World Journal of Endocrine Surgery

Register      Login

VOLUME 11 , ISSUE 3 ( September-December, 2019 ) > List of Articles


Clinical Challenges in Nonfunctional Pheochromocytomas

Su-Ann Lui, Han B Oh, Kong B Tan

Keywords : Catecholamines, Incidentalomas, Pheochromocytoma

Citation Information : Lui S, Oh HB, Tan KB. Clinical Challenges in Nonfunctional Pheochromocytomas. World J Endoc Surg 2019; 11 (3):86-90.

DOI: 10.5005/jp-journals-10002-1264

License: CC BY-NC 4.0

Published Online: 01-06-2015

Copyright Statement:  Copyright © 2019; The Author(s).


Pheochromocytomas (PCCs) are rare endocrine tumors that arise from neural crest cells of the adrenal medulla. They commonly secrete catecholamines and other biological peptides that account for the symptoms namely, hypertension, palpitations, and episodic headaches associated with the condition. However, the symptoms and clinical presentations are highly variable due to variations in catecholamine biosynthesis and secretion because of differences in gene expression. A small proportion of tumors hardly synthesize or release any catecholamines and may have no symptoms and are termed as nonfunctional or subclinical PCCs. The nonfunctional tumors are commonly picked up as incidentalomas and biochemical work-up is usually negative. Undiagnosed subclinical normotensive PCCs could lead to catastrophic consequences during surgery and subsequently.

  1. Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet. 2005;366(9486):665–675. DOI: 10.1016/S0140-6736(05)67139-5.
  2. Kopetschke R, Slisko M, Kilisli A, et al. Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol 2009;161(2):355–361. DOI: 10.1530/EJE-09-0384.
  3. Noshiro T, Shimizu K, Watanabe T, et al. Changes in clinical features and long-term prognosis in patients with pheochromocytoma. Am J Hypertens 2000;13(1 Pt 1):35–43. DOI: 10.1016/S0895-7061(99)00139-9.
  4. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005;23(34):8812–8818. DOI: 10.1200/JCO.2005.03.1484.
  5. Neumann HP, Cybulla M, Shibata H, et al. New genetic causes of pheochromocytoma: current concepts and the clinical relevance. Keio J Med 2005;54(1):15–21. DOI: 10.2302/kjm.54.15.
  6. Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993;329(21):1531–1538. DOI: 10.1056/NEJM199311183292103.
  7. Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev 1994;15(3):356–368. DOI: 10.1210/edrv-15-3-356.
  8. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003;24(4):539–553. DOI: 10.1210/er.2002-0013.
  9. Besser GM, Thorner MO. Comprehensive clinical endocrinology, 3rd ed., Edinburgh: Mosby; 2002.
  10. Fonseca V, Bouloux PM. Phaeochromocytoma and paraganglioma. Baillieres Clin Endocrinol Metab 1993;7(2):509–544. DOI: 10.1016/S0950-351X(05)80186-7.
  11. Leong CH, Wong KK, Saw D. Asymptomatic phaeochromocytoma of the bladder co-existing with carcinoma. Br J Urol 1976;48(2):123–126. DOI: 10.1111/j.1464-410X.1976.tb02996.x.
  12. Krane NK. Clinically unsuspected pheochromocytomas. Experience at Henry Ford Hospital and a review of the literature. Arch Intern Med 1986;146(1):54–57. DOI: 10.1001/archinte.1986.00360130064008.
  13. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981;56(6):354–360.
  14. Simpson ET, Marszalek WW, Ramsaroop R. Nonfunctioning pheochromocytoma. Urology 1985;25(6):632–633. DOI: 10.1016/0090-4295(85)90299-7.
  15. Mannelli M, Ianni L, Cilotti A, et al. Pheochromocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol 1999;141(6): 619–624. DOI: 10.1530/eje.0.1410619.
  16. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000;85(2): 637–644. DOI: 10.1210/jc.85.2.637.
  17. Haissaguerre M, Courel M, Caron P, et al. Normotensive incidentally discovered pheochromocytomas display specific biochemical, cellular, and molecular characteristics. J Clin Endocrinol Metab 2013;98(11):4346–4354. DOI: 10.1210/jc.2013-1844.
  18. Eng C, Mulligan LM, Smith DP, et al. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol 1995;43(1): 123–127. DOI: 10.1111/j.1365-2265.1995.tb01903.x.
  19. Zuber SM, Kantorovich V, Pacak K. Hypertension in pheochromocytoma: characteristics and treatment. Endocrinol Metab Clin North Am 2011;40(2):295–311. DOI: 10.1016/j.ecl.2011.02.002, vii.
  20. Stenstrom G, Sjostrom L, Smith U. Diabetes mellitus in phaeochromocytoma. Fasting blood glucose levels before and after surgery in 60 patients with phaeochromocytoma. Acta Endocrinol (Copenh) 1984;106(4):511–515. DOI: 10.1530/acta.0.1060511.
  21. Eisenhofer G, Walther MM, Huynh TT, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 2001;86(5):1999–2008. DOI: 10.1210/jcem.86.5.7496.
  22. Eisenhofer G, Huynh TT, Pacak K, et al. Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer 2004;11(4):897–911. DOI: 10.1677/erc.1.00838.
  23. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260(5112):1317–1320. DOI: 10.1126/science.8493574.
  24. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276(19):1575–1579. DOI: 10.1001/jama.1996.03540190047028.
  25. White R, Viskochil D, O'Connell P. Identification and characterization of the gene for neurofibromatosis type 1. Curr Opin Neurobiol 1991;1(3):462–467. DOI: 10.1016/0959-4388(91)90070-N.
  26. Burnichon N, Briere JJ, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010;19(15):3011–3020. DOI: 10.1093/hmg/ddq206.
  27. 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 2001;69(1):49–54. DOI: 10.1086/321282.
  28. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000;26(3):268–270. DOI: 10.1038/81551.
  29. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287(5454):848–851. DOI: 10.1126/science.287.5454.848.
  30. Bayley JP, Kunst HP, Cascon A, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 2010;11(4):366–372. DOI: 10.1016/S1470-2045(10)70007-3.
  31. Qin Y, Yao L, King EE, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 2010;42(3):229–233. DOI: 10.1038/ng.533.
  32. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011;43(7):663–667. DOI: 10.1038/ng.861.
  33. Yao L, Schiavi F, Cascon A, et al. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA 2010;304(23):2611–2619. DOI: 10.1001/jama.2010.1830.
  34. Eisenhofer G, Lenders JW, Goldstein DS, et al. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem 2005;51(4):735–744. DOI: 10.1373/clinchem.2004.045484.
  35. Timmers HJ, Kozupa A, Eisenhofer G, et al. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 2007;92(3):779–786. DOI: 10.1210/jc.2006-2315.
  36. Eisenhofer G, Pacak K, Huynh TT, et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer 2011;18(1):97–111. DOI: 10.1677/ERC-10-0211.
  37. Burnichon N, Vescovo L, Amar L, et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 2011;20(20):3974–3985. DOI: 10.1093/hmg/ddr324.
  38. Chen H, Sippel RS, O'Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 2010;39(6):775–783. DOI: 10.1097/MPA.0b013e3181ebb4f0.
  39. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014;99(6):1915–1942. DOI: 10.1210/jc. 2014-1498.
  40. Shao Y, Chen R, Shen Z-J, et al. Preoperative alpha blockade for normotensive pheochromocytoma: is it necessary? J Hypertens 2011;29(12):2429–2432. DOI: 10.1097/HJH.0b013e32834d24d9.
  41. Song G, Joe BN, Yeh BM, et al. Risk of catecholamine crisis in patients undergoing resection of unsuspected pheochromocytoma. Int Braz J Urol 2011;37(1):35–40; discussion-1. DOI: 10.1590/S1677-55382011000100005.
  42. Shen SJ, Cheng HM, Chiu AW, et al. Perioperative hypertensive crisis in clinically silent pheochromocytomas: report of four cases. Chang Gung Med J 2005;28(1):44–50.
  43. Lafont M, Fagour C, Haissaguerre M, et al. Per-operative hemodynamic instability in normotensive patients with incidentally discovered pheochromocytomas. J Clin Endocrinol Metab 2015;100(2):417–421. DOI: 10.1210/jc.2014-2998.
  44. Yu R, Nissen NN, Chopra P, et al. Diagnosis and treatment of pheochromocytoma in an academic hospital from 1997 to 2007. Am J Med 2009;122(1):85–95. DOI: 10.1016/j.amjmed.2008. 08.021.
  45. Hariskov S, Schumann R. Intraoperative management of patients with incidental catecholamine producing tumors: A literature review and analysis. J Anaesthesiol Clin Pharmacol 2013;29(1):41–46. DOI: 10.4103/0970-9185.105793.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.