21st Century Adult Cancer Sourcebook: Pheochromocytoma and Paraganglioma - Clinical Data for Patients, Families, and Physicians
Edition 1.0 - October 2011
National Cancer Institute
Smashwords Edition
Copyright 2011 Progressive Management
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PART ONE
Chapter 1A: Pheochromocytoma Patient and Health Professional Information
Chapter 2A: Pheochromocytoma Clinical Trials
PART TWO
Chapter 1B: Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (NCI)
Chapter 2B: Glossary of Clinical Trial Terms
Chapter 3B: Clinical Trials Background Information
Chapter 4B: Cancer Clinical Trials -The Basic Workbook
Chapter 5B: Cancer Clinical Trials - The In-Depth Program
Chapter 6B: Clinical Trials at NIH
Chapter 7B: How To Find A Cancer Treatment Trial: A Ten Step Guide
Chapter 8B: Taking Part in Cancer Treatment Research Studies
Chapter 9B: Cancer Clinical Trials
Chapter 10B: Access to Investigational Drugs
Chapter 12B: Taking Time: Support for People with Cancer
Chapter 13B: Facing Forward - Life After Cancer Treatment
Chapter 14B: Chemotherapy and You
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PART ONE
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Chapter 1A: Pheochromocytoma Patient and Health Professional Information
Pheochromocytoma and Paraganglioma Treatment
General Information About Pheochromocytoma and Paraganglioma
Definition of pheochromocytoma: Tumor that forms in the center of the adrenal gland (gland located above the kidney) that causes it to make too much adrenaline. Pheochromocytomas are usually benign (not cancer) but can cause high blood pressure, pounding headaches, heart palpitations, flushing of the face, nausea, and vomiting.
Pheochromocytomas and extra-adrenal paragangliomas are rare tumors arising from neural crest tissue that develops into sympathetic and parasympathetic paraganglia throughout the body. Sympathetic paraganglia include the following:
• 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 following:
• The carotid body.
• Other paraganglia along the cervical and thoracic branches of the vagus and glossopharyngeal nerves.
The most recent World Health Organization classification utilizes 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.[1]
The incidence of pheochromocytoma is 2 to 8 per million persons per year.[2,3] Pheochromocytoma is present in 0.1% to 1% of patients with hypertension,[4-6] and it is present in approximately 5% of patients with incidentally discovered adrenal masses.[7] 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.[8] The incidence is equal between males and females,[9] and there are no known environmental, dietary, or lifestyle risk factors that have been linked to the development of pheochromocytoma.
Of all pheochromocytomas and extra-adrenal paragangliomas, 25% occur in the setting of an hereditary syndrome.[8-10] The following major genetic syndromes have been identified as carrying an increased risk of pheochromocytoma:
• Multiple endocrine neoplasia type 2A and 2B (MEN 2A and MEN2B).
• von Hippel-Lindau disease.
• Neurofibromatosis type 1.
• Subunit gene SDHD. Many cases of familial paraganglioma are caused by mutations in the succinate dehydrogenase (succinate: ubiquinone oxidoreductase) subunit gene SDHD (formerly referred to as familial pheochromocytoma-paraganglioma syndrome type
• SDHAF2 (sometimes referred to as SDH5) (formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 2).[12]
• SDHC (formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 3).[13]
• SDHB (formerly referred to as familial pheochromocytoma-paraganglioma syndrome type 4).[14]
• SDHA.[15]
Pheochromocytomas and extra-adrenal paragangliomas can also occur in the following two other very rare syndromes:
• The Carney triad of extra-adrenal paraganglioma, gastrointestinal stromal tumor (GIST),[16] and pulmonary chondroma.
• The Carney-Stratakis dyad of paraganglioma and GIST.[17]
More genetic causes of pheochromocytoma and paraganglioma are yet to be discovered. For example, truncating germline mutations in the transmembrane-encoding gene TMEM127 on chromosome 2q11 have been shown to be present in approximately 30% of affected patients with familial disease and in about 3% of patients with apparently sporadic pheochromocytomas without a known genetic cause.[18] TMEM127 is a negative regulator of mammalian target of rapamycin (mTOR) effector proteins.
Patients with pheochromocytomas and sympathetic extra-adrenal paragangliomas may present with symptoms of excess catecholamine production, including the following:
• Hypertension.
• Headache.
• Perspiration.
• Forceful palpitations.
• Tremor.
• Facial pallor.
These symptoms are often paroxysmal, although sustained hypertension in between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma.[19] Symptoms of catecholamine excess can be spontaneous or induced by a variety of events, including the following:
• 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).
• Foods high in tyramine (e.g., red wine, chocolate, and cheese).
• Urination (e.g., bladder wall tumor, which is rare).
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.
Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and 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.[20-23]
The diagnosis of pheochromocytoma is established by biochemical testing to document excess catecholamine secretion. Controversy exists as to the optimal single test to make the diagnosis. Measurement of plasma-free fractionated metanephrines (e.g., metanephrine and normetanephrine) has a high sensitivity (97%-99%) but a relatively low specificity (85%).
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.[24,25]
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 the following:
• 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.
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 false-positive results. False-positive results can be caused by any of the following:[19,24]
• Common medications (e.g., tricyclic antidepressants).
• Physical or emotional stress.
• Inappropriately low reference ranges based on normal laboratory data rather than clinical data sets.[26]
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. [19] Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.[27]
Once the biochemical diagnosis of a catecholamine-secreting tumor is confirmed, localization studies should be performed.
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. [28] Both have similar sensitivities (90%-100%) and specificities (70%-80%).[28]
CT imaging provides excellent anatomic detail. MRI provides good anatomic detail.
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. 123I-metaiodobenzylguanidine (MIBG) scintigraphy coupled with CT imaging provides anatomic and functional information with good sensitivity (80%-90%) and specificity (95%-100%).[28]
131I-MIBG can be used in the same way, but the image quality is not as high as with 123I-MIBG.[29]
Other functional imaging alternatives include 111In-octreotide scintigraphy and 18F-fluorodeoxyglucose positron emission tomography, both of which can be coupled with CT imaging for improved anatomic detail. It is rare for localization of a catecholamine-secreting tumor to be unsuccessful if currently available imaging methods are used.
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%.[8,9,30] 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 mutation 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).[8] 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 currently 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.
Genetic testing is 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.
In patients with a unilateral pheochromocytoma and no personal or family history suggestive of hereditary disease, genetic testing can be considered if patients are between the ages of 40 years and 50 years, but genetic testing is not recommended if patients are older than 50 years. If a mutation is identified, predictive genetic testing should be offered to asymptomatic at-risk family members.
Definitive treatment for localized and regional pheochromocytoma, including localized disease recurrence, consists of alpha- and beta-adrenergic blockade followed by surgery. For patients with unresectable or metastatic disease, treatment may include a combination of the following:
• Catecholamine blockade.
• Surgery.
• Chemotherapy.
• Radiofrequency ablation.
• Cryoablation.
• Radiation therapy.
Refer to the Regional Pheochromocytoma section, the Metastatic Pheochromocytoma section, and the Recurrent Pheochromocytoma section of this summary for more information on treatment.
References
1. DeLellis RA, Lloyd RV, Heitz PU, et al., eds.: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2004. World Health Organization classification of tumours, vol. 8.
2. 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.
3. Stenstrbm G, Svardsudd K: Pheochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data. Acta Med Scand 220 (3): 225-32, 1986.
4. Sinclair AM, Isles CG, Brown I, et al.: Secondary hypertension in a blood pressure clinic. Arch Intern Med 147 (7): 1289-93, 1987.
5. Anderson GH Jr, 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.
6. 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.
7. Young WF Jr: Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 29 (1): 159-85, x, 2000.
8. Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002.
9. Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005.
10. Jimenez 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.
11. 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.
12. 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.
13. Niemann S, Muller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26 (3): 268-70, 2000.
14. 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.
15. Burnichon N, Briere JJ, Libe R, et al.: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19 (15): 3011-20, 2010.
16. 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.
17. 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.
18. Qin Y, Yao L, King EE, et al.: Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 42 (3): 229-33, 2010.
19. Lenders JW, Eisenhofer G, Mannelli M, et al.: Phaeochromocytoma. Lancet 366 (9486): 665-75, 2005 Aug 20-26.
20. Klein R, Lloyd R, Young W: Hereditary Paraganglioma-Pheochromocytoma Syndromes. In: Pagon R, Bird T, Dolan C, et al., eds.: GeneReviews. Seattle, WA: University of Washington, 2009, pp. Available on line. Last accessed October 19, 2010.
21. 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.
22. 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.
23. Young WF Jr: Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 356 (6): 601-10, 2007.
24. Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002.
25. 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.
26. 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.
27. Young WF Jr: Phaeochromocytoma: how to catch a moonbeam in your hand. Eur J Endocrinol 136 (1): 28-9, 1997.
28. Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89 (2): 479-91, 2004.
29. 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.
30. 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.
Cellular Classification of Pheochromocytoma and Paraganglioma
Pathologic Classification
Pheochromocytoma and paraganglioma characteristically form small nests of uniform polygonal chromaffin cells ("zellballen"). A diagnosis of malignancy can only be made by identifying tumor deposits in tissues that do not normally contain chromaffin cells (e.g., lymph nodes, liver, bone, lung, and other distant metastatic sites).
Regional or distant metastatic disease is documented on initial pathology in only 3% to 8% of patients; thus, an attempt has been made to identify tumor characteristics associated with future malignant behavior. Pathologic features associated with malignancy include the following:
• Large tumor size.
• Increased number of mitoses.
• DNA aneuploidy.
• Extensive tumor necrosis.
In the absence of clearly documented malignancy, no combination of clinical, histopathologic, or biochemical features has been shown to reliably predict the biologic behavior of pheochromocytoma. If no definite malignancy is identified, pathology generally provides insufficient prognostic information regarding the likelihood of recurrence or metastasis. These tumors cannot be considered benign by default; patients require continued lifelong surveillance.[1-7]
References
1. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
2. Thompson LD: Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26 (5): 551-66, 2002.
3. Nativ O, Grant CS, Sheps SG, et al.: The clinical significance of nuclear DNA ploidy pattern in 184 patients with pheochromocytoma. Cancer 69 (11): 2683-7, 1992.
4. Wu D, Tischler AS, Lloyd RV, et al.: Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol 33 (4): 599-608, 2009.
5. Kimura N, Watanabe T, Noshiro T, et al.: 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 16 (1): 23-32, 2005.
6. Linnoila RI, Keiser HR, Steinberg SM, et al.: Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 21 (11): 1168-80, 1990.
7. Tischler AS: Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med 132 (8): 1272-84, 2008.
Stage Information for Pheochromocytoma and Paraganglioma
There is no standard staging system for pheochromocytoma and paraganglioma. Patients have traditionally been divided into categories based on the presence of localized (apparently benign), regional, and metastatic disease.
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.[1-3]
Approximately 50% of patients with recurrent disease experience distant metastasis.[3] The 5-year survival in the setting of metastatic disease (whether identified at the time of initial diagnosis or identified postoperatively as recurrent disease) is 40% to 45%.[4]
References
1. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
2. 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.
3. 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.
4. Averbuch SD, Steakley CS, Young RC, et al.: Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109 (4): 267-73, 1988.
Treatment Option Overview
Only limited data are available from phase II or phase III clinical trials to guide the management of patients diagnosed with pheochromocytoma or paraganglioma.
Surgery is the mainstay of treatment for most patients; however, preoperative medical preparation is critical. Alpha-adrenergic blockade should be initiated at the time of diagnosis and maximized preoperatively to prevent potentially life-threatening cardiovascular complications, which can occur as a result of excess catecholamine secretion during surgery. Complications may include the following:
• Hypertensive crisis.
• Arrhythmia.
• Myocardial infarction.
• Pulmonary edema.
Phenoxybenzamine (a nonselective alpha-antagonist) is the usual drug of choice; prazosin, terazosin, and doxazosin (selective alpha-1-antagonists) are alternative choices.[1,2] Prazosin, terazosin, and doxazosin are shorter acting than phenoxybenzamine, and therefore, the duration of postoperative hypotension is theoretically less than with phenoxybenzamine; however, there is less overall experience with selective alpha-1-antagonists than with phenoxybenzamine.
A preoperative treatment period of 1 to 3 weeks is usually sufficient; resolution of spells and a target low normal blood pressure for age indicate that alpha-adrenergic blockade is adequate. During alpha-adrenergic blockade, liberal salt and fluid intake should be encouraged because volume loading reduces excessive orthostatic hypotension both preoperatively and postoperatively. If tachycardia develops or if blood pressure control is not optimal with alpha-adrenergic blockade, a beta-adrenergic blocker (e.g., metoprolol or propranolol) can be added but only after alpha-blockade. Beta-adrenergic blockade must never be initiated before alpha-adrenergic blockade; doing so blocks beta-adrenergic receptor-mediated vasodilation and results in unopposed alpha-adrenergic receptor-mediated vasoconstriction, which can lead to a life-threatening crisis.
References
1. Cubeddu LX, Zarate NA, Rosales CB, et al.: Prazosin and propranolol in preoperative management of pheochromocytoma. Clin Pharmacol Ther 32 (2): 156-60, 1982.
2. Prys-Roberts C, Farndon JR: Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 26 (8): 1037-42, 2002.
Localized Pheochromocytoma
Treatment Options
Surgical resection, i.e., adrenalectomy, is the definitive treatment for patients with localized pheochromocytoma. If preoperative imaging reveals an adrenal pheochromocytoma that is approximately 6 cm or smaller in diameter, without radiographic evidence of invasion into adjacent structures or evidence of regional or metastatic disease (i.e., presumably a benign tumor), and there is a normal contralateral adrenal gland, a minimally invasive adrenalectomy is the generally preferred approach. Both anterior transabdominal laparoscopic adrenalectomy as well as posterior retroperitoneoscopic adrenalectomy have been demonstrated to be safe for the majority of patients with a modestly sized, radiographically benign pheochromocytoma.[1,2] If preoperative imaging suggests malignancy, or if the patient has an extra-adrenal paraganglioma or multifocal disease, an open approach is generally preferred.
Intraoperative hypertension can be controlled with intravenous infusion of phentolamine, sodium nitroprusside, or a short-acting calcium-channel blocker (e.g., nicardipine). Tumor removal may be followed by a sudden drop in blood pressure that may require rapid volume replacement and intravenous vasoconstrictors (e.g., norepinephrine or phenylephrine). Postoperatively, patients should remain in a monitored environment for 24 hours. Postoperative hypotension is managed primarily by volume expansion, and postoperative hypertension usually responds to diuretics.
Inherited Pheochromocytoma
Treatment Options
The surgical management of pheochromocytoma in patients with the hereditary syndromes multiple endocrine neoplasia type 2 (MEN2) and von Hippel-Lindau (VHL) disease has been controversial. In both of these syndromes, pheochromocytoma is bilateral in at least 50% of patients; however, malignancy is very uncommon. Bilateral total adrenalectomy commits all patients to lifelong steroid dependence, and up to 25% of patients will experience Addisonian crisis (acute adrenal insufficiency). [3,4]
Current recommendations generally favor preservation of adrenal cortical tissue in patients with MEN2 and VHL syndromes when possible. Patients who initially present with unilateral pheochromocytoma should undergo unilateral adrenalectomy, and patients who present with bilateral pheochromocytomas or who develop pheochromocytoma in their remaining adrenal gland should undergo cortical-sparing adrenalectomy, when technically feasible.[3]
In a single-institution study involving 56 patients with pheochromocytoma, 57% of patients (i.e., 17 of 30 patients) who underwent one or more cortical-sparing adrenalectomies avoided the need for routine steroid replacement; the clinical recurrence rate was low (i.e., 3 of 30 patients) and none of the patients developed metastatic disease.[5][Level of evidence: 3iiDii] A similar approach may be reasonable in other hereditary pheochromocytoma-paraganglioma syndromes that are characterized by benign disease, but there are currently insufficient data upon which to base unequivocal recommendations.
Follow-Up Evaluation
Long-term follow-up is essential for all patients with pheochromocytoma or extra-adrenal paraganglioma, even if initial pathology demonstrates no findings that are concerning for malignancy. 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 non-catecholamine-producing tumor should initially undergo annual imaging with computed tomography imaging or magnetic resonance imaging and periodic imaging with radiolabeled metaiodobenzylguanidine to monitor for recurrence or metastasis. Patients who have undergone resection of a pheochromocytoma or paraganglioma in the setting of a hereditary syndrome require lifelong annual biochemical screening in addition to routine screening for other component tumors of their specific syndrome.[6]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized benign pheochromocytoma and paraganglioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
1. Walz MK, Alesina PF, Wenger FA, et al.: Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients. Surgery 140 (6): 943-8; discussion 948-50, 2006.
2. Gagner M, Breton G, Pharand D, et al.: Is laparoscopic adrenalectomy indicated for pheochromocytomas? Surgery 120 (6): 1076-9; discussion 1079-80, 1996.
3. Lee JE, Curley SA, Gagel RF, et al.: Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120 (6): 1064-70; discussion 1070-1, 1996.
4. de Graaf JS, Dullaart RP, Zwierstra RP: Complications after bilateral adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2-- a plea to conserve adrenal function. Eur J Surg 165 (9): 843-6, 1999.
5. Yip L, Lee JE, Shapiro SE, et al.: Surgical management of hereditary pheochromocytoma. J Am Coll Surg 198 (4): 525-34; discussion 534-5, 2004.
6. GeneTests: Medical Genetics Information Resource [Database]. Seattle, WA: University of Washington, 2010. Available online. Last accessed Aug 24, 2010.
Regional Pheochromocytoma
Treatment Options
Surgical resection is the definitive treatment for pheochromocytoma or extra-adrenal paraganglioma that is regionally advanced (e.g., from direct tumor extension into adjacent organs or because of regional lymph node involvement). Data to guide management are limited because regional disease is diagnosed in very few patients who present with pheochromocytoma.[1] However, aggressive surgical resection to remove all existing disease can render patients symptom free.[2] Surgical management of these patients may require en bloc resection of all or part of adjacent organs (e.g., kidney, liver, inferior vena cava) along with extended lymph node dissection. Patients who have undergone complete resection of regional pheochromocytoma require lifelong monitoring for disease recurrence.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with regional pheochromocytoma and paraganglioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
1. 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.
2. Zarnegar R, Kebebew E, Duh QY, et al.: Malignant pheochromocytoma. Surg Oncol Clin N Am 15 (3): 555-71, 2006.
Metastatic Pheochromocytoma
Treatment Options
The most common sites of metastasis for pheochromocytoma or extra-adrenal paraganglioma are lymph nodes, bones, lungs, and liver. Patients with known or suspected malignancy should undergo staging with computed tomography or magnetic resonance imaging as well as functional imaging (e.g., with 123I-metaiodobenzylguanidine [MIBG]) to determine the extent and location of disease. Patients are often very symptomatic from excess catecholamine secretion. Phenoxybenzamine is effective, and metyrosine, which is a drug that blocks catecholamine synthesis, can be added if needed.
If all identifiable disease is resectable, including a limited number of distant metastases, surgery can provide durable palliation of symptoms and occasional long-term remission. If disease is unresectable, surgical debulking will not improve survival; however, it is occasionally indicated for symptom palliation.
Chemotherapy has not been shown to improve survival in patients with metastatic pheochromocytoma; however, chemotherapy can be attempted for the palliation of symptoms. The best-established chemotherapy regimen is a combination of cyclophosphamide, vincristine, and dacarbazine (the Averbuch protocol).[1] Results of this regimen in 18 patients after 22 years of follow-up demonstrated a complete response rate of 11%, a partial response rate of 44%, a biochemical response rate of 72%, and a median survival of 3.3 years.[2][Level of evidence: 3iiiDiv] Several other chemotherapy regimens have been used in small numbers of patients, but the overall results were disappointing.[3,4]
Novel targeted therapies are emerging as potential treatment strategies for metastatic pheochromocytoma. Disappointing initial results were reported with the mammalian target of rapamycin (mTOR) inhibitor everolimus,[5] but results from a very small number of patients treated with the tyrosine kinase inhibitor sunitinib have been more promising.[6,7]
131I-MIBG radiation therapy has been used for the treatment of MIBG-avid metastases.[8,9] In a phase
II study of high-dose 131I-MIBG radiation therapy involving 49 patients, 8% had a complete response, 14% had a partial response, and the estimated 5-year survival was 64%.[10][Level of evidence: 3iiiDiv] Approximately 60% of metastatic pheochromocytoma or paraganglioma sites are MIBG-avid;[10] protocol-based treatment with other experimental radiolabeled agents, such as radiolabeled somatostatin, can be considered for metastases that do not take up MIBG.
Other palliative treatment modalities include external-beam radiation therapy (e.g., for palliation of bone metastases) and embolization, radiofrequency ablation, or cryoablation (e.g., for palliation of bulky hepatic metastases or isolated bony metastases).
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic pheochromocytoma and paraganglioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site. References
1. Averbuch SD, Steakley CS, Young RC, et al.: Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109 (4): 267-73, 1988.
2. Huang H, Abraham J, Hung E, et al.: Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113 (8): 2020-8, 2008.
3. Nakane M, Takahashi S, Sekine I, et al.: Successful treatment of malignant pheochromocytoma with combination chemotherapy containing anthracycline. Ann Oncol 14 (9): 1449-51, 2003.
4. Kulke MH, Stuart K, Enzinger PC, et al.: Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24 (3): 401-6, 2006.
5. Druce MR, Kaltsas GA, Fraenkel M, et al.: Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res 41 (9): 697-702, 2009.
6. Jimenez C, Cabanillas ME, Santarpia L, et al.: Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 94 (2): 386-91, 2009.
7. Joshua AM, Ezzat S, Asa SL, et al.: Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 94 (1): 5-9, 2009
8. Buscombe JR, Cwikla JB, Caplin ME, et al.: Long-term efficacy of low activity meta-[131I] iodobenzylguanidine therapy in patients with disseminated neuroendocrine tumours depends on initial response. Nucl Med Commun 26 (11): 969-76, 2005.
9. Scholz T, Eisenhofer G, Pacak K, et al.: Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 92 (4): 1217-25, 2007.
10. Gonias S, Goldsby R, Matthay KK, et al.: Phase II study of high-dose [131I] metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 27 (25): 4162-8, 2009.
Recurrent Pheochromocytoma
Treatment Options
After resection of a localized pheochromocytoma presumed to represent a benign tumor and documented normal postoperative biochemical testing, disease recurrence occurs in 6.5% to 16.5% of patients, and 50% of patients with disease recurrence develop metastatic disease.[1-3] Insufficient data exist to determine recurrence rates after complete surgical resection of regional or metastatic disease.
Treatment for recurrent disease involves appropriate medical management (i.e., alpha-adrenergic blockade) followed by complete surgical resection, when possible. Palliation of symptoms, including those related to catecholamine excess and local mass effect, is the primary focus of treatment for disease that is not resectable. Chemotherapy, targeted therapies, high-dose 131I metaiodobenzylguanidine radiation therapy, ablation therapies, and radiation therapy are options for patients with local-regional or metastatic disease who are not considered candidates for surgical resection. (Refer to the Metastatic Pheochromocytoma section of this summary for more information.)
Patients with inherited pheochromocytoma or paraganglioma are at risk for the development of recurrent disease in the form of additional primary tumors. Follow-up evaluation and management of additional primary tumors in such patients is essential. (Refer to the Localized Pheochromocytoma section of this summary for more information.)
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent pheochromocytoma and paraganglioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
1. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
2. 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.
3. 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.
Pheochromocytoma During Pregnancy
Pheochromocytoma diagnosed during pregnancy is extremely rare (0.007% of all pregnancies).[1,2] However, this situation deserves mention because women with hereditary conditions that increase the risk of developing pheochromocytoma are often also of child-bearing age, and the outcome of undiagnosed pheochromocytoma during pregnancy can be catastrophic.
Prenatal diagnosis clearly results in decreased mortality for both mother and neonate.[3] Prior to 1970, a prenatal diagnosis of pheochromocytoma was made in only approximately 25% of cases, and the mortality rate for both mother and neonate was around 50%.[4,5] The prenatal diagnosis rate rose to greater than 80% through the 1980s and 1990s, and decreased maternal and neonatal mortality rates were 6% and 15%, respectively.[4,6]