Guidelines Summary

In 2014, the Endocrine Society (ES), the American Association for Clinical Chemistry (AACC), and the European Society of Endocrinology (ESE) released joint clinical practice guidelines for the management of pheochromocytoma and paraganglioma (referred to together as PPGL). The guidelines include recommendations (based on strong evidence) and suggestions (based on weaker evidence).^[68]

In patients suspected of having PPGL, biochemical testing via measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended. The use of liquid chromatography with mass spectrometry or electrochemical detection methods is suggested over other laboratory methods. Patients with a known germline mutation that predisposes to PPGL should undergo periodic biochemical testing.^[68]

The 2010 guidelines from the North American Neuroendocrine Tumor Society (NANETS) recommend biochemical testing for pheochromocytoma that includes measurements of fractionated metanephrines in plasma, urine, or both, as available, in the following cases^[37]:

Symptomatic patients
Patients with an adrenal incidentaloma
Patients who have a hereditary risk for developing a pheochromocytoma or paraganglioma (extra-adrenal pheochromocytoma)

For imaging studies, the joint ES/AACC/ESE guidelines recommend CT scanning as first line, rather than MRI. However, MRI is an option in certain patients, such as those with metastatic PPGL, those allergic to CT contrast media, and those for whom radiation exposure should be limited, such as pregnant women.^[68]

The National Comprehensive Cancer Network guidelines recommend the following tests for the evaluation of suspected PPGL^[69]:

Plasma free or 24-hour urine fractionated metanephrines
Contrast-enhanced chest/abdominal/pelvic multiphasic CT scanning or MRI
Genetic counseling

If metastatic disease is suspected, the guidelines recommend the following additional tests^[69]:

MIBG scan
Somatostatin receptor scintigraphy
Fluorodeoxyglucose PET (FDG-PET)/CT scan
If bone symptoms, bone scan

For genetic testing, ES/AACC/ESE recommendations are as follows^[68]:

Patients with PPGLs should be engaged in shared decision-making for genetic testing
Patients with paraganglioma should undergo testing of succinate dehydrogenase mutations
Patients with metastatic disease should undergo testing for SDHB mutations
Genetic testing should include pretest and posttest genetic counseling

For preoperative management, ES/AACC/ESE recommendations include the following^[68]:

Blockade of hormonally functional PPGL to prevent cardiovascular complications
Medical treatment to normalize blood pressure and heart rate
A high-sodium diet with supplemental fluid intake to prevent severe hypotension after removal of the tumor

The ES/AACC/ESE guidelines recommend minimally invasive (eg, laparoscopic) adrenalectomy for most adrenal pheochromocytomas, with open resection reserved for very large or invasive pheochromocytomas. Open resection is suggested for paragangliomas, although laparoscopic resection is an option for smaller tumors. Partial adrenalectomy is also a possibility for certain types of patients.^[68]

In the immediate postoperative period, the ES/AACC/ESE guidelines recommend monitoring of blood pressure, heart rate, and glucose levels. Postoperative measurement of plasma or urine metanephrine levels and lifelong annual biochemical testing are suggested.^[68]

The 2010 NANETS recommendations for treatment of advanced disease include the following^[37]:

Surgical debulking to release tumor pressure on surrounding tissues or to decrease tumor mass
In select patients, radiofrequency ablation or cryoablation are options
Chemotherapy is preferred in patients with negative MIBG scintigraphy and in those with rapidly progressing tumors
External-beam irradiation of bone metastases or radiofrequency and cryoablation in selected cases only

Medication

Därr R, Lenders JWM, Hofbauer LC, Naumann B, Bornstein SR, Eisenhofer G. Pheochromocytoma: Update on Disease Management. Ther Adv in Endo and Metab. 2012;3(1):11-26. [Full Text].
Waguespack SG, Rich T, Grubbs E, Ying AK, Perrier ND, Ayala-Ramirez M, et al. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2010 May. 95(5):2023-37. [QxMD MEDLINE Link].
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. 2002 May. 26(5):551-66. [QxMD MEDLINE Link].
Bholah R, Bunchman TE. Review of Pediatric Pheochromocytoma and Paraganglioma. Front Pediatr. 2017. 5:155. [QxMD MEDLINE Link]. [Full Text].
Sheps SG, Jiang NS, Klee GG, van Heerden JA. Recent developments in the diagnosis and treatment of pheochromocytoma. Mayo Clin Proc. 1990 Jan. 65(1):88-95. [QxMD MEDLINE Link].
Yeterian EH, Pandya DN. Corticothalamic connections of the superior temporal sulcus in rhesus monkeys. Exp Brain Res. 1991. 83(2):268-84. [QxMD MEDLINE Link].
Elenkova A, Matrozova J, Zacharieva S, Kirilov G, Kalinov K. Adiponectin - A possible factor in the pathogenesis of carbohydrate metabolism disturbances in patients with pheochromocytoma. Cytokine. 2010 Jun. 50(3):306-10. [QxMD MEDLINE Link].
Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer. 2011 Feb. 18(1):97-111. [QxMD MEDLINE Link].
Ferreira VM, Marcelino M, Piechnik SK, et al. Pheochromocytoma Is Characterized by Catecholamine-Mediated Myocarditis, Focal and Diffuse Myocardial Fibrosis, and Myocardial Dysfunction. J Am Coll Cardiol. 2016 May 24. 67 (20):2364-74. [QxMD MEDLINE Link]. [Full Text].
Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011 Mar. 57(3):411-20. [QxMD MEDLINE Link]. [Full Text].
Eisenhofer G, Rivers G, Rosas AL, Quezado Z, Manger WM, Pacak K. Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf. 2007. 30(11):1031-62. [QxMD MEDLINE Link].
Eng C. Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med. 1996 Sep 26. 335(13):943-51. [QxMD MEDLINE Link].
Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011 Jun 19. 43(7):663-7. [QxMD MEDLINE Link].
Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012 May 15. 18(10):2828-37. [QxMD MEDLINE Link].
Neumann HP, Berger DP, Sigmund G, Blum U, Schmidt D, Parmer RJ, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993 Nov 18. 329(21):1531-8. [QxMD MEDLINE Link].
Gergics P, Patocs A, Toth M, Igaz P, Szucs N, Liko I, et al. Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. Eur J Endocrinol. 2009 Sep. 161(3):495-502. [QxMD MEDLINE Link].
Niemann S, Becker-Follmann J, Nurnberg G, Ruschendorf F, Sieweke N, et al. Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Am J Med Genet. 2001 Jan 1. 98(1):32-6. [QxMD MEDLINE Link].
Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010 Aug 1. 19(15):3011-20. [QxMD MEDLINE Link]. [Full Text].
Kunst HP, Rutten MH, de Mönnink JP, Hoefsloot LH, Timmers HJ, Marres HA, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011 Jan 15. 17(2):247-54. [QxMD MEDLINE Link].
van den Akker EL, de Krijger RR, de Herder WW, Drop SL. Congenital hemihypertrophy and pheochromocytoma, not a coincidental combination?. Eur J Pediatr. 2002 Mar. 161(3):157-60. [QxMD MEDLINE Link].
Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983 Dec. 58(12):802-4. [QxMD MEDLINE Link].
Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007 Feb 8. 356(6):601-10. [QxMD MEDLINE Link].
Berends AMA, Buitenwerf E, de Krijger RR, et al. Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: A nationwide study and systematic review. Eur J Intern Med. 2018 Jan 17. [QxMD MEDLINE Link].
Iglesias P, Santacruz E, Garcia-Sancho P, et al. Pheochromocytoma: a three-decade clinical experience in a multicenter study. Rev Clin Esp. 2020 Jul 6. [QxMD MEDLINE Link].
Hamidi O, Young WF Jr, Gruber L, et al. Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: a systematic review and meta-analysis. Clin Endocrinol (Oxf). 2017 Jul 26. [QxMD MEDLINE Link].
Dhir M, Li W, Hogg ME, et al. Clinical Predictors of Malignancy in Patients with Pheochromocytoma and Paraganglioma. Ann Surg Oncol. 2017 Sep 7. [QxMD MEDLINE Link].
Parikh PP, Rubio GA, Farra JC, Lew JI. Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma. J Surg Res. 2017 Jul. 215:204-10. [QxMD MEDLINE Link].
Boulkina LS, Newton CA, Drake AJ 3rd, Tanenberg RJ. Acute myocardial infarction attributable to adrenergic crises in a patient with pheochromocytoma and neurofibromatosis 1. Endocr Pract. 2007 May-Jun. 13(3):269-73. [QxMD MEDLINE Link].
Lenders JW. Pheochromocytoma and pregnancy: a deceptive connection.Eur J Endocrinol. 2012 Feb;166(2):143-50. Epub 2011 Sep 2.
Yokomoto-Umakoshi M, Umakoshi H, Ogata M, et al. Coexistence of osteoporosis and atherosclerosis in pheochromocytoma: new insights into its long-term management. Osteoporos Int. 2020 Jul 2. [QxMD MEDLINE Link].
Prejbisz A, Lenders JW, Eisenhofer G, Januszewicz A. Cardiovascular manifestations of phaeochromocytoma. J Hypertens. 2011 Nov. 29(11):2049-60. [QxMD MEDLINE Link].
La Batide-Alanore A, Chatellier G, Plouin PF. Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens. 2003 Sep. 21(9):1703-7. [QxMD MEDLINE Link].
Gagnon N, Mansour S, Bitton Y, Bourdeau I. TAKOTSUBO-LIKE CARDIOMYOPATHY IN A LARGE COHORT OF PATIENTS WITH PHEOCHROMOCYTOMA AND PARAGANGLIOMA. Endocr Pract. 2017 Jul 13. [QxMD MEDLINE Link].
Tucker ME. Endocrine Society first to address rare adrenal-tumor care. Medscape Medical News. June 5, 2014. [Full Text].
Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Jun. 99(6):1915-42. [QxMD MEDLINE Link].
Chen Y, Xiao H, Zhou X, et al. ACCURACY OF PLASMA FREE METANEPHRINES IN THE DIAGNOSIS OF PHEOCHROMOCYTOMA AND PARAGANGLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS. Endocr Pract. 2017 Jul 13. [QxMD MEDLINE Link].
[Guideline] Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010 Aug. 39(6):775-83. [QxMD MEDLINE Link]. [Full Text].
Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best?. JAMA. 2002 Mar 20. 287(11):1427-34. [QxMD MEDLINE Link].
de Jong WH, Eisenhofer G, Post WJ, Muskiet FA, de Vries EG, Kema IP. Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab. 2009 Aug. 94(8):2841-9. [QxMD MEDLINE Link].
Jimenez C, Cote G, Arnold A, Gagel RF. Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes?. J Clin Endocrinol Metab. 2006 Aug. 91(8):2851-8. [QxMD MEDLINE Link].
Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW, Keiser HR, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003 Jun. 88(6):2656-66. [QxMD MEDLINE Link].
Lenders JW, Pacak K, Huynh TT, Sharabi Y, Mannelli M, Bratslavsky G, et al. Low sensitivity of glucagon provocative testing for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2010 Jan. 95(1):238-45. [QxMD MEDLINE Link]. [Full Text].
Szolar DH, Korobkin M, Reittner P, Berghold A, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology. 2005 Feb. 234(2):479-85. [QxMD MEDLINE Link].
Buitenwerf E, Korteweg T, Visser A, et al. Unenhanced CT imaging is highly sensitive to exclude pheochromocytoma: a multicenter study. Eur J Endocrinol. 2018 Feb 21. [QxMD MEDLINE Link].
Park BK, Kim CK, Kwon GY, Kim JH. Re-evaluation of pheochromocytomas on delayed contrast-enhanced CT: washout enhancement and other imaging features. Eur Radiol. 2007 Nov. 17(11):2804-9. [QxMD MEDLINE Link].
Baid SK, Lai EW, Wesley RA, Ling A, Timmers HJ, Adams KT, et al. Brief communication: radiographic contrast infusion and catecholamine release in patients with pheochromocytoma. Ann Intern Med. 2009 Jan 6. 150(1):27-32. [QxMD MEDLINE Link]. [Full Text].
Bessell-Browne R, O'Malley ME. CT of pheochromocytoma and paraganglioma: risk of adverse events with i.v. administration of nonionic contrast material. AJR Am J Roentgenol. 2007 Apr. 188(4):970-4. [QxMD MEDLINE Link].
Blake MA, Kalra MK, Maher MM, Sahani DV, Sweeney AT, Mueller PR, et al. Pheochromocytoma: an imaging chameleon. Radiographics. 2004 Oct. 24 Suppl 1:S87-99. [QxMD MEDLINE Link].
Faria JF, Goldman SM, Szejnfeld J, Melo H, Kater C, Kenney P, et al. Adrenal masses: characterization with in vivo proton MR spectroscopy--initial experience. Radiology. 2007 Dec. 245(3):788-97. [QxMD MEDLINE Link].
Kim S, Salibi N, Hardie AD, Xu J, Lim RP, Lee VS, et al. Characterization of adrenal pheochromocytoma using respiratory-triggered proton MR spectroscopy: initial experience. AJR Am J Roentgenol. 2009 Feb. 192(2):450-4. [QxMD MEDLINE Link].
Wiseman GA, Pacak K, O'Dorisio MS, Neumann DR, Waxman AD, Mankoff DA, et al. Usefulness of 123I-MIBG scintigraphy in the evaluation of patients with known or suspected primary or metastatic pheochromocytoma or paraganglioma: results from a prospective multicenter trial. J Nucl Med. 2009 Sep. 50(9):1448-54. [QxMD MEDLINE Link].
Fottner C, Helisch A, Anlauf M, Rossmann H, Musholt TJ, Kreft A, et al. 6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression. J Clin Endocrinol Metab. 2010 Jun. 95(6):2800-10. [QxMD MEDLINE Link].
Jacobson AF, Deng H, Lombard J, Lessig HJ, Black RR. 123I-meta-iodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis. J Clin Endocrinol Metab. 2010 Jun. 95(6):2596-606. [QxMD MEDLINE Link].
Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, et al. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol. 2007 Jun 1. 25(16):2262-9. [QxMD MEDLINE Link].
Luster M, Karges W, Zeich K, Pauls S, Verburg FA, Dralle H, et al. Clinical value of 18F-fluorodihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA PET/CT) for detecting pheochromocytoma. Eur J Nucl Med Mol Imaging. 2010 Mar. 37(3):484-93. [QxMD MEDLINE Link].
Yamamoto S, Hellman P, Wassberg C, Sundin A. 11C-hydroxyephedrine positron emission tomography imaging of pheochromocytoma: a single center experience over 11 years. J Clin Endocrinol Metab. 2012 Jul. 97(7):2423-32. [QxMD MEDLINE Link].
Wong C, Yu R. Preoperative preparation for pheochromocytoma resection: physician survey and clinical practice. Exp Clin Endocrinol Diabetes. 2010 Jul. 118(7):400-4. [QxMD MEDLINE Link].
Kwon SY, Lee KS, Lee JN, et al. Risk factors for hypertensive attack during pheochromocytoma resection. Investig Clin Urol. 2016 May. 57 (3):184-90. [QxMD MEDLINE Link]. [Full Text].
Butz JJ, Yan Q, McKenzie TJ, et al. Perioperative outcomes of syndromic paraganglioma and pheochromocytoma resection in patients with von Hippel-Lindau disease, multiple endocrine neoplasia type 2, or neurofibromatosis type 1. Surgery. 2017 Sep 14. [QxMD MEDLINE Link].
Pravenec M, Kren V, Klír P, Simonet L, Kurtz T. Identification of genes determining spontaneous hypertension. Review article. Sb Lek. 1991 Jun. 93(5-6):136-41. [QxMD MEDLINE Link]. [Full Text].
Araujo-Castro M, Garcia Centeno R, Lopez-García MC, et al. Risk factors for intraoperative complications in pheochromocytomas. Endocr Relat Cancer. 2021 Aug 1. [QxMD MEDLINE Link].
Scholten A, Vriens MR, Cromheecke GJ, Borel Rinkes IH, Valk GD. Hemodynamic instability during resection of pheochromocytoma in MEN versus non-MEN patients. Eur J Endocrinol. 2011 Jul. 165(1):91-6. [QxMD MEDLINE Link].
Holscher I, van den Berg TJ, Dreijerink KMA, Engelsman AF, Nieveen van Dijkum EJM. Recurrence Rate of Sporadic Pheochromocytomas After Curative Adrenalectomy: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2021 Jan 23. 106 (2):588-97. [QxMD MEDLINE Link].
Nau P, Demyttenaere S, Muscarella P, Narula V, Hazey JW, Ellison EC, et al. Pheochromocytoma does not increase risk in laparoscopic adrenalectomy. Surg Endosc. 2010 Nov. 24(11):2760-4. [QxMD MEDLINE Link].
Li QY, Li F. Laparoscopic adrenalectomy in pheochromocytoma: retroperitoneal approach versus transperitoneal approach. J Endourol. 2010 Sep. 24(9):1441-5. [QxMD MEDLINE Link].
Scholten A, Valk GD, Ulfman D, Borel Rinkes IH, Vriens MR. Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Ann Surg. 2011 Dec. 254(6):1022-7. [QxMD MEDLINE Link].
Donatini G, Kraimps JL, Caillard C, et al. Pheochromocytoma diagnosed during pregnancy: lessons learned from a series of ten patients. Surg Endosc. 2018 Feb 27. [QxMD MEDLINE Link].
[Guideline] Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014 Jun. 99 (6):1915-42. [QxMD MEDLINE Link]. [Full Text].
[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors, Version 2.2016. NCCN. May 25, 2016; Accessed: October 2, 2016.
Butz JJ, Weingarten TN, Cavalcante AN, et al. Perioperative hemodynamics and outcomes of patients on metyrosine undergoing resection of pheochromocytoma or paraganglioma. Int J Surg. 2017 Aug 10. 46:1-6. [QxMD MEDLINE Link].
Jimenez C, Chin B, Noto R, et al. Azedra (iobenguane I 131) in patients with metastatic and/or recurrent and/or unresectable pheochromocytoma or paraganglioma: biochemical tumor marker results of a multicenter, open-label pivotal phase 2 study (OR02-5). Endocrine Society (ENDO) Annual Meeting. Chicago, IL. 2018 Mar 17.
Barone JE. Pheochromocytoma Crisis Is Not a Surgical Emergency. Medscape Medical News. January 18, 2013. Available at http://www.medscape.com/viewarticle/777889. Accessed: January 29, 2013.
Scholten A, Cisco RM, Vriens MR, Cohen JK, Mitmaker EJ, Liu C, et al. Pheochromocytoma crisis is not a surgical emergency. J Clin Endocrinol Metab. 2013 Feb. 98(2):581-91. [QxMD MEDLINE Link].

Media Gallery

Axial, T2-weighted magnetic resonance imaging (MRI) scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.
Abdominal computed tomography (CT) scan demonstrating left suprarenal mass of soft-tissue attenuation representing a paraganglioma.
Adrenalectomy specimen containing pheochromocytoma. Non-neoplastic adrenal cortex (yellow) surrounds a small tan-red tumor in the medullary region, representing a pheochromocytoma.
H and E, high power, showing classic "balls of cells" feature of a pheochromocytoma. Endocrine tumors such as a pheochromocytoma typically show some degree of nuclear pleomorphism ("endocrine atypia") which does not indicate malignancy.

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