Horm Metab Res 2008; 40(5): 329-337
DOI: 10.1055/s-2008-1073156
Review

© Georg Thieme Verlag KG Stuttgart · New York

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

G. Eisenhofer 1 , 2 , G. Siegert 1 , J. Kotzerke 3 , S. R. Bornstein 2 , K. Pacak 4
  • 1Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden, Germany
  • 2Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Germany
  • 3Department of Nuclear Medicine, University Hospital Carl Gustav Carus Dresden, Germany
  • 4Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Further Information

Publication History

received 26.11.2007

accepted 18.12.2007

Publication Date:
19 May 2008 (online)

Abstract

Findings from five independent studies - with close to 350 patients with pheochromocytoma and more than 2 500 in whom the tumor was excluded - indicate that measurements of plasma free metanephrines provide an overall diagnostic sensitivity of 98% and specificity of 92%. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing true- from false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with 131I-labelled m-iodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies.

References

  • 1 Manger WM. An overview of pheochromocytoma: history, current concepts, vagaries, and diagnostic challenges.  Ann N Y Acad Sci. 2006;  1073 1-20
  • 2 Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, MacNicol AM, Tischler AS. Pheochromocytoma: recommendations for clinical practice from the First International Symposium.  Nat Clin Pract Endocrinol Metab. 2007;  3 92-102
  • 3 Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine.  Pharmacol Rev. 2004;  56 331-349
  • 4 Eisenhofer G, Keiser H, Friberg P, Mezey E, Huynh TT, Hiremagalur B, Ellingson T, Duddempudi S, Eijsbouts A, Lenders JW. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors.  J Clin Endocrinol Metab. 1998;  83 2175-2185
  • 5 Lenders JW, Keiser HR, Goldstein DS, Willemsen JJ, Friberg P, Jacobs MC, Kloppenborg PW, Thien T, Eisenhofer G. Plasma metanephrines in the diagnosis of pheochromocytoma.  Ann Intern Med. 1995;  123 101-109
  • 6 Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2.  N Engl J Med. 1999;  340 1872-1879
  • 7 Raber W, Raffesberg W, Bischof M, Scheuba C, Niederle B, Gasic S, Waldhausl W, Roden M. Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma.  Arch Intern Med. 2000;  160 2957-2963
  • 8 Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS, Eisenhofer G. Biochemical diagnosis of pheochromocytoma: which test is best?.  JAMA. 2002;  287 1427-1434
  • 9 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;  88 553-558
  • 10 Unger N, Pitt C, Schmidt IL, Walz MK, Schmid KW, Philipp T, Mann K, Petersenn S. Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass.  Eur J Endocrinol. 2006;  154 409-417
  • 11 Vaclavik J, Stejskal D, Lacnak B, Lazarova M, Jedelsky L, Kadalova L, Janosova M, Frysak Z, Vlcek P. Free plasma metanephrines as a screening test for pheochromocytoma in low-risk patients.  J Hypertens. 2007;  25 1427-1431
  • 12 Eisenhofer G, Goldstein DS, Sullivan P, Csako G, Brouwers FM, Lai EW, Adams KT, Pacak K. Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine.  J Clin Endocrinol Metab. 2005;  90 2068-2075
  • 13 Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.  J Clin Endocrinol Metab. 2007;  92 779-786
  • 14 Grossman A, Pacak K, Sawka A, Lenders JW, Harlander D, Peaston RT, Reznek R, Sisson J, Eisenhofer G. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus?.  Ann N Y Acad Sci. 2006;  1073 332-347
  • 15 Lenders JW, Willemsen JJ, Eisenhofer G, Ross HA, Pacak K, Timmers HJ, Sweep CG. Is supine rest necessary before blood sampling for plasma metanephrines?.  Clin Chem. 2007;  53 352-354
  • 16 Lee JA, Zarnegar R, Shen WT, Kebebew E, Clark OH, Duh QY. Adrenal incidentaloma, borderline elevations of urine or plasma metanephrine levels, and the “subclinical” pheochromocytoma.  Arch Surg. 2007;  142 870-873 , ; discussion 873-874
  • 17 Perry CG, Sawka AM, Singh R, Thabane L, Bajnarek J, Young Jr WF. The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma.  Clin Endocrinol (Oxf). 2007;  66 703-708
  • 18 Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines VMA, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma.  J Clin Endocrinol Metab. 2007;  92 4602-4608
  • 19 Lagerstedt SA, O’Kane DJ, Singh RJ. Measurement of plasma free metanephrine and normetanephrine by liquid chromatography-tandem mass spectrometry for diagnosis of pheochromocytoma.  Clin Chem. 2004;  50 603-611
  • 20 Jong WH de, Graham KS, Molen JC van der, Links TP, Morris MR, Ross HA, Vries EG de, Kema IP. Plasma free metanephrine measurement using automated online solid-phase extraction HPLC tandem mass spectrometry.  Clin Chem. 2007;  53 1684-1693
  • 21 Algeciras-Schimnich A, Preissner CM, Young Jr WF, Singh RJ, Grebe SK. Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma.  J Clin Endocrinol Metab. 2008;  93 91-95
  • 22 Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW, Keiser HR, Pacak K. Biochemical diagnosis of pheochromocytoma: How to distinguish true- from false-positive test results.  J Clin Endocrinol Metab. 2003;  88 2656-2666
  • 23 Mannelli M. Management and treatment of pheochromocytomas and paragangliomas.  Ann N Y Acad Sci. 2006;  1073 405-416
  • 24 Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma.  J Clin Endocrinol Metab. 2005;  90 2110-2116
  • 25 John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted?.  Urology. 1999;  53 679-683
  • 26 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.  Cancer Res. 2003;  63 5615-5621
  • 27 Takahashi K, Ashizawa N, Minami T, Suzuki S, Sakamoto I, Hayashi K, Tomiyasu S, Sumikawa K, Kitamura K, Eto T, Yano K. Malignant pheochromocytoma with multiple hepatic metastases treated by chemotherapy and transcatheter arterial embolization.  Intern Med. 1999;  38 349-354
  • 28 Pacak K, Fojo T, Goldstein DS, Eisenhofer G, Walther MM, Linehan WM, Bachenheimer L, Abraham J, Wood BJ. Radiofrequency ablation: a novel approach for treatment of metastatic pheochromocytoma.  J Natl Cancer Inst. 2001;  93 648-649
  • 29 Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, Keiser HR. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine.  Ann Intern Med. 1988;  109 267-273
  • 30 Scholz T, Eisenhofer G, Pacak K, Dralle H, Lehnert H. Clinical review: Current treatment of malignant pheochromocytoma.  J Clin Endocrinol Metab. 2007;  92 1217-1225
  • 31 Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B, Travagli JP. et al . Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases.  J Endocrinol Invest. 1992;  15 631-642
  • 32 Srimuninnimit V, Wampler GL. Case report of metastatic familial pheochromocytoma treated with cisplatin and 5-fluorouracil.  Cancer Chemother Pharmacol. 1991;  28 217-219
  • 33 Iwabuchi M, Oki Y, Nakamura H. Palliative chemotherapy for malignant pheochromocytoma: symptomatic palliation of two cases.  Intern Med. 1999;  38 433-435
  • 34 Nakane M, Takahashi S, Sekine I, Fukui I, Koizumi M, Kage K, Ito Y, Aiba K, Horikoshi N, Hatake K, Ishikawa Y, Ogata E. Successful treatment of malignant pheochromocytoma with combination chemotherapy containing anthracycline.  Ann Oncol. 2003;  14 1449-1451
  • 35 Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.  J Clin Oncol. 2006;  24 401-406
  • 36 Chrisoulidou A, Kaltsas G, Ilias I, Grossman AB. The diagnosis and management of malignant phaeochromocytoma and paraganglioma.  Endocr Relat Cancer. 2007;  14 569-585
  • 37 Fitzgerald PA, Goldsby RE, Huberty JP, Price DC, Hawkins RA, Veatch JJ, Dela Cruz F, Jahan TM, Linker CA, Damon L, Matthay KK. Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).  Ann N Y Acad Sci. 2006;  1073 465-490
  • 38 Lamarre-Cliche M, Gimenez-Roqueplo AP, Billaud E, Baudin E, Luton JP, Plouin PF. Effects of slow-release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma.  Clin Endocrinol (Oxf). 2002;  57 629-634
  • 39 Mundschenk J, Unger N, Schulz S, Hollt V, Steinke R, Lehnert H. Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy.  J Clin Endocrinol Metab. 2003;  88 5150-5157
  • 40 Ahlman H. Malignant pheochromocytoma: state of the field with future projections.  Ann N Y Acad Sci. 2006;  1073 449-464
  • 41 Mairs RJ, Cunningham SH, Russell J, Armour A, Owens J, MacKellar K, Gaze MN. No-carrier-added iodine-131-MIBG: evaluation of a therapeutic preparation.  J Nucl Med. 1995;  36 1088-1095
  • 42 Boyd M, Ross S, Owens J, Hunter D, Babich J, Zalutsky MR, Hamilton TG, Bell S, Mairs RJ. Preclinical evaluation of no-carrier-added [131I]Meta-Iodobenzyl Guanidine, for the treatment of tumours transfected with the noradrenaline transporter gene.  Lett Drug Des Discovery. 2004;  1 1-5
  • 43 Verberne HJ, Bruin K de, Habraken JB, Somsen GA, Eersels JL, Moet F, Booij J, Eck-Smit BL van. No-carrier-added versus carrier-added 123I-metaiodobenzylguanidine for the assessment of cardiac sympathetic nerve activity.  Eur J Nucl Med Mol Imaging. 2006;  33 483-490
  • 44 Owens J, Bolster AA, Prosser JE, Cunningham S, Mairs RJ, Neilly JB, Reed NS, Hilditch TE. No-carrier-added 123I-MIBG: an initial clinical study in patients with phaeochromocytoma.  Nucl Med Commun. 2000;  21 437-440
  • 45 Brogsitter C, Pinkert J, Bredow J, Kittner T, Kotzerke J. Enhanced tumor uptake in neuroendocrine tumors after intraarterial application of 131I-MIBG.  J Nucl Med. 2005;  46 2112-2116
  • 46 Raffel DM, Jung YW, Gildersleeve DL, Sherman PS, Moskwa JJ, Tluczek LJ, Chen W. Radiolabeled phenethylguanidines: novel imaging agents for cardiac sympathetic neurons and adrenergic tumors.  J Med Chem. 2007;  50 2078-2088
  • 47 Vaidyanathan G, Friedman HS, Keir ST, Zalutsky MR. Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model.  Nucl Med Biol. 1996;  23 851-856
  • 48 Vaidyanathan G, Zhao XG, Strickland DK, Zalutsky MR. No-carrier-added iodine-131-FIBG: evaluation of an MIBG analog.  J Nucl Med. 1997;  38 330-334
  • 49 Vaidyanathan G, Zhao XG, Larsen RH, Zalutsky MR. 3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells.  Br J Cancer. 1997;  76 226-233
  • 50 Vaidyanathan G, Welsh PC, Vitorello KC, Snyder S, Friedman HS, Zalutsky MR. A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells.  Eur J Nucl Med Mol Imaging. 2004;  31 1362-1370
  • 51 Fullerton NE, Boyd M, Ross SC, Pimlott SL, Babich J, Kirk D, Zalutsky MR, Mairs RJ. Comparison of radiohaloanalogues of meta-iodobenzylguanidine (MIBG) for a combined gene- and targeted radiotherapy approach to bladder carcinoma.  Med Chem. 2005;  1 611-618
  • 52 Vaidyanathan G, Affleck DJ, Alston KL, Zhao XG, Hens M, Hunter DH, Babich J, Zalutsky MR. A kit method for the high level synthesis of [211At]MABG.  Bioorg Med Chem. 2007;  15 3430-3436
  • 53 Boyd M, Cunningham SH, Brown MM, Mairs RJ, Wheldon TE. Noradrenaline transporter gene transfer for radiation cell kill by 131I meta-iodobenzylguanidine.  Gene Ther. 1999;  6 1147-1152
  • 54 Altmann A, Kissel M, Zitzmann S, Kubler W, Mahmut M, Peschke P, Haberkorn U. Increased MIBG uptake after transfer of the human norepinephrine transporter gene in rat hepatoma.  J Nucl Med. 2003;  44 973-980
  • 55 Mairs RJ, Ross SC, MacCluskey AG, Boyd M. A transfectant mosaic xenograft model for evaluation of targeted radiotherapy in combination with gene therapy in vivo.  J Nucl Med. 2007;  48 1519-1526
  • 56 Ramamoorthy S, Melikian HE, Qian Y, Blakely RD. Biosynthesis, N-glycosylation, and surface trafficking of biogenic amine transporter proteins.  Methods Enzymol. 1998;  296 347-370
  • 57 Bomanji J, Levison DA, Flatman WD, Horne T, Bouloux PM, Ross G, Britton KE, Besser GM. Uptake of iodine-123 MIBG by pheochromocytomas, paragangliomas, and neuroblastomas: a histopathological comparison.  J Nucl Med. 1987;  28 973-978
  • 58 Kolby L, Bernhardt P, Levin-Jakobsen AM, Johanson V, Wangberg B, Ahlman H, Forssell-Aronsson E, Nilsson O. Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters.  Br J Cancer. 2003;  89 1383-1388
  • 59 Bomanji JB, Hyder SW, Gaze MN, Gacinovic S, Costa DC, Coulter C, Ell PJ. Functional imaging as an aid to decision-making in metastatic paraganglioma.  Br J Radiol. 2001;  74 266-269
  • 60 Kolby L, Bernhardt P, Johanson V, Wangberg B, Muth A, Jansson S, Forssell-Aronsson E, Nilsson O, Ahlman H. Can quantification of VMAT and SSTR expression be helpful for planning radionuclide therapy of malignant pheochromocytomas?.  Ann N Y Acad Sci. 2006;  1073 491-497
  • 61 Harst E van der, Herder WW de, Bruining HA, Bonjer HJ, Krijger RR de, Lamberts SW, Meiracker AH van de, Boomsma F, Stijnen T, Krenning EP, Bosman FT, Kwekkeboom DJ. [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas.  J Clin Endocrinol Metab. 2001;  86 685-693
  • 62 Ezuddin S, Fragkaki C. MIBG and FDG PET findings in a patient with malignant pheochromocytoma: a significant discrepancy.  Clin Nucl Med. 2005;  30 579-581
  • 63 Mamede M, Carrasquillo JA, Chen CC, Del Corral P, Whatley M, Ilias I, Ayala A, Pacak K. Discordant localization of 2-[18F]-fluoro-2-deoxy-D-glucose in 6-[18F]-fluorodopamine- and [(123)I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites.  Nucl Med Commun. 2006;  27 31-36
  • 64 Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, Lenders JW, Pacak K. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochro-mocytoma and paraganglioma.  J Clin Oncol. 2007;  25 2262-2269
  • 65 Sisson JC, Shapiro B, Shulkin BL, Urba S, Zempel S, Spaulding S. Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy.  Am J Clin Oncol. 1999;  22 364-370
  • 66 Vaidyanathan G, Affleck DJ, Norman J, O’Dorisio S, Zalutsky MR. A radioiodinated MIBG-octreotate conjugate exhibiting enhanced uptake and retention in SSTR2-expressing tumor cells.  Bioconjug Chem. 2007;  18 2122-2130
  • 67 Brouwers FM, Petricoin 3rd EF, Ksinantova L, Breza J, Rajapakse V, Ross S, Johann D, Mannelli M, Shulkin BL, Kvetnansky R, Eisenhofer G, Walther MM, Hitt BA, Conrads TP, Veenstra TD, Mannion DP, Wall MR, Wolfe GM, Fusaro VA, Liotta LA, Pacak K. Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma.  Endocr Relat Cancer. 2005;  12 263-272
  • 68 Anouar Y, Yon L, Guillemot J, Thouennon E, Barbier L, Gimenez-Roqueplo AP, Bertherat J, Lefebvre H, Klein M, Muresan M, Grouzmann E, Plouin PF, Vaudry H, Elkahloun AG. Development of novel tools for the diagnosis and prognosis of pheochromocytoma using peptide marker immunoassay and gene expression profiling approaches.  Ann N Y Acad Sci. 2006;  1073 533-540
  • 69 Brouwers FM, Elkahloun AG, Munson PJ, Eisenhofer G, Barb J, Linehan WM, Lenders JW, Krijger R De, Mannelli M, Udelsman R, Ocal IT, Shulkin BL, Bornstein SR, Breza J, Ksinantova L, Pacak K. Gene expression profiling of benign and malignant pheochromocytoma.  Ann N Y Acad Sci. 2006;  1073 541-556
  • 70 Eisenhofer G, Bornstein SR, Brouwers FM, Cheung NK, Dahia PL, Krijger RR De, Giordano TJ, Greene LA, Goldstein DS, Lehnert H, Manger WM, Maris JM, Neumann HP, Pacak K, Shulkin BL, Smith DI, Tischler AS, Young Jr WF. Malignant pheochromocytoma: current status and initiatives for future progress.  Endocr Relat Cancer. 2004;  11 423-436
  • 71 Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update.  Nat Rev Cancer. 2005;  5 857-866
  • 72 Smith EH, Janknecht R, Maher 3rd LJ. Succinate inhibition of {alpha}-ketoglutarate-dependent enzymes in a yeast model of paraganglioma.  Hum Mol Genet. 2007;  16 3136-3148

Correspondence

G. EisenhoferPhD 

Institute of Clinical Chemistry and Laboratory Medicine and Department of Internal Medicine III

University Hospital Carl Gustav Carus Dresden

Fetscherstraße 74

01307 Dresden

Germany

Phone: +49/351/458 45 95

Fax: +49/351/458 58 87

Email: graeme.eisenhofer@uniklinikum-dresden.de

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