Skip to main content
SpringerLink
Log in

Screening for Pheochromocytomas and Paragangliomas

  • Hypertension: Kidney, Sodium, and Renin-Angiotensin System (A Mimran and R Carey, Section Editors)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Pheochromocytomas and paragangliomas are highly heterogeneous neuroendocrine tumors that must be considered not only in patients with hypertension and other manifestations of catecholamine excess but also in patients with incidentalomas or mutations in one of the ten tumor susceptibility genes identified to date. To first think of the tumor remains the critical step for screening in patients with signs and symptoms. In these patients, biochemical testing is straightforward and should include measurements of plasma or urinary metanephrines, comprising separately measured normetanephrine and metanephrine. Tumors due to an underlying germline mutation are often found in the absence of hypertension or other signs or symptoms of the tumor. Screening for disease in these patients can benefit from an individualized approach according to the particular mutation. Additional measurements of methoxytyramine, the metabolite of dopamine, can be useful in patients with mutations of succinate dehydrogenase genes or patients who are at risk for malignancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Anderson Jr GH, Blakeman N, Streeten DH. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens. 1994;12(5):609–15.

    Article  PubMed  Google Scholar 

  2. Ariton M, Juan CS, AvRuskin TW. Pheochromocytoma: clinical observations from a Brooklyn tertiary hospital. Endocr Pract. 2000;6(3):249–52.

    PubMed  CAS  Google Scholar 

  3. 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. 2004;27(3):193–202.

    Article  PubMed  Google Scholar 

  4. Martell N, Rodriguez-Cerrillo M, Grobbee DE, et al. High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension. Blood Pres. 2003;12(3):149–54.

    Article  CAS  Google Scholar 

  5. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc. 1981;56(6):354–60.

    PubMed  CAS  Google Scholar 

  6. McNeil AR, Blok BH, Koelmeyer TD, et al. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust New Zeal J Med. 2000;30(6):648–52.

    Article  PubMed  CAS  Google Scholar 

  7. Lo CY, Lam KY, Wat MS, Lam KS. Adrenal pheochromocytoma remains a frequently overlooked diagnosis. Am J Surg. 2000;179(3):212–5.

    Article  PubMed  CAS  Google Scholar 

  8. Walther MM, Reiter R, Keiser HR, et al. Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol. 1999;162(3 Pt 1):659–64.

    Article  PubMed  CAS  Google Scholar 

  9. 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):637–44.

    Article  PubMed  CAS  Google Scholar 

  10. Singh RJ. Advances in metanephrine testing for the diagnosis of pheochromocytoma. Clin Lab Med. 2004;24(1):85–103.

    Article  PubMed  Google Scholar 

  11. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metabol. 2007;3(2):92–102.

    Article  Google Scholar 

  12. Whiting MJ, Doogue MP. Advances in biochemical screening for phaeochromocytoma using biogenic amines. Clin Biochem Rev. 2009;30(1):3–17.

    PubMed  Google Scholar 

  13. Eisenhofer G, Keiser H, Friberg P, et al. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. J Clin Endocrinol Metab. 1998;83(6):2175–85.

    Article  PubMed  CAS  Google Scholar 

  14. Eisenhofer G, Rundquist B, Aneman A, et al. Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines. J Clin Endocrinol Metab. 1995;80(10):3009–17.

    Article  PubMed  CAS  Google Scholar 

  15. Eisenhofer G, Huynh TT, Hiroi M, Pacak K. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocr Metab Disord. 2001;2(3):297–311.

    Article  PubMed  CAS  Google Scholar 

  16. Raber W, Raffesberg W, Bischof M, et al. Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Arch Intern Med. 2000;160(19):2957–63.

    Article  PubMed  CAS  Google Scholar 

  17. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287(11):1427–34.

    Article  PubMed  CAS  Google Scholar 

  18. Sawka AM, Jaeschke R, Singh RJ, Young Jr WF. 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. 2003;88:553–8.

    Article  PubMed  CAS  Google Scholar 

  19. Unger N, Pitt C, Schmidt IL, et al. Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass. Eur J Endocrinol. 2006;154(3):409–17.

    Article  PubMed  CAS  Google Scholar 

  20. Vaclavik J, Stejskal D, Lacnak B, et al. Free plasma metanephrines as a screening test for pheochromocytoma in low-risk patients. J Hypertens. 2007;25(7):1427–31.

    Article  PubMed  CAS  Google Scholar 

  21. • Hickman PE, Leong M, Chang J, et al. Plasma free metanephrines are superior to urine and plasma catecholamines and urine catecholamine metabolites for the investigation of phaeochromocytoma. Pathology. 2009;41(2):173–7. This study confirms the diagnostic superiority of plasma free metanephrines over other biochemical tests for the diagnosis of pheochromocytoma.

    Article  PubMed  CAS  Google Scholar 

  22. 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). 2007;66(5):703–8.

    Article  CAS  Google Scholar 

  23. Eisenhofer G. Free or total metanephrines for diagnosis of pheochromocytoma: what is the difference? Clin Chem. 2001;47(6):988–9.

    PubMed  CAS  Google Scholar 

  24. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004;56(3):331–49.

    Article  PubMed  CAS  Google Scholar 

  25. Lenders JW, Keiser HR, Goldstein DS, et al. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med. 1995;123(2):101–9.

    PubMed  CAS  Google Scholar 

  26. • de Jong WH, Eisenhofer G, Post WJ, et al. Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab. 2009;94(8):2841–9. This study established that plasma and urinary methoxytyramine, as well as urinary normetanephrine, were increased by common food sources containing catecholamines. These findings indicate the importance of an overnight fast before sampling of blood for measurements of plasma methoxytyramine and more extended dietary restrictions for urinary measurements.

    Article  PubMed  Google Scholar 

  27. • Yu R, Wei M. False positive test results for pheochromocytoma from 2000 to 2008. Exp Clin Endocrinol Diabetes. 2010;118(9):577–85. False-positive test results of biochemical testing were examined in this retrospective analysis, which established a particularly high rate for testing of urinary metanephrines, mainly because of physiological influences, effects of medications, and laboratory error.

    Article  PubMed  CAS  Google Scholar 

  28. • Peaston RT, Graham KS, Chambers E, et al. Performance of plasma free metanephrines measured by liquid chromatography-tandem mass spectrometry in the diagnosis of pheochromocytoma. Clin Chim Acta. 2010;411(7–8):546–52. This is an examination of the utility of LC-MS/MS measurements of plasma metanephrines for the diagnosis of pheochromocytoma in comparison to enzyme immunoassay measurements. The study established a useful mass spectrometric method but also showed negative bias of immunoassay measurements with subsequent propensity for false-negative test results.

    Article  PubMed  CAS  Google Scholar 

  29. Pillai D, Ross HA, Kratzsch J, et al. Proficiency test of plasma free and total metanephrines: report from a study group. Clin Chem Lab Med. 2009;47:786–90.

    Article  PubMed  CAS  Google Scholar 

  30. • Pillai D, Callen S. Pilot quality assurance programme for plasma metanephrines. Ann Clin Biochem. 2010;47(Pt 2):137–42. This is a summary of the results of an interlaboratory quality assurance program examining the accuracy and precision of different assay methods for measuring plasma free metanephrines. The analysis indicates limited diagnostic precision of immunoassay measurements. The accuracy data suggest negative bias.

    Article  PubMed  CAS  Google Scholar 

  31. Lenders JW, Willemsen JJ, Eisenhofer G, et al. Is supine rest necessary before blood sampling for plasma metanephrines? Clin Chem. 2007;53(2):352–4.

    Article  PubMed  CAS  Google Scholar 

  32. Young Jr WF. Adrenal causes of hypertension: pheochromocytoma and primary aldosteronism. Rev Endocr Metab Disord. 2007;8(4):309–20.

    Article  PubMed  CAS  Google Scholar 

  33. Grossman A, Pacak K, Sawka A, et al. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci. 2006;1073:332–47.

    Article  PubMed  CAS  Google Scholar 

  34. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003;88(6):2656–66.

    Article  PubMed  CAS  Google Scholar 

  35. Eisenhofer G, Friberg P, Pacak K, et al. Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism? Clin Sci (Lond). 1995;88(5):533–42.

    CAS  Google Scholar 

  36. Bravo EL, Tarazi RC, Fouad FM, et al. Clonidine-suppression test: a useful aid in the diagnosis of pheochromocytoma. N Engl J Med. 1981;305(11):623–6.

    Article  PubMed  CAS  Google Scholar 

  37. Mannelli M, Ercolino T, Giache V, et al. Genetic screening for pheochromocytoma: should SDHC gene analysis be included? J Med Genet. 2007;44(9):586–7.

    Article  PubMed  CAS  Google Scholar 

  38. • Bayley JP, Kunst HP, Cascon A, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11(4):366–72. This report establishes mutations of the SDHAF2 gene as a novel cause of familial paraganglioma.

    Article  PubMed  CAS  Google Scholar 

  39. •• Qin Y, Yao L, King EE, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42(3):229–33. This report establishes mutations of the TMEM127 gene as a novel cause of hereditary pheochromocytoma.

    Article  PubMed  CAS  Google Scholar 

  40. Burnichon N, Briere JJ, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–20.

    Article  PubMed  CAS  Google Scholar 

  41. •• 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):663–7. This report identifies the tenth pheochromocytoma susceptibility gene.

    Article  PubMed  CAS  Google Scholar 

  42. Bryant J, Farmer J, Kessler LJ, et al. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Canc Inst. 2003;95(16):1196–204.

    Article  CAS  Google Scholar 

  43. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23(34):8812–8.

    Article  PubMed  CAS  Google Scholar 

  44. Mannelli M, Castellano M, Schiavi F, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94(5):1541–7.

    Article  PubMed  CAS  Google Scholar 

  45. Friedman JM, Birch PH. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet. 1997;70(2):138–43.

    Article  PubMed  CAS  Google Scholar 

  46. Eisenhofer G, Timmers H, Lenders JW, et al. Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab. 2011;96:375–84.

    Article  PubMed  CAS  Google Scholar 

  47. Gagel RF. Multiple endocrine neoplasia. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors. Williams textbook of endocrinology. 9th ed. Philadelphia: WB Saunders Company; 1998. p. 1627–49.

    Google Scholar 

  48. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459–66.

    Article  PubMed  CAS  Google Scholar 

  49. Castellano M, Mori L, Giacche M, et al. Genetic mutation screening in an Italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients. Ann N Y Acad Sci. 2006;1073:156–65.

    Article  PubMed  CAS  Google Scholar 

  50. Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002;39(3):178–83.

    Article  PubMed  CAS  Google Scholar 

  51. • Eisenhofer G, Pacak K, Huynh TT, et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer. 2011;18(1):97–111. This article establishes mutation-dependent phenotypic differences in catecholamine biosynthetic and secretory pathways in different hereditary forms of pheochromocytoma. These differences parallel differences indicated by gene expression profiling studies.

    Article  CAS  Google Scholar 

  52. Eisenhofer G, Bornstein SR, Brouwers FM, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Canc. 2004;11(3):423–36.

    Article  CAS  Google Scholar 

  53. •• Eisenhofer G, Lenders JW, Siegert G, et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2011 Oct 28 (Epub ahead of print). In this report, plasma concentrations of methoxytyramine are reported as a novel biomarker of malignant pheochromocytoma. The study also establishes the relative contributions of tumor size and extra-adrenal tumor location as risk factors for metastatic disease and the contributions of both to the high risk of malignancy associated with SDHB mutations.

  54. Remine W, Chong G, van Heerden J, et al. Current management of pheochromocytoma. Ann Surg. 1974;179:740–8.

    Article  PubMed  CAS  Google Scholar 

  55. John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted? Urology. 1999;53(4):679–83.

    Article  PubMed  CAS  Google Scholar 

  56. Shen WT, Sturgeon C, Clark OH, et al. Should pheochromocytoma size influence surgical approach? a comparison of 90 malignant and 60 benign pheochromocytomas. Surgery. 2004;136(6):1127–9.

    Article  Google Scholar 

  57. 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. 2011;96(3):717–25.

    Article  PubMed  CAS  Google Scholar 

  58. Feng F, Zhu Y, Wang X, et al. Predictive factors for malignant pheochromocytoma: analysis of 136 patients. J Urol. 2011;185(5):1583–90.

    Article  PubMed  Google Scholar 

  59. Park J, Song C, Park M, et al. Predictive characteristics of malignant pheochromocytoma. Korean J Urol. 2011;52(4):241–6.

    Article  PubMed  Google Scholar 

  60. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003;63(17):5615–21.

    PubMed  CAS  Google Scholar 

  61. Brouwers FM, Eisenhofer G, Tao JJ, et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006;91(11):4505–9.

    Article  PubMed  CAS  Google Scholar 

  62. Tippett PA, McEwan AJ, Ackery DM. A re-evaluation of dopamine excretion in phaeochromocytoma. Clin Endocrinol (Oxf). 1986;25(4):401–10.

    Article  CAS  Google Scholar 

  63. Januszewicz W, Wocial B, Januszewicz A, et al. Dopamine and dopa urinary excretion in patients with pheochromocytoma–diagnostic implications. Blood Pres. 2001;10(4):212–6.

    Article  CAS  Google Scholar 

  64. van der Harst E, de Herder WW, de Krijger RR, et al. The value of plasma markers for the clinical behaviour of phaeochromocytomas. Eur J Endocrinol. 2002;147(1):85–94.

    Article  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Institute of Clinical Chemistry and Laboratory Medicine and the Department of Medicine, University of Dresden, Fetscherstrasse 74, 01307, Dresden, Germany

    Graeme Eisenhofer

Authors
  1. Graeme Eisenhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Graeme Eisenhofer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eisenhofer, G. Screening for Pheochromocytomas and Paragangliomas. Curr Hypertens Rep 14, 130–137 (2012). https://doi.org/10.1007/s11906-012-0246-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-012-0246-y

Keywords

Search

Navigation