Pheochromocytoma/Paraganglioma: Update on Diagnosis and Management

  • Ivana Jochmanova
  • Karel Pacak
Part of the Contemporary Endocrinology book series (COE)


After more than a century since they were described, pheochromocytomas and paragangliomas (PHEOs/PGLs) still pose great diagnostic and therapeutic challenges. Recent discoveries and progress in the understanding of molecular and metabolic changes associated with tumorigenesis allowed us to get closer to deciphering the secrets of these tumors. New knowledge allows us to develop novel diagnostic methods and identify specific treatment targets to improve the care of PHEO/PGL patients.


Pheochromocytoma Paraganglioma Diagnosis Management 













Acetyl coenzyme A


ATP citrate lyase


Autosomal dominant




AMP-activated protein kinase


Adenosine triphosphate


Alpha thalassemia/mental retardation syndrome X-linked


2-Aminobicyclo(2,2,1)-heptane-2-carboxylic acid


Blood pressure


Bis-2-[5-phenylacetamido-1, 2, 4-thiadiazol-2-yl] ethyl sulfide




Computed tomography


Cyclophosphamide, vincristine, dacarbazine




External beam radiation therapy


Epigallocatechin gallate


Egl-9 family hypoxia-inducible factor 1/2 (see also PHD2/1)


Fumarate hydratase


Glutamate dehydrogenase 1


Glucose transporter


Glutamate oxaloacetate transaminase 2




Glutamate pyruvate transaminase 2


Hypoxia-inducible factor


Hypoxia-inducible factor 2 alpha




Head and neck paraganglioma


High-performance liquid chromatography


Heart rate


Harvey rat sarcoma viral oncogene homolog


Isocitrate dehydrogenase


Kinesin family member 1B


L-type amino acid transporter 1


Lactate dehydrogenase A


myc-associated factor X gene


Monocarboxylase transporter


Malate dehydrogenase 2


Multiple endocrine neoplasia, type 2A/2B






Magnetic resonance imaging


Messenger RNA






Neurofibromatosis type 1


Neurofibromin 1






Pyruvate dehydrogenase


Positron emission tomography




Peroxisome proliferator-activated receptor-γ coactivator 1α




HIF prolyl hydroxylase domain-containing protein 1/2 (see also EGLN2/1)




Paternal inheritance


Pyruvate kinase, isoenzyme 2


Response evaluation criteria in solid tumors


Rearranged during transfection proto-oncogene


Radio-frequency ablation


Reactive oxygen species


Succinate dehydrogenase


Succinate dehydrogenase subunits A, B, C, and D


SDH assembly factor 2


Thoracic and abdominal paraganglioma


Transmembrane protein 127


Vascular endothelial growth factor


von Hippel-Lindau


Conflict of Interest Declaration

The authors declare that they have no conflict of interest.


  1. 1.
    DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and genetics of tumours of endocrine organs., World Health Organization classification of tumours, vol. 8. Lyon: IARC Press; 2004.Google Scholar
  2. 2.
    Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, 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. doi: 10.1210/jc.2010-1946.PubMedCrossRefGoogle Scholar
  3. 3.
    Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. 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. doi: 10.1210/jc.2006-0423.PubMedCrossRefGoogle Scholar
  4. 4.
    Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, 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. 2012;48(11):1739–49. doi: 10.1016/j.ejca.2011.07.016.PubMedCrossRefGoogle Scholar
  5. 5.
    McNeil AR, Blok BH, Koelmeyer TD, Burke MP, Hilton JM. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust NZ J Med. 2000;30(6):648–52.CrossRefGoogle Scholar
  6. 6.
    Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr Probl Cancer. 2014;38(1):7–41. doi: 10.1016/j.currproblcancer.2014.01.001.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Pacak K, Lenders JWM, Eisenhofer G. Pheochromocytoma. Diagnosis, localization, and treatment. Malden, MA: Blackwell Publishing, Inc.; 2007.Google Scholar
  8. 8.
    Pacak K, Timmers HJLM, Eisenhofer G. Pheochromocytoma. In: Jameson JL, DeGroot LJ, De Kretser DM, Giudice L, Grossman A, Melmed S, Potts JT, Weir GC, editors. Endocrinology: Adult & pediatric. Philadelphia, PA: Elsevier/Saunders; 2016. p. 1902–1930.e1906.CrossRefGoogle Scholar
  9. 9.
    Plouin PF, Degoulet P, Tugaye A, Ducrocq MB, Menard J. Screening for phaeochromocytoma: in which hypertensive patients? A semiological study of 2585 patients, including 11 with phaeochromocytoma (author’s transl). Nouv Press Med. 1981;10(11):869–72.Google Scholar
  10. 10.
    Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366(9486):665–75. doi:  10.1016/S0140-6736(05)67139-5.
  11. 11.
    Reisch N, Peczkowska M, Januszewicz A, Neumann HP. Pheochromocytoma: presentation, diagnosis and treatment. J Hypertens. 2006;24(12):2331–9. doi:  10.1097/01.hjh.0000251887.01885.54.
  12. 12.
    Kantorovich V, Pacak K. Pheochromocytoma hypertensive crisis. In: Loriaux L, editor. Endocrine emergencies. Recognition and treatment. New York, NY: Humana Press; 2014. p. 139–47.CrossRefGoogle Scholar
  13. 13.
    Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev. 2003;24(4):539–53. doi:  10.1210/er.2002-0013.
  14. 14.
    van der Harst E, de Herder WW, de Krijger RR, Bruining HA, Bonjer HJ, Lamberts SW, van den Meiracker AH, Stijnen TH, Boomsma F. The value of plasma markers for the clinical behaviour of phaeochromocytomas. Eur J Endocrinol. 2002;147(1):85–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Mannelli M, Lenders JW, Pacak K, Parenti G, Eisenhofer G. Subclinical phaeochromocytoma. Best Pract Res Clin Endocrinol Metab. 2012;26(4):507–15. doi: 10.1016/j.beem.2011.10.008.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Brouwers FM, Eisenhofer G, Lenders JW, Pacak K. Emergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma. Endocrinol Metab Clin N Am. 2006;35(4):699–724. viii. doi:  10.1016/j.ecl.2006.09.014.
  17. 17.
    Brouwers FM, Lenders JW, Eisenhofer G, Pacak K. Pheochromocytoma as an endocrine emergency. Rev Endocr Metab Disord. 2003;4(2):121–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Baguet JP, Hammer L, Mazzuco TL, Chabre O, Mallion JM, Sturm N, Chaffanjon P. Circumstances of discovery of phaeochromocytoma: a retrospective study of 41 consecutive patients. Eur J Endocrinol. 2004;150(5):681–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Mannelli M, Ianni L, Cilotti A, Conti A. Pheochromocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol. 1999;141(6):619–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens. 2002;4(1):62–72.CrossRefGoogle Scholar
  21. 21.
    Zelinka T, Strauch B, Pecen L, Widimsky J Jr. Diurnal blood pressure variation in pheochromocytoma, primary aldosteronism and Cushing’s syndrome. J Hum Hypertens. 2004;18(2):107–11. doi:  10.1038/sj.jhh.1001644.
  22. 22.
    Zelinka T, Strauch B, Petrak O, Holaj R, Vrankova A, Weisserova H, Pacak K, Widimsky J Jr. Increased blood pressure variability in pheochromocytoma compared to essential hypertension patients. J Hypertens. 2005;23(11):2033–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Levenson JA, Safar ME, London GM, Simon AC. Haemodynamics in patients with phaeochromocytoma. Clin Sci (Lond). 1980;58(5):349–56.CrossRefGoogle Scholar
  24. 24.
    Giavarini A, Chedid A, Bobrie G, Plouin PF, Hagege A, Amar L. Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma. Heart. 2013;99(19):1438–44. doi: 10.1136/heartjnl-2013-304073.PubMedCrossRefGoogle Scholar
  25. 25.
    Tagawa M, Nanba H, Suzuki H, Nakamura Y, Uchiyama H, Ochiai S, Terunuma M, Yahata K, Minamino T. Ventricular rhythm and hypotension in a patient with pheochromocytoma-induced myocardial damage and reverse takotsubo cardiomyopathy. Intern Med. 2015;54(18):2343–9. doi: 10.2169/internalmedicine.54.4732.PubMedCrossRefGoogle Scholar
  26. 26.
    Wu XM, Chen JJ, Wu CK, Lin LY, Tseng CD. Pheochromocytoma presenting as acute myocarditis with cardiogenic shock in two cases. Intern Med. 2008;47(24):2151–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Hodin R, Lubitz C, Phitayakorn R, Stephen A. Diagnosis and management of pheochromocytoma. Curr Probl Surg. 2014;51(4):151–87. doi: 10.1067/j.cpsurg.2013.12.001.PubMedCrossRefGoogle Scholar
  28. 28.
    Lenders, J. W., Q. Y. Duh, G. Eisenhofer, A. P. Gimenez-Roqueplo, S. K. Grebe, M. H. Murad, M. Naruse, K. Pacak, W. F. Young, Jr., and Society Endocrine. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. doi: 10.1210/jc.2014-1498.CrossRefGoogle Scholar
  29. 29.
    Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92(11):4069–79. doi:  10.1210/jc.2007-1720.
  30. 30.
    Barancik M. Inadvertent diagnosis of pheochromocytoma after endoscopic premedication. Dig Dis Sci. 1989;34(1):136–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Bittar DA. Innovar-induced hypertensive crises in patients with pheochromocytoma. Anesthesiology. 1979;50(4):366–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Cook RF, Katritsis D. Hypertensive crisis precipitated by a monoamine oxidase inhibitor in a patient with phaeochromocytoma. BMJ. 1990;300(6724):614.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Jan T, Metzger BE, Baumann G. Epinephrine-producing pheochromocytoma with hypertensive crisis after corticotropin injection. Am J Med. 1990;89(6):824–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Manger WM, Gifford RW Jr. Pheochromocytoma: current diagnosis and management. Cleve Clin J Med. 1993;60(5):365–78.PubMedCrossRefGoogle Scholar
  35. 35.
    Bravo EL, Gifford RW Jr. Pheochromocytoma. Endocrinol Metab Clin N Am. 1993;22(2):329–41.Google Scholar
  36. 36.
    Ionescu CN, Sakharova OV, Harwood MD, Caracciolo EA, Schoenfeld MH, Donohue TJ. Cyclic rapid fluctuation of hypertension and hypotension in pheochromocytoma. J Clin Hypertens (Greenwich). 2008;10(12):936–40. doi: 10.1111/j.1751-7176.2008.00046.x.CrossRefGoogle Scholar
  37. 37.
    Ueda T, Oka N, Matsumoto A, Miyazaki H, Ohmura H, Kikuchi T, Nakayama M, Kato S, Imaizumi T. Pheochromocytoma presenting as recurrent hypotension and syncope. Intern Med. 2005;44(3):222–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Bouloux PG, Fakeeh M. Investigation of phaeochromocytoma. Clin Endocrinol. 1995;43(6):657–64.CrossRefGoogle Scholar
  39. 39.
    Fung MM, Viveros OH, O'Connor DT. Diseases of the adrenal medulla. Acta Physiol (Oxford). 2008;192(2):325–35. doi: 10.1111/j.1748-1716.2007.01809.x.CrossRefGoogle Scholar
  40. 40.
    Gifford RW Jr, Bravo EL, Manger WM. Diagnosis and management of pheochromocytoma. Cardiology. 1985;72(Suppl 1):126–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Adlan MA, Bondugulapati LN, Premawardhana LD. Glucose intolerance and diabetes mellitus in endocrine disorders—two case reports and a review. Curr Diabetes Rev. 2010;6(5):266–73.PubMedCrossRefGoogle Scholar
  42. 42.
    Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev. 1994;15(3):356–68.PubMedCrossRefGoogle Scholar
  43. 43.
    Chiasson JL, Shikama H, Chu DT, Exton JH. Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle. J Clin Investig. 1981;68(3):706–13.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Colwell JA. Inhibition of insulin secretion by catecholamines in pheochromocytoma. Ann Intern Med. 1969;71(2):251–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Hamaji M. Pancreatic alpha- and beta-cell function in pheochromocytoma. J Clin Endocrinol Metab. 1979;49(3):322–5.PubMedCrossRefGoogle Scholar
  46. 46.
    La Batide-Alanore A, Chatellier G, Plouin PF. Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens. 2003;21(9):1703–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Rosen SG, Clutter WE, Shah SD, Miller JP, Bier DM, Cryer PE. Direct alpha-adrenergic stimulation of hepatic glucose production in human subjects. Am J Phys. 1983;245(6):E616–26.Google Scholar
  48. 48.
    Viale G, Dell'Orto P, Moro E, Cozzaglio L, Coggi G. Vasoactive intestinal polypeptide-, somatostatin-, and calcitonin- producing adrenal pheochromocytoma associated with the watery diarrhea (WDHH) syndrome. First case report with immunohistochemical findings. Cancer. 1985;55(5):1099–106.PubMedCrossRefGoogle Scholar
  49. 49.
    Callender GG, Rich T, Lee JE, Perrier ND, Grubbs EG. Pheochromocytoma. In: Yao JC, Hoff PM, Hoff AO, editors. Neuroendocrine tumors. New York, NY: Humana Press; 2011. p. 221–43.CrossRefGoogle Scholar
  50. 50.
    Jochmanova I, Zelinka T, Widimsky J Jr, Pacak K. HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors. Physiol Res. 2014;63(Suppl 2):S251–62.PubMedGoogle Scholar
  51. 51.
    Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134(4):315–29.PubMedCrossRefGoogle Scholar
  52. 52.
    Eisenhofer G, Goldstein DS, Kopin IJ, Crout JR. Pheochromocytoma: rediscovery as a catecholamine-metabolizing tumor. Endocr Pathol. 2003;14:193–212.PubMedCrossRefGoogle Scholar
  53. 53.
    Eisenhofer G, Lenders JWM, Pacak K. Biochemical diagnosis of pheochromocytoma. In: Lehnert H, editor. Pheochromocytoma. Pathophysiology and clinical management. Basel, Switzerland: Karger; 2004. p. 76–106.Google Scholar
  54. 54.
    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;340:1872–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Eisenhofer G, Peitzsch M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin Chem. 2014;60(12):1486–99. doi: 10.1373/clinchem.2014.224832.PubMedCrossRefGoogle Scholar
  56. 56.
    Hickman PE, Leong M, Chang J, Wilson SR, McWhinney B. 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. doi: 10.1080/00313020802579284.PubMedCrossRefGoogle Scholar
  57. 57.
    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(11):1427–34.PubMedCrossRefGoogle Scholar
  58. 58.
    Mullins F, O'Shea P, FitzGerald R, Tormey W. Enzyme-linked immunoassay for plasma-free metanephrines in the biochemical diagnosis of phaeochromocytoma in adults is not ideal. Clin Chem Lab Med. 2012;50(1):105–10. doi: 10.1515/CCLM.2011.742.CrossRefGoogle Scholar
  59. 59.
    Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium October 2005. Nat Clin Pract Endocrinol Metab. 2007;3(2):92–102. doi: 10.1038/ncpendmet0396.PubMedCrossRefGoogle Scholar
  60. 60.
    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(19):2957–63.PubMedCrossRefGoogle Scholar
  61. 61.
    Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. 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(2):553–8. doi:  10.1210/jc.2002-021251.
  62. 62.
    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(3):409–17. doi:  10.1530/eje.1.02097.
  63. 63.
    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(7):1427–31. doi: 10.1097/HJH.0b013e32813aeb5a. 00004872-200707000-00019 [pii]PubMedCrossRefGoogle Scholar
  64. 64.
    Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic Acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2007;92(12):4602–8. doi: 10.1210/jc.2005-2668.PubMedCrossRefGoogle Scholar
  65. 65.
    Peitzsch M, Prejbisz A, Kroiss M, Beuschlein F, Arlt W, Januszewicz A, Siegert G, Eisenhofer G. Analysis of plasma 3-methoxytyramine, normetanephrine and metanephrine by ultraperformance liquid chromatography-tandem mass spectrometry: utility for diagnosis of dopamine-producing metastatic phaeochromocytoma. Ann Clin Biochem. 2013;50(Pt 2):147–55. doi: 10.1258/acb.2012.012112.PubMedGoogle Scholar
  66. 66.
    Bravo EL, Tarazi RC, Fouad FM, Vidt DG, Gifford RW Jr. Clonidine-suppression test: a useful aid in the diagnosis of pheochromocytoma. N Engl J Med. 1981;305(11):623–6.PubMedCrossRefGoogle Scholar
  67. 67.
    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(6):2656–66. doi:  10.1210/jc.2002-030005.
  68. 68.
    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;90:2086–75. doi:  10.1210/jc.2004-2025.
  69. 69.
    Poirier E, Thauvette D, Hogue JC. Management of exclusively dopamine-secreting abdominal pheochromocytomas. J Am Coll Surg. 2013;216(2):340–6. doi: 10.1016/j.jamcollsurg.2012.10.002.PubMedCrossRefGoogle Scholar
  70. 70.
    Eiden LE, Iacangelo A, Hsu CM, Hotchkiss AJ, Bader MF, Aunis D. Chromogranin A synthesis and secretion in chromaffin cells. J Neurochem. 1987;49(1):65–74.PubMedCrossRefGoogle Scholar
  71. 71.
    Grossrubatscher E, Dalino P, Vignati F, Gambacorta M, Pugliese R, Boniardi M, Rossetti O, Marocchi A, Bertuzzi M, Loli P. The role of chromogranin A in the management of patients with phaeochromocytoma. Clin Endocrinol. 2006;65(3):287–93. doi: 10.1111/j.1365-2265.2006.02591.x.CrossRefGoogle Scholar
  72. 72.
    Zuber S, Wesley R, Prodanov T, Eisenhofer G, Pacak K, Kantorovich V. Clinical utility of chromogranin A in SDHx-related paragangliomas. Eur J Clin Investig. 2014;44(4):365–71. doi: 10.1111/eci.12245.CrossRefGoogle Scholar
  73. 73.
    Cleary S, Phillips JK, Huynh TT, Pacak K, Fliedner S, Elkahloun AG, Munson P, Worrell RA, Eisenhofer G. Chromogranin a expression in phaeochromocytomas associated with von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2. Horm Metab Res. 2007;39(12):876–83. doi: 10.1055/s-2007-993135.PubMedCrossRefGoogle Scholar
  74. 74.
    d'Herbomez M, Do Cao C, Vezzosi D, Borzon-Chasot F, Baudin E, endocrines groupe des tumeurs. Chromogranin A assay in clinical practice. Ann Endocrinol (Paris). 2010;71(4):274–80. doi: 10.1016/j.ando.2010.04.004.CrossRefGoogle Scholar
  75. 75.
    Berenyi MR, Singh G, Gloster ES, Davidson MI, Woldenberg DH. ACTH-producing pheochromocytoma. Arch Pathol Lab Med. 1977;101(1):31–5.PubMedGoogle Scholar
  76. 76.
    Kumar M, Kumar V, Talukdar B, Mohta A, Khurana N. Cushing syndrome in an infant due to cortisol secreting adrenal pheochromocytoma: a rare association. J Pediatr Endocrinol Metab. 2010;23(6):621–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Nijhoff MF, Dekkers OM, Vleming LJ, Smit JW, Romijn JA, Pereira AM. ACTH-producing pheochromocytoma: clinical considerations and concise review of the literature. Eur J Intern Med. 2009;20(7):682–5. doi: 10.1016/j.ejim.2009.08.002.PubMedCrossRefGoogle Scholar
  78. 78.
    Eisenhofer G. Editorial: biochemical diagnosis of pheochromocytoma—is it time to switch to plasma-free metanephrines? J Clin Endocrinol Metab. 2003;88(2):550–2.PubMedCrossRefGoogle Scholar
  79. 79.
    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(2):352–4. doi: 10.1373/clinchem.2006.076489.PubMedCrossRefGoogle Scholar
  80. 80.
    Peaston RT, Lennard TW, Lai LC. Overnight excretion of urinary catecholamines and metabolites in the detection of pheochromocytoma. J Clin Endocrinol Metab. 1996;81:1378–84.PubMedGoogle Scholar
  81. 81.
    Neary NM, King KS, Pacak K. Drugs and pheochromocytoma—don’t be fooled by every elevated metanephrine. N Engl J Med. 2011;364(23):2268–70. doi: 10.1056/NEJMc1101502#SA1.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Jasperson KW, Kohlmann W, Gammon A, Slack H, Buchmann L, Hunt J, Kirchhoff AC, Baskin H, Shaaban A, Schiffman JD. Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. Familial Cancer. 2014;13(2):257–65. doi: 10.1007/s10689-013-9639-6.PubMedCrossRefGoogle Scholar
  83. 83.
    Maurea S, Cuocolo A, Reynolds JC, Neumann RD, Salvatore M. Diagnostic imaging in patients with paragangliomas. Computed tomography, magnetic resonance and MIBG scintigraphy comparison. Q J Nucl Med. 1996;40(4):365–71.PubMedGoogle Scholar
  84. 84.
    Kantorovich V, Pacak K. Pheochromocytoma and paraganglioma. Prog Brain Res. 2010;182:343–73. doi: 10.1016/S0079-6123(10)82015-1.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Schmedtje JF Jr, Sax S, Pool JL, Goldfarb RA, Nelson EB. Localization of ectopic pheochromocytomas by magnetic resonance imaging. Am J Med. 1987;83(4):770–2.PubMedCrossRefGoogle Scholar
  86. 86.
    Taieb D, Timmers HJ, Hindie E, Guillet BA, Neumann HP, Walz MK, Opocher G, et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2012;39(12):1977–95. doi: 10.1007/s00259-012-2215-8.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I, Reincke M, Moser E, Neumann HP. Pheochromocytomas: detection with 18F DOPA whole body PET—initial results. Radiology. 2002;222(2):507–12.PubMedCrossRefGoogle Scholar
  88. 88.
    Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST, Goldstein DS. 6-[18F]fluorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma. Hypertension. 2001;38(1):6–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Whatley M, Goldstein DS. Diagnostic localization of pheochromocytoma: the coming of age of positron emission tomography. Ann N Y Acad Sci. 2002;970:170–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Shapiro B, Gross MD, Shulkin B. Radioisotope diagnosis and therapy of malignant pheochromocytoma. Trends Endocrinol Metab. 2001;12(10):469–75.PubMedCrossRefGoogle Scholar
  91. 91.
    Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC. Pheochromocytomas: Imaging with 2-[Fluorine-18]fluoro-2-deoxy-D-glucose PET. Nucl Med. 1999;212:35–41.Google Scholar
  92. 92.
    Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Eisenhofer G, King KS, et al. Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography. J Natl Cancer Inst. 2012;104(9):700–8. doi: 10.1093/jnci/djs188.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Timmers HJ, Taieb D, Pacak K. Current and future anatomical and functional imaging approaches to pheochromocytoma and paraganglioma. Horm Metab Res. 2012;44(5):367–72. doi: 10.1055/s-0031-1299712.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Janssen I, Chen CC, Millo CM, Ling A, Taieb D, Lin FI, Adams KT, et al. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2016;43(10):1784–91. doi: 10.1007/s00259-016-3357-x.PubMedCrossRefGoogle Scholar
  95. 95.
    Janssen I, Chen CC, Taieb D, Patronas NJ, Millo CM, Adams KT, Nambuba J, et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. J Nucl Med. 2016;57(2):186–91. doi: 10.2967/jnumed.115.161018.PubMedCrossRefGoogle Scholar
  96. 96.
    Kroiss A, Putzer D, Uprimny C, Decristoforo C, Gabriel M, Santner W, Kranewitter C, et al. Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr 3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine. Eur J Nucl Med Mol Imaging. 2011;38(5):865–73. doi: 10.1007/s00259-010-1720-x.PubMedCrossRefGoogle Scholar
  97. 97.
    Maurice JB, Troke R, Win Z, Ramachandran R, Al-Nahhas A, Naji M, Dhillo W, et al. A comparison of the performance of (6)(8)Ga-DOTATATE PET/CT and (1)(2)(3)I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2012;39(8):1266–70. doi: 10.1007/s00259-012-2119-7.PubMedCrossRefGoogle Scholar
  98. 98.
    Havekes B, King K, Lai EW, Romijn JA, Corssmit EP, Pacak K. New imaging approaches to phaeochromocytomas and paragangliomas. Clin Endocrinol. 2010;72(2):137–45. doi: 10.1111/j.1365-2265.2009.03648.x.CrossRefGoogle Scholar
  99. 99.
    Nakatani T, Hayama T, Uchida J, Nakamura K, Takemoto Y, Sugimura K. Diagnostic localization of extra-adrenal pheochromocytoma: comparison of (123)I-MIBG imaging and (131)I-MIBG imaging. Oncol Rep. 2002;9(6):1225–7.PubMedGoogle Scholar
  100. 100.
    Timmers HJ, Eisenhofer G, Carrasquillo JA, Chen CC, Whatley M, Ling A, Adams KT, Pacak K. Use of 6-[18F]-fluorodopamine positron emission tomography (PET) as first-line investigation for the diagnosis and localization of non-metastatic and metastatic phaeochromocytoma (PHEO). Clin Endocrinol. 2009;71(1):11–7. doi: 10.1111/j.1365-2265.2008.03496.x.CrossRefGoogle Scholar
  101. 101.
    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 pheochromocytoma and paraganglioma. J Clin Oncol. 2007;25(16):2262–9. doi: 10.1200/JCO.2006.09.6297.PubMedCrossRefGoogle Scholar
  102. 102.
    van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, et al. [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in benign and malignant pheochromocytomas. J Clin Endocrinol Metab. 2001;86(2):685–93.PubMedGoogle Scholar
  103. 103.
    Van Der Horst-Schrivers AN, Jager PL, Boezen HM, Schouten JP, Kema IP, Links TP. Iodine-123 metaiodobenzylguanidine scintigraphy in localising phaeochromocytomas—experience and meta-analysis. Anticancer Res. 2006;26(2B):1599–604.Google Scholar
  104. 104.
    Bombardieri E, Giammarile F, Aktolun C, Baum RP, Bischof Delaloye A, Maffioli L, Moncayo R, et al. 131I/123I-metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging. 2010;37(12):2436–46. doi: 10.1007/s00259-010-1545-7.PubMedCrossRefGoogle Scholar
  105. 105.
    Solanki KK, Bomanji J, Moyes J, Mather SJ, Trainer PJ, Britton KE. A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG). Nucl Med Commun. 1992;13(7):513–21.PubMedCrossRefGoogle Scholar
  106. 106.
    Stefanelli A, Treglia G, Bruno I, Rufini V, Giordano A. Pharmacological interference with 123I-metaiodobenzylguanidine: a limitation to developing cardiac innervation imaging in clinical practice? Eur Rev. Med Pharmacol Sci. 2013;17(10):1326–33.PubMedGoogle Scholar
  107. 107.
    Hartung-Knemeyer V, Rosenbaum-Krumme S, Buchbender C, Poppel T, Brandau W, Jentzen W, Antoch G, Forsting M, Bockisch A, Kuhl H. Malignant pheochromocytoma imaging with [124I]mIBG PET/MR. J Clin Endocrinol Metab. 2012;97(11):3833–4. doi: 10.1210/jc.2012-1958.PubMedCrossRefGoogle Scholar
  108. 108.
    Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT, Pacak K. Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2009;94(12):4757–67. doi: 10.1210/jc.2009-1248.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Goldstein DS, Eisenhofer G, Dunn BB, Armando I, Lenders J, Grossman E, Holmes C, et al. Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans. J Am Coll Cardiol. 1993;22(7):1961–71.PubMedCrossRefGoogle Scholar
  110. 110.
    Shulkin BL, Wieland DM, Schwaiger MS, et al. PET scanning with hydroxyephedrine: A new approach to the localization of pheochromocytoma. J Nucl Med. 1992;33:1125–31.PubMedGoogle Scholar
  111. 111.
    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;97:2423–32. doi: 10.1210/jc.2011-3342.PubMedCrossRefGoogle Scholar
  112. 112.
    Chen CC, Carrasquillo JA. Molecular imaging of adrenal neoplasms. J Surg Oncol. 2012;106(5):532–42. doi: 10.1002/jso.23162.PubMedCrossRefGoogle Scholar
  113. 113.
    Timmers HJ, Hadi M, Carrasquillo JA, Chen CC, Martiniova L, Whatley M, Ling A, Eisenhofer G, Adams KT, Pacak K. The effects of carbidopa on uptake of 6-18F-Fluoro-L-DOPA in PET of pheochromocytoma and extraadrenal abdominal paraganglioma. J Nucl Med. 2007;48(10):1599–606. doi: 10.2967/jnumed.107.042721.PubMedCrossRefGoogle Scholar
  114. 114.
    Fiebrich HB, Brouwers AH, Kerstens MN, Pijl ME, Kema IP, de Jong JR, Jager PL, et al. 6-[F-18]Fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with (123)I-metaiodobenzylguanidine scintigraphy, computer tomography, and magnetic resonance imaging in localizing tumors causing catecholamine excess. J Clin Endocrinol Metab. 2009;94(10):3922–30. doi: 10.1210/jc.2009-1054.PubMedCrossRefGoogle Scholar
  115. 115.
    King KS, Chen CC, Alexopoulos DK, Whatley MA, Reynolds JC, Patronas N, Ling A, et al. Functional imaging of SDHx-related head and neck paragangliomas: comparison of 18F-fluorodihydroxyphenylalanine, 18F-fluorodopamine, 18F-fluoro-2-deoxy-D-glucose PET, 123I-metaiodobenzylguanidine scintigraphy, and 111In-pentetreotide scintigraphy. J Clin Endocrinol Metab. 2011;96(9):2779–85. doi: 10.1210/jc.2011-0333.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Krenning EP, Kwekkeboom DJ, Pawels S, Kvols LK, Reubi JC. Somatostatin receptor scintigraphy. In: Freeman LM, editor. Nuclear Medicine Annual 1995. New York: Raven Press; 1995. p. 242–4.Google Scholar
  117. 117.
    Kaltsas G, Korbonits M, Heintz E, Mukherjee JJ, Jenkins PJ, Chew SL, Reznek R, et al. Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J Clin Endocrinol Metab. 2001;86(2):895–902.PubMedCrossRefGoogle Scholar
  118. 118.
    Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89(2):479–91. doi:  10.1210/jc.2003-031091.
  119. 119.
    Ambrosini V, Fanti S. 68Ga-DOTA-peptides in the diagnosis of NET. PET Clin. 2014;9(1):37–42. doi: 10.1016/j.cpet.2013.08.007.PubMedCrossRefGoogle Scholar
  120. 120.
    Fanti S, Ambrosini V, Tomassetti P, Castellucci P, Montini G, Allegri V, Grassetto G, Rubello D, Nanni C, Franchi R. Evaluation of unusual neuroendocrine tumours by means of 68Ga-DOTA-NOC PET. Biomed Pharmacother. 2008;62(10):667–71. doi: 10.1016/j.biopha.2008.01.010.PubMedCrossRefGoogle Scholar
  121. 121.
    Kroiss A, Putzer D, Decristoforo C, Uprimny C, Warwitz B, Nilica B, Gabriel M, et al. 68Ga-DOTA-TOC uptake in neuroendocrine tumour and healthy tissue: differentiation of physiological uptake and pathological processes in PET/CT. Eur J Nucl Med Mol Imaging. 2013;40(4):514–23. doi: 10.1007/s00259-012-2309-3.PubMedCrossRefGoogle Scholar
  122. 122.
    Kroiss A, Putzer D, Frech A, Decristoforo C, Uprimny C, Gasser RW, Shulkin BL, et al. A retrospective comparison between 68Ga-DOTA-TOC PET/CT and 18F-DOPA PET/CT in patients with extra-adrenal paraganglioma. Eur J Nucl Med Mol Imaging. 2013;40(12):1800–8. doi: 10.1007/s00259-013-2548-y.PubMedCrossRefGoogle Scholar
  123. 123.
    Naji M, Zhao C, Welsh SJ, Meades R, Win Z, Ferrarese A, Tan T, Rubello D, Al-Nahhas A. 68Ga-DOTA-TATE PET vs. 123I-MIBG in identifying malignant neural crest tumours. Mol Imaging Biol. 2011;13(4):769–75. doi: 10.1007/s11307-010-0396-8.PubMedCrossRefGoogle Scholar
  124. 124.
    Naswa N, Sharma P, Nazar AH, Agarwal KK, Kumar R, Ammini AC, Malhotra A, Bal C. Prospective evaluation of (6)(8)Ga-DOTA-NOC PET-CT in phaeochromocytoma and paraganglioma: preliminary results from a single centre study. Eur Radiol. 2012;22(3):710–9. doi: 10.1007/s00330-011-2289-x.PubMedCrossRefGoogle Scholar
  125. 125.
    Naswa N, Sharma P, Soundararajan R, Patnecha M, Lata S, Kumar R, Malhotra A, Bal C. Preoperative characterization of indeterminate large adrenal masses with dual tracer PET-CT using fluorine-18 fluorodeoxyglucose and gallium-68-DOTANOC: initial results. Diagn Interv Radiol. 2013;19(4):294–8. doi: 10.5152/dir.2013.048.PubMedGoogle Scholar
  126. 126.
    Sharma P, Thakar A, Suman KCS, Dhull VS, Singh H, Naswa N, Reddy RM, et al. 68Ga-DOTANOC PET/CT for baseline evaluation of patients with head and neck paraganglioma. J Nucl Med. 2013;54(6):841–7. doi: 10.2967/jnumed.112.115485.PubMedCrossRefGoogle Scholar
  127. 127.
    Maher ER. Phaeochromocytoma and paraganglioma: next-generation sequencing and evolving Mendelian syndromes. Clin Med. 2014;14(4):440–4. doi: 10.7861/clinmedicine.14-4-440.CrossRefGoogle Scholar
  128. 128.
    Tsirlin A, Oo Y, Sharma R, Kansara A, Gliwa A, Banerji MA. Pheochromocytoma: a review. Maturitas. 2014;77(3):229–38. doi: 10.1016/j.maturitas.2013.12.009.PubMedCrossRefGoogle Scholar
  129. 129.
    Vicha A, Musil Z, Pacak K. Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options. Curr Opin Endocrinol Diabetes Obes. 2013;20(3):186–91. doi: 10.1097/MED.0b013e32835fcc45.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23(34):8812–8. doi:  10.1200/JCO.2005.03.1484.
  131. 131.
    Benn DE, Robinson BG. Genetic basis of phaeochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2006;20(3):435–50. doi:  10.1016/j.beem.2006.07.005.
  132. 132.
    Mannelli M, Castellano M, Schiavi F, Filetti S, Giacche M, Mori L, Pignataro V, 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. doi: 10.1210/jc.2008-2419.PubMedCrossRefGoogle Scholar
  133. 133.
    Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57(3):411–20. doi: 10.1373/clinchem.2010.153320.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer. 2011;18(1):97–111. doi: 10.1677/ERC-10-0211.PubMedCrossRefGoogle Scholar
  135. 135.
    Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol. 2013;78(2):165–75. doi: 10.1111/cen.12071.CrossRefGoogle Scholar
  136. 136.
    Jafri M, Maher ER. The genetics of phaeochromocytoma: using clinical features to guide genetic testing. Eur J Endocrinol. 2012;166(2):151–8. doi: 10.1530/EJE-11-0497.PubMedCrossRefGoogle Scholar
  137. 137.
    Karasek D, Shah U, Frysak Z, Stratakis C, Pacak K. An update on the genetics of pheochromocytoma. J Hum Hypertens. 2013;27(3):141–7. doi: 10.1038/jhh.2012.20.PubMedCrossRefGoogle Scholar
  138. 138.
    Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43(7):663–7. doi: 10.1038/ng.861.PubMedCrossRefGoogle Scholar
  139. 139.
    Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459–66.PubMedCrossRefGoogle Scholar
  140. 140.
    Plouin PF, Fitzgerald P, Rich T, Ayala-Ramirez M, Perrier ND, Baudin E, Jimenez C. Metastatic pheochromocytoma and paraganglioma: focus on therapeutics. Horm Metab Res. 2012;44:390–9. doi: 10.1055/s-0031-1299707.PubMedCrossRefGoogle Scholar
  141. 141.
    Mazza A, Armigliato M, Marzola MC, Schiavon L, Montemurro D, Vescovo G, Zuin M, et al. Anti-hypertensive treatment in pheochromocytoma and paraganglioma: current management and therapeutic features. Endocrine. 2014;45(3):469–78. doi: 10.1007/s12020-013-0007-y.PubMedCrossRefGoogle Scholar
  142. 142.
    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;39(6):775–83. doi: 10.1097/MPA.0b013e3181ebb4f0.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Kinney MA, Narr BJ, Warner MA. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth. 2002;16(3):359–69.PubMedCrossRefGoogle Scholar
  144. 144.
    Van Stratum M, Levarlet M, Lambilliotte JP, Lignian H, de Rood M. Use of labetalol during anesthesia for pheochromocytoma removal. Acta Anaesthesiol Belg. 1983;34(4):233–40.PubMedGoogle Scholar
  145. 145.
    Siddiqi HK, Yang HY, Laird AM, Fox AC, Doherty GM, Miller BS, Gauger PG. Utility of oral nicardipine and magnesium sulfate infusion during preparation and resection of pheochromocytomas. Surgery. 2012;152(6):1027–36. doi: 10.1016/j.surg.2012.08.023.PubMedCrossRefGoogle Scholar
  146. 146.
    Conzo G, Musella M, Corcione F, De Palma M, Avenia N, Milone M, Della Pietra C, et al. Laparoscopic treatment of pheochromocytomas smaller or larger than 6 cm. A clinical retrospective study on 44 patients. Laparoscopic adrenalectomy for pheochromocytoma. Ann Ital Chir. 2013;84(4):417–22.PubMedGoogle Scholar
  147. 147.
    Conzo G, Tartaglia E, Gambardella C, Esposito D, Sciascia V, Mauriello C, Nunziata A, et al. Minimally invasive approach for adrenal lesions: Systematic review of laparoscopic versus retroperitoneoscopic adrenalectomy and assessment of risk factors for complications. Int J Surg. 2016;28(Suppl 1):S118–23. doi: 10.1016/j.ijsu.2015.12.042.PubMedCrossRefGoogle Scholar
  148. 148.
    Wang W, Li P, Wang Y, Wang Y, Ma Z, Wang G, Gao J, Zhou H. Effectiveness and safety of laparoscopic adrenalectomy of large pheochromocytoma: a prospective, nonrandomized, controlled study. Am J Surg. 2015;210(2):230–5. doi: 10.1016/j.amjsurg.2014.11.012.PubMedCrossRefGoogle Scholar
  149. 149.
    Goers TA, Abdo M, Moley JF, Matthews BD, Quasebarth M, Brunt LM. Outcomes of resection of extra-adrenal pheochromocytomas/paragangliomas in the laparoscopic era: a comparison with adrenal pheochromocytoma. Surg Endosc. 2013;27(2):428–33. doi: 10.1007/s00464-012-2451-9.PubMedCrossRefGoogle Scholar
  150. 150.
    Kim HH, Kim GH, Sung GT. Laparoscopic adrenalectomy for pheochromocytoma: comparison with conventional open adrenalectomy. J Endourol. 2004;18(3):251–5. doi:  10.1089/089277904773582859.
  151. 151.
    Aliyev S, Karabulut K, Agcaoglu O, Wolf K, Mitchell J, Siperstein A, Berber E. Robotic versus laparoscopic adrenalectomy for pheochromocytoma. Ann Surg Oncol. 2013;20(13):4190–4. doi: 10.1245/s10434-013-3134-z.PubMedCrossRefGoogle Scholar
  152. 152.
    Arghami A, Dy BM, Bingener J, Osborn J, Richards ML. Single-port robotic-assisted adrenalectomy: feasibility, safety, and cost-effectiveness. JSLS. 2015;19(1):e2014 00218. doi: 10.4293/JSLS.2014.00218.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Asher KP, Gupta GN, Boris RS, Pinto PA, Linehan WM, Bratslavsky G. Robot-assisted laparoscopic partial adrenalectomy for pheochromocytoma: the National Cancer Institute technique. Eur Urol. 2011;60(1):118–24. doi: 10.1016/j.eururo.2011.03.046.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Benhammou JN, Boris RS, Pacak K, Pinto PA, Linehan WM, Bratslavsky G. Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of followup. J Urol. 2010;184(5):1855–9. doi: 10.1016/j.juro.2010.06.102.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Kaye DR, Storey BB, Pacak K, Pinto PA, Linehan WM, Bratslavsky G. Partial adrenalectomy: underused first line therapy for small adrenal tumors. J Urol. 2010;184(1):18–25. doi: 10.1016/j.juro.2010.03.052.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Sanford TH, Storey BB, Linehan WM, Rogers CA, Pinto PA, Bratslavsky G. Outcomes and timing for intervention of partial adrenalectomy in patients with a solitary adrenal remnant and history of bilateral phaeochromocytomas. BJU Int. 2011;107(4):571–5. doi: 10.1111/j.1464-410X.2010.09568.x.PubMedCrossRefGoogle Scholar
  157. 157.
    Alesina PF, Hinrichs J, Meier B, Schmid KW, Neumann HP, Walz MK. Minimally invasive cortical-sparing surgery for bilateral pheochromocytomas. Langenbeck's Arch Surg. 2012;397(2):233–8. doi: 10.1007/s00423-011-0851-2.CrossRefGoogle Scholar
  158. 158.
    Grubbs EG, Rich TA, Ng C, Bhosale PR, Jimenez C, Evans DB, Lee JE, Perrier ND. Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg. 2013;216(2):280–9. doi: 10.1016/j.jamcollsurg.2012.10.012.PubMedCrossRefGoogle Scholar
  159. 159.
    Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery. 1996;120:1064–70. discussion 1070PubMedCrossRefGoogle Scholar
  160. 160.
    Neumann HP, Reincke M, Bender BU, Elsner R, Janetschek G. Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma. J Clin Endocrinol Metab. 1999;84(8):2608–10.PubMedGoogle Scholar
  161. 161.
    Neumann HP, Bender BU, Reincke M, Eggstein S, Laubenberger J, Kirste G. Adrenal-sparing surgery for phaeochromocytoma. Br J Surg. 1999;86(1):94–7.PubMedCrossRefGoogle Scholar
  162. 162.
    Adjalle R, Plouin PF, Pacak K, Lehnert H. Treatment of malignant pheochromocytoma. Horm Metab Res. 2009;41(9):687–96. doi: 10.1055/s-0029-1231025.PubMedCrossRefGoogle Scholar
  163. 163.
    Arnas-Leon C, Sanchez V, Santana Suarez AD, Quintana Arroyo S, Acosta C, Martinez Martin FJ. Complete remission in metastatic pheochromocytoma treated with extensive surgery. Cureus. 2016;8(1):e447. doi: 10.7759/cureus.447.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Ellis RJ, Patel D, Prodanov T, Sadowski S, Nilubol N, Adams K, Steinberg SM, Pacak K, Kebebew E. Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted? J Am Coll Surg. 2013;217(3):489–96. doi: 10.1016/j.jamcollsurg.2013.04.027.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Buhl T, Mortensen J, Kjaer A. I-123 MIBG imaging and intraoperative localization of metastatic pheochromocytoma: a case report. Clin Nucl Med. 2002;27(3):183–5.PubMedCrossRefGoogle Scholar
  166. 166.
    Una-Gorospe JA, Munoz-Iglesias J, De Sequera-Rahola M, Anton L. Usefulness of single photon emission computed tomography (SPECT)/computed tomography and radioguided surgery in a patient with recurrent pheochromocytoma. Indian J Nucl Med. 2013;28(1):59–60. doi: 10.4103/0972-3919.116801.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Ramakrishna H. Pheochromocytoma resection: current concepts in anesthetic management. J Anaesthesiol Clin Pharmacol. 2015;31(3):317–23. doi: 10.4103/0970-9185.161665.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Minami T, Adachi T, Fukuda K. An effective use of magnesium sulfate for intraoperative management of laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. Anesth Analg. 2002;95(5):1243–4.PubMedCrossRefGoogle Scholar
  169. 169.
    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(4):2110–6. doi:  10.1210/jc.2004-1398.
  170. 170.
    Plouin PF, Chatellier G, Fofol I, Corvol P. Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension. 1997;29(5):1133–9.PubMedCrossRefGoogle Scholar
  171. 171.
    Linnoila RI, Keiser HR, Steinberg SM, Lack EE. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol. 1990;21(11):1168–80.PubMedCrossRefGoogle Scholar
  172. 172.
    Eisenhofer G, Bornstein SR, Brouwers FM, Cheung NK, Dahia PL, de Krijger RR, Giordano TJ, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer. 2004;11(3):423–36.PubMedCrossRefGoogle Scholar
  173. 173.
    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.PubMedCrossRefGoogle Scholar
  174. 174.
    Stumvoll M, Fritsche A, Pickert A, Overkamp D. Features of malignancy in a benign pheochromocytoma. Horm Res. 1997;48(3):135–6.PubMedCrossRefGoogle Scholar
  175. 175.
    Goldstein RE, O'Neill JA Jr, Holcomb GW 3rd, Morgan WM 3rd, Neblett WW 3rd, Oates JA, Brown N, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg. 1999;229(6):755–64.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Mundschenk J, Lehnert H. Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes. 1998;106(5):373–6.PubMedCrossRefGoogle Scholar
  177. 177.
    John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted? Urology. 1999;53(4):679–83.PubMedCrossRefGoogle Scholar
  178. 178.
    Angelousi A, Kassi E, Zografos G, Kaltsas G. Metastatic pheochromocytoma and paraganglioma. Eur J Clin Investig. 2015;45(9):986–97. doi: 10.1111/eci.12495.CrossRefGoogle Scholar
  179. 179.
    Baudin E, Habra MA, Deschamps F, Cote G, Dumont F, Cabanillas M, Arfi-Roufe J, et al. Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma. Eur J Endocrinol. 2014;171(3):R111–22. doi: 10.1530/EJE-14-0113.PubMedCrossRefGoogle Scholar
  180. 180.
    Scholz T, Eisenhofer G, Pacak K, Dralle H, Lehnert H. Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. 2007;92(4):1217–25. doi:  10.1210/jc.2006-1544.
  181. 181.
    Carrasquillo JA, Pandit-Taskar N, Chen CC. Radionuclide therapy of adrenal tumors. J Surg Oncol. 2012;106(5):632–42. doi: 10.1002/jso.23196.PubMedCrossRefGoogle Scholar
  182. 182.
    Carrasquillo JA, Pandit-Taskar N, Chen CC. I-131 metaiodobenzylguanidine therapy of pheochromocytoma and paraganglioma. Semin Nucl Med. 2016;46(3):203–14. doi: 10.1053/j.semnuclmed.2016.01.011.PubMedCrossRefGoogle Scholar
  183. 183.
    Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Investig. 1997;20(11):648–58.CrossRefGoogle Scholar
  184. 184.
    Cecchin D, Schiavi F, Fanti S, Favero M, Manara R, Fassina A, Briani C, et al. Peptide receptor radionuclide therapy in a case of multiple spinal canal and cranial paragangliomas. J Clin Oncol. 2011;29(7):e171–4. doi: 10.1200/JCO.2010.31.7131.PubMedCrossRefGoogle Scholar
  185. 185.
    Garkavij M, Nickel M, Sjogreen-Gleisner K, Ljungberg M, Ohlsson T, Wingardh K, Strand SE, Tennvall J. 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer. 2010;116(4 Suppl):1084–92. doi: 10.1002/cncr.24796.PubMedCrossRefGoogle Scholar
  186. 186.
    Gulenchyn KY, Yao X, Asa SL, Singh S, Law C. Radionuclide therapy in neuroendocrine tumours: a systematic review. Clin Oncol (R Coll Radiol). 2012;24(4):294–308. doi: 10.1016/j.clon.2011.12.003.CrossRefGoogle Scholar
  187. 187.
    Menda Y, O'Dorisio MS, Kao S, Khanna G, Michael S, Connolly M, Babich J, O'Dorisio T, Bushnell D, Madsen M. Phase I trial of 90Y-DOTATOC therapy in children and young adults with refractory solid tumors that express somatostatin receptors. J Nucl Med. 2010;51(10):1524–31. doi: 10.2967/jnumed.110.075226.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    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(11):5150–7. doi:  10.1210/jc.2003-030262.
  189. 189.
    Plouin PF, Bertherat J, Chatellier G, Billaud E, Azizi M, Grouzmann E, Epelbaum J. Short-term effects of octreotide on blood pressure and plasma catecholamines and neuropeptide Y levels in patients with phaeochromocytoma: a placebo-controlled trial. Clin Endocrinol. 1995;42(3):289–94.CrossRefGoogle Scholar
  190. 190.
    van Essen M, Krenning EP, Kooij PP, Bakker WH, Feelders RA, de Herder WW, Wolbers JG, Kwekkeboom DJ. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med. 2006;47(10):1599–606.PubMedGoogle Scholar
  191. 191.
    Zovato S, Kumanova A, Dematte S, Sansovini M, Bodei L, Di Sarra D, Casagranda E, et al. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in individuals with neck or mediastinal paraganglioma (PGL). Horm Metab Res. 2012;44(5):411–4. doi: 10.1055/s-0032-1311637.PubMedCrossRefGoogle Scholar
  192. 192.
    Mamlouk MD, vanSonnenberg E, Stringfellow G, Smith D, Wendt A. Radiofrequency ablation and biopsy of metastatic pheochromocytoma: emphasizing safety issues and dangers. J Vasc Interv Radiol. 2009;20(5):670–3. doi: 10.1016/j.jvir.2009.01.031.PubMedCrossRefGoogle Scholar
  193. 193.
    McBride JF, Atwell TD, Charboneau WJ, Young WF Jr, Wass TC, Callstrom MR. Minimally invasive treatment of metastatic pheochromocytoma and paraganglioma: efficacy and safety of radiofrequency ablation and cryoablation therapy. J Vasc Interv Radiol. 2011;22(9):1263–70. doi: 10.1016/j.jvir.2011.06.016.PubMedCrossRefGoogle Scholar
  194. 194.
    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(8):648–9.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Venkatesan AM, Locklin J, Lai EW, Adams KT, Fojo AT, Pacak K, Wood BJ. Radiofrequency ablation of metastatic pheochromocytoma. J Vasc Interv Radiol. 2009;20(11):1483–90. doi: 10.1016/j.jvir.2009.07.031.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Fishbein L. Pheochromocytoma and paraganglioma: genetics, diagnosis, and treatment. Hematol Oncol Clin North Am. 2016;30(1):135–50. doi: 10.1016/j.hoc.2015.09.006.PubMedCrossRefGoogle Scholar
  197. 197.
    Fishbein L, Bonner L, Torigian DA, Nathanson KL, Cohen DL, Pryma D, Cengel KA. External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG. Horm Metab Res. 2012;44(5):405–10. doi: 10.1055/s-0032-1308992.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Vogel J, Atanacio AS, Prodanov T, Turkbey BI, Adams K, Martucci V, Camphausen K, Fojo AT, Pacak K, Kaushal A. External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma. Front Oncol. 2014;4:166. doi: 10.3389/fonc.2014.00166.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Jackson CG. Glomus tympanicum and glomus jugulare tumors. Otolaryngol Clin N Am. 2001;34(5):941–70. viiCrossRefGoogle Scholar
  200. 200.
    Chino JP, Sampson JH, Tucci DL, Brizel DM, Kirkpatrick JP. Paraganglioma of the head and neck: long-term local control with radiotherapy. Am J Clin Oncol. 2009;32(3):304–7. doi: 10.1097/COC.0b013e318187dd94.PubMedCrossRefGoogle Scholar
  201. 201.
    Guss ZD, Batra S, Limb CJ, Li G, Sughrue ME, Redmond K, Rigamonti D, et al. Radiosurgery of glomus jugulare tumors: a meta-analysis. Int J Radiat Oncol Biol Phys. 2011;81(4):e497–502. doi: 10.1016/j.ijrobp.2011.05.006.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Hafez RF, Morgan MS, Fahmy OM. An intermediate term benefits and complications of gamma knife surgery in management of glomus jugulare tumor. World J Surg Oncol. 2016;14(1):36. doi: 10.1186/s12957-016-0779-7.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Schuster D, Sweeney AD, Stavas MJ, Tawfik KY, Attia A, Cmelak AJ, Wanna GB. Initial radiographic tumor control is similar following single or multi-fractionated stereotactic radiosurgery for jugular paragangliomas. Am J Otolaryngol. 2016;37(3):255–8. doi: 10.1016/j.amjoto.2016.01.002.PubMedCrossRefGoogle Scholar
  204. 204.
    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(4):267–73.PubMedCrossRefGoogle Scholar
  205. 205.
    Ayala-Ramirez M, Feng L, Habra MA, Rich T, Dickson PV, Perrier N, Phan A, Waguespack S, Patel S, Jimenez C. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer. 2012;118(11):2804–12. doi: 10.1002/cncr.26577.PubMedCrossRefGoogle Scholar
  206. 206.
    Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM, Pacak K, Fojo T. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer. 2008;113(8):2020–8. doi:  10.1002/cncr.23812.
  207. 207.
    Nomura K, Kimura H, Shimizu S, Kodama H, Okamoto T, Obara T, Takano K. Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy. J Clin Endocrinol Metab. 2009;94(8):2850–6. doi:  10.1210/jc.2008-2697.
  208. 208.
    Tanabe A, Naruse M, Nomura K, Tsuiki M, Tsumagari A, Ichihara A. Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma. Horm Cancer. 2013;4(2):103–10. doi: 10.1007/s12672-013-0133-2.PubMedCrossRefGoogle Scholar
  209. 209.
    He J, Makey D, Fojo T, Adams KT, Havekes B, Eisenhofer G, Sullivan P, Lai EW, Pacak K. Successful chemotherapy of hepatic metastases in a case of succinate dehydrogenase subunit B-related paraganglioma. Endocrine. 2009;36(2):189–93. doi:  10.1007/s12020-009-9219-6.
  210. 210.
    Bravo EL, Kalmadi SR, Gill I. Clinical utility of temozolomide in the treatment of malignant paraganglioma: a preliminary report. Horm Metab Res. 2009;41(9):703–6. doi: 10.1055/s-0029-1224135.PubMedCrossRefGoogle Scholar
  211. 211.
    Kruijtzer CM, Beijnen JH, Swart M, Schellens JH. Successful treatment with paclitaxel of a patient with metastatic extra- adrenal pheochromocytoma (paraganglioma). A case report and review of the literature. Cancer Chemother Pharmacol. 2000;45(5):428–31. doi:  10.1007/s002800051013.
  212. 212.
    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(3):401–6. doi: 10.1200/JCO.2005.03.6046.PubMedCrossRefGoogle Scholar
  213. 213.
    Mora J, Cruz O, Parareda A, Sola T, de Torres C. Treatment of disseminated paraganglioma with gemcitabine and docetaxel. Pediatr Blood Cancer. 2009;53(4):663–5. doi: 10.1002/pbc.22006.PubMedCrossRefGoogle Scholar
  214. 214.
    Jochmanova I, Yang C, Zhuang Z, Pacak K. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. J Natl Cancer Inst. 2013;105(17):1270–83. doi: 10.1093/jnci/djt201.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Jochmanova I, Zhuang Z, Pacak K. Pheochromocytoma: gasping for air. Horm Cancer. 2015;6(5–6):191–205. doi: 10.1007/s12672-015-0231-4.PubMedCrossRefGoogle Scholar
  216. 216.
    Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev. Endocrinol. 2015;11(2):101–11. doi: 10.1038/nrendo.2014.188.PubMedCrossRefGoogle Scholar
  217. 217.
    Justus CR, Sanderlin EJ, Yang LV. Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci. 2015;16(5):11055–86. doi: 10.3390/ijms160511055.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Wigerup C, Pahlman S, Bexell D. Review: therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. 2016;164:152–69. doi: 10.1016/j.pharmthera.2016.04.009.PubMedCrossRefGoogle Scholar
  219. 219.
    Granja S, Pinheiro C, Reis RM, Martinho O, Baltazar F. Glucose addiction in cancer therapy: advances and drawbacks. Curr Drug Metab. 2015;16(3):221–42. doi:  10.2174/1389200216666150602145145.
  220. 220.
    Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene. 2015;35:3619–25. doi: 10.1038/onc.2015.447.PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–82. doi: 10.1016/j.ccr.2008.05.005.PubMedCrossRefGoogle Scholar
  222. 222.
    Mashima T, Seimiya H, Tsuruo T. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer. 2009;100(9):1369–72. doi: 10.1038/sj.bjc.6605007.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Mullen GE, Yet L. Progress in the development of fatty acid synthase inhibitors as anticancer targets. Bioorg Med Chem Lett. 2015;25(20):4363–9. doi: 10.1016/j.bmcl.2015.08.087.PubMedCrossRefGoogle Scholar
  224. 224.
    Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev. Drug Discov. 2011;10(9):671–84. doi: 10.1038/nrd3504.PubMedCrossRefGoogle Scholar
  225. 225.
    Iacobazzi V, Infantino V. Citrate—new functions for an old metabolite. Biol Chem. 2014;395(4):387–99. doi: 10.1515/hsz-2013-0271.PubMedCrossRefGoogle Scholar
  226. 226.
    Jochmanova I, Pacak K. Pheochromoctyoma: the first metabolic endocrine cancer. Clin Cancer Res. 2016;22:5001–11. doi:  10.1158/1078-0432.CCR-16-0606.
  227. 227.
    Aita Y, Ishii KA, Saito Y, Ikeda T, Kawakami Y, Shimano H, Hara H, Takekoshi K. Sunitinib inhibits catecholamine synthesis and secretion in pheochromocytoma tumor cells by blocking VEGF receptor 2 via PLC-gamma-related pathways. Am J Physiol Endocrinol Metab. 2012;303(8):E1006–14. doi: 10.1152/ajpendo.00156.2012.PubMedCrossRefGoogle Scholar
  228. 228.
    Saito Y, Tanaka Y, Aita Y, Ishii KA, Ikeda T, Isobe K, Kawakami Y, Shimano H, Hara H, Takekoshi K. Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6 K1 pathways through modulation of Bcl-2 and BAD. Am J Physiol Endocrinol Metab. 2012;302(6):E615–25. doi: 10.1152/ajpendo.00035.2011.PubMedCrossRefGoogle Scholar
  229. 229.
    Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, Caramella C, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab. 2012;97(11):4040–50. doi: 10.1210/jc.2012-2356.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Jimenez C, Cabanillas ME, Santarpia L, Jonasch E, Kyle KL, Lano EA, Matin SF, 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. 2009;94(2):386–91.PubMedCrossRefGoogle Scholar
  231. 231.
    Joshua AM, Ezzat S, Asa SL, Evans A, Broom R, Freeman M, Knox JJ. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab. 2009;94(1):5–9. doi: 10.1210/jc.2008-1836.PubMedCrossRefGoogle Scholar
  232. 232.
    Prochilo T, Savelli G, Bertocchi P, Abeni C, Rota L, Rizzi A, Zaniboni A. Targeting VEGF-VEGFR pathway by sunitinib in peripheral primitive neuroectodermal tumor, paraganglioma and epithelioid hemangioendothelioma: three case reports. Case Rep Oncol. 2013;6(1):90–7. doi: 10.1159/000348429.PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Druce MR, Kaltsas GA, Fraenkel M, Gross DJ, Grossman AB. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res. 2009;41(9):697–702. doi: 10.1055/s-0029-1220687.PubMedCrossRefGoogle Scholar
  234. 234.
    Oh DY, Kim TW, Park YS, Shin SJ, Shin SH, Song EK, Lee HJ, Lee KW, Bang YJ. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer. 2012;118(24):6162–70. doi: 10.1002/cncr.27675.PubMedCrossRefGoogle Scholar
  235. 235.
    Cao S, Cao R, Liu X, Luo X, Zhong W. Design, synthesis and biological evaluation of novel benzothiazole derivatives as selective PI3Kbeta inhibitors. Molecules. 2016;21(7):876. doi: 10.3390/molecules21070876.CrossRefGoogle Scholar
  236. 236.
    Wong MH, Xue A, Baxter RC, Pavlakis N, Smith RC. Upstream and downstream co-inhibition of mitogen-activated protein kinase and PI3K/Akt/mTOR pathways in pancreatic ductal adenocarcinoma. Neoplasia. 2016;18(7):425–35. doi: 10.1016/j.neo.2016.06.001.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Peloton Therapeutics, Inc. A Phase 1, dose-escalation trial of PT2385 tablets in patients with advanced clear cell renal cell Carcinoma; 2014. Accessed 11 May 2016.
  238. 238.
    Cervantes-Madrid D, Romero Y, Duenas-Gonzalez A. Reviving lonidamine and 6-Diazo-5-oxo-L-norleucine to be used in combination for metabolic cancer therapy. Biomed Res Int. 2015;2015:690492. doi: 10.1155/2015/690492.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene. 2006;25(34):4633–46. doi: 10.1038/sj.onc.1209597.PubMedCrossRefGoogle Scholar
  240. 240.
    Yang C, Matro JC, Huntoon KM, Ye DY, Huynh TT, Fliedner SM, Breza J, Zhuang Z, Pacak K. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J. 2012;26(11):4506–16. doi: 10.1096/fj.12-210146.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23(6):739–52. doi: 10.1016/j.ccr.2013.04.018.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Section on Medical NeuroendocrinologyEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthBethesdaUSA
  2. 2.1st Department of Internal MedicineMedical Faculty of P.J. Šafárik University in KošiceKošiceSlovakia

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