioma-Pheochromocytoma Syndromes. In: Adam MP, Feldman J, Mirzaa GM, et al., eds.: GeneReviews. University of Washington, Seattle, 1993-2024, pp. Available online. Last accessed October 29, 2024.
18. Letouzé E, Martinelli C, Loriot C, et al.: SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23 (6): 739-52, 2013.
19. Castro-Vega LJ, Buffet A, De Cubas AA, et al.: Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23 (9): 2440-6, 2014.
20. Clark GR, Sciacovelli M, Gaude E, et al.: Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 99 (10): E2046-50, 2014.
21. Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74 (6): 543-52, 1999.
22. Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002.
23. Neumann HP, Pawlu C, Peczkowska M, et al.: Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292 (8): 943-51, 2004.
24. Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99 (6): 1915-42, 2014.
25. Lenders JW, Eisenhofer G, Mannelli M, et al.: Phaeochromocytoma. Lancet 366 (9486): 665-75, 2005 Aug 20-26.
26. Kopetschke R, Slisko M, Kilisli A, et al.: Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol 161 (2): 355-61, 2009.
27. Motta-Ramirez GA, Remer EM, Herts BR, et al.: Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 185 (3): 684-8, 2005.
28. Young WF: Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 356 (6): 601-10, 2007.
29. Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002.
30. Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003.
31. Perry CG, Sawka AM, Singh R, et al.: The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf) 66 (5): 703-8, 2007.
32. Young WF: Phaeochromocytoma: how to catch a moonbeam in your hand. Eur J Endocrinol 136 (1): 28-9, 1997.
33. Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89 (2): 479-91, 2004.
34. Furuta N, Kiyota H, Yoshigoe F, et al.: Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. Int J Urol 6 (3): 119-24, 1999.
35. Janssen I, Wolf KI, Chui CH, et al.: Relevant Discordance Between 68Ga-DOTATATE and 68Ga-DOTANOC in SDHB-Related Metastatic Paraganglioma: Is Affinity to Somatostatin Receptor 2 the Key? Clin Nucl Med 42 (3): 211-213, 2017.
36. Janssen I, Chen CC, Millo CM, et al.: PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 43 (10): 1784-91, 2016.
37. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
38. van Heerden JA, Roland CF, Carney JA, et al.: Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 14 (3): 325-9, 1990 May-Jun.
39. Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005.
40. Ayala-Ramirez M, Feng L, Johnson MM, et al.: Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 96 (3): 717-25, 2011.
41. Fishbein L, Ben-Maimon S, Keefe S, et al.: SDHB mutation carriers with malignant pheochromocytoma respond better to CVD. Endocr Relat Cancer 24 (8): L51-L55, 2017.
42. Hamidi O, Young WF, Gruber L, et al.: Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 87 (5): 440-450, 2017.
43. Asai S, Katabami T, Tsuiki M, et al.: Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas. Horm Cancer 8 (2): 108-118, 2017.
44. Andrews KA, Ascher DB, Pires DEV, et al.: Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet 55 (6): 384-394, 2018.
45. Fishbein L, Merrill S, Fraker DL, et al.: Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol 20 (5): 1444-50, 2013.
46. Neumann HPH, Young WF, Eng C: Pheochromocytoma and Paraganglioma. N Engl J Med 381 (6): 552-565, 2019.