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The Adrenal Medulla and Extra-adrenal Paraganglia: Then and Now

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Abstract

The past 25 years have witnessed revolutionary changes in the care of patients with pheochromocytomas and extra-adrenal paragangliomas. Germline mutations of at least 13 genes are now associated with tumor development, a greater degree of hereditary susceptibility than for any other human neoplasm. Somatic mutations, either of the same genes or of several additional ones with closely related functions, are also increasingly recognized. Clinicians are now aware of the genetic implications of a pheochromocytoma or paraganglioma. All patients are therefore offered genetic testing and receive lifelong surveillance. Almost all of the mutated genes have well-described correlations with clinical and biochemical phenotypes. Tumors arising in patients with mutations of the SDHB gene have at least a 30 % chance of metastasizing and typically produce norepinephrine and/or dopamine. Assay of plasma-free metanephrines serves as a highly sensitive and specific biochemical screen for the presence of catecholamine-producing tumors, and the dopamine metabolite methoxytyramine serves as a useful marker for detecting minimally functional tumors or their metastases. New functional imaging techniques provide highly sensitive tumor localization. In addition to differential diagnosis, pathologists play new roles in helping to identify hereditary disease and guiding the sequence of genetic testing.

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References

  1. Gimenez-Roqueplo AP, Dahia PL, Robledo M: An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res 44:328–33, 2012

    Article  PubMed  CAS  Google Scholar 

  2. Baysal BE, Ferrell RE, Willett-Brozick JE, et al.: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–51, 2000

    Article  PubMed  CAS  Google Scholar 

  3. Niemann S, Muller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26:268–70, 2000

    Article  PubMed  CAS  Google Scholar 

  4. Astuti D, Latif F, Dallol A, et al.: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54, 2001

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Boedeker CC, Hensen EF, Neumann HP, et al.: Genetics of hereditary head and neck paragangliomas. Head Neck 2013

  7. Pasini B, Stratakis CA: SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med 266:19–42, 2009

    Article  PubMed  CAS  Google Scholar 

  8. Malinoc A, Sullivan M, Wiech T, et al.: Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3. Endocr Relat Cancer 19:283–90, 2012

    Article  PubMed  CAS  Google Scholar 

  9. Xekouki P, Stratakis CA: Succinate dehydrogenase (SDHx) mutations in pituitary tumors: could this be a new role for mitochondrial complex II and/or Krebs cycle defects? Endocr Relat Cancer 19:C33–40, 2012

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Beckers A: Means, motive, and opportunity: SDH mutations are suspects in pituitary tumors. J Clin Endocrinol Metab 98:2274–6, 2013

    Article  PubMed  CAS  Google Scholar 

  11. Eisenhofer G, Tischler AS, de Krijger RR: Diagnostic tests and biomarkers for pheochromocytoma and extra-adrenal paraganglioma: from routine laboratory methods to disease stratification. Endocr Pathol 23:4–14, 2012

    Article  PubMed  CAS  Google Scholar 

  12. Jimenez C, Rohren E, Habra MA, et al.: Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep 15:356–71, 2013

    Article  PubMed  Google Scholar 

  13. Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, et al.: Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol 24:2382–91, 2010

    Article  PubMed  CAS  Google Scholar 

  14. Shankavaram U, Fliedner SM, Elkahloun AG, et al.: Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas. Neoplasia 15:435–47, 2013

    PubMed Central  PubMed  CAS  Google Scholar 

  15. Dahia PL: The genetic landscape of pheochromocytomas and paragangliomas: somatic mutations take center stage. J Clin Endocrinol Metab 98:2679–81, 2013

    Article  PubMed  CAS  Google Scholar 

  16. Burnichon N, Buffet A, Parfait B, et al.: Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum Mol Genet 21:5397–405, 2012

    Article  PubMed  CAS  Google Scholar 

  17. Toledo RA, Qin Y, Srikantan S, et al.: In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr Relat Cancer 20:349–59, 2013

    Article  PubMed  CAS  Google Scholar 

  18. Pacak K, Jochmanova I, Prodanov T, et al.: New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol 31:1690–8, 2013

    Article  PubMed  Google Scholar 

  19. Crona J, Delgado Verdugo A, Maharjan R, et al.: Somatic Mutations in H-RAS in Sporadic Pheochromocytoma and Paraganglioma Identified by Exome Sequencing. J Clin Endocrinol Metab 2013

  20. Eisenhofer G, Goldstein DS, Kopin IJ, Crout JR: Pheochromocytoma: rediscovery as a catecholamine-metabolizing tumor. Endocr Pathol 14:193–212, 2003

    Article  PubMed  CAS  Google Scholar 

  21. Manger WM: The protean manifestations of pheochromocytoma. Horm Metab Res 41:658–63, 2009

    Article  PubMed  CAS  Google Scholar 

  22. Timmers HJ, Pacak K, Huynh TT, et al.: Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. J Clin Endocrinol Metab 93:4826–32, 2008

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Balogova S, Talbot JN, Nataf V, et al.: 18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type. Eur J Nucl Med Mol Imaging 40:943–66, 2013

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Hartung-Knemeyer V, Rosenbaum-Krumme S, Buchbender C, et al.: Malignant pheochromocytoma imaging with [124I]mIBG PET/MR. J Clin Endocrinol Metab 97:3833–4, 2012

    Article  PubMed  CAS  Google Scholar 

  25. Kabasakal L, Demirci E, Ocak M, et al.: Comparison of (6)(8)Ga-DOTATATE and (6)(8)Ga-DOTANOC PET/CT imaging in the same patient group with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 39:1271–7, 2012

    Article  PubMed  Google Scholar 

  26. Taieb D, Neumann H, Rubello D, Al-Nahhas A, Guillet B, Hindie E: Modern nuclear imaging for paragangliomas: beyond SPECT. J Nucl Med 53:264–74, 2012

    Article  PubMed  CAS  Google Scholar 

  27. Timmers HJ, Taieb D, Pacak K: Current and future anatomical and functional imaging approaches to pheochromocytoma and paraganglioma. Horm Metab Res 44:367–72, 2012

    Article  PubMed  CAS  Google Scholar 

  28. Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89:479–91, 2004

    Article  PubMed  CAS  Google Scholar 

  29. Taieb D, Timmers HJ, Hindie E, et al.: EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 39:1977–95, 2012

    Article  PubMed  CAS  Google Scholar 

  30. Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, et al.: Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators. J Clin Endocrinol Metab 98:E162-73, 2013

    Article  PubMed  CAS  Google Scholar 

  31. Sharma P, Thakar A, Suman KCS, et al.: 68Ga-DOTANOC PET/CT for baseline evaluation of patients with head and neck paraganglioma. J Nucl Med 54:841–7, 2013

    Article  PubMed  CAS  Google Scholar 

  32. Mayerhoefer ME, Ba-Ssalamah A, Weber M, et al.: Gadoxetate-enhanced versus diffusion-weighted MRI for fused Ga-68-DOTANOC PET/MRI in patients with neuroendocrine tumours of the upper abdomen. Eur Radiol 23:1978–85, 2013

    Article  PubMed  Google Scholar 

  33. Waguespack SG, Rich T, Grubbs E, et al.: A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 95:2023–37, 2010

    Article  PubMed  CAS  Google Scholar 

  34. Sovinz P, Urban C, Uhrig S, et al.: Pheochromocytoma in a 2.75-year-old-girl with a germline von Hippel–Lindau mutation Q164R. Am J Med Genet A 152A:1752–5, 2010

    Article  PubMed  CAS  Google Scholar 

  35. 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 184:1855–9, 2010

    Article  PubMed Central  PubMed  Google Scholar 

  36. Manny TB, Pompeo AS, Hemal AK: Robotic partial adrenalectomy using indocyanine green dye with near-infrared imaging: the initial clinical experience. Urology 82:738–42, 2013

    Article  PubMed  Google Scholar 

  37. Ayala-Ramirez M, Chougnet CN, Habra MA, et al.: Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab 97:4040–50, 2012

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Chae YC, Angelin A, Lisanti S, et al.: Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 4:2139, 2013

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Nolting S, Garcia E, Alusi G, et al.: Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. J Mol Endocrinol 49:79–96, 2012

    Article  PubMed  CAS  Google Scholar 

  40. Welander J, Garvin S, Bohnmark R, et al.: Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma. J Clin Endocrinol Metab 98:E1379–80, 2013

    Article  PubMed  CAS  Google Scholar 

  41. Tischler AS: Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med 132:1272–84, 2008

    PubMed  Google Scholar 

  42. DeLellis RA, Lloyd RV, Heitz PU, Eng C: Tumours of Endocrine Organs. In World Health Organization Classification of Tumors. IARC Press, Lyon, 2004

  43. 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 21:1168–80, 1990

    Article  PubMed  CAS  Google Scholar 

  44. Thompson LD: Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26:551–66, 2002

    Article  PubMed  Google Scholar 

  45. Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y: Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 16:23–32, 2005

    Article  PubMed  Google Scholar 

  46. Strong VE, Kennedy T, Al-Ahmadie H, et al.: Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis. Surgery 143:759–68, 2008

    Article  PubMed  Google Scholar 

  47. Wu D, Tischler AS, Lloyd RV, et al.: Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol 33:599–608, 2009

    Article  PubMed  Google Scholar 

  48. Dahia PL, Ross KN, Wright ME, et al.: A HIF1alpha Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas. PLoS Genet 1:e8, 2005

    Article  PubMed Central  CAS  Google Scholar 

  49. van Nederveen FH, Gaal J, Favier J, et al.: An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 10:764–71, 2009

    Article  PubMed  CAS  Google Scholar 

  50. Korpershoek E, Favier J, Gaal J, et al.: SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 96:E1472–6, 2011

    Article  PubMed  CAS  Google Scholar 

  51. Gill AJ: Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology 44:285–92, 2012

    Article  PubMed  CAS  Google Scholar 

  52. Erlic Z, Neumann HP: Diagnosing patients with hereditary paraganglial tumours. Lancet Oncol 10:741, 2009

    Article  PubMed  Google Scholar 

  53. Dahia PL, Ross KN, Wright ME, et al.: A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1:72–80, 2005

    Article  PubMed  CAS  Google Scholar 

  54. Dahia PL: Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas. Ann N Y Acad Sci 1073:208–20, 2006

    Article  PubMed  CAS  Google Scholar 

  55. Mete O, Tischler AS, R dK, et al.: Protocol for the Examination of Specimens from Patients with Pheochromocytomas and Extra-adrenal Paragangliomas. Arch Pathol Lab Med 2013

  56. Tudorancea A, Francois P, Trouillas J, et al.: Von Hippel–Lindau disease and aggressive GH-PRL pituitary adenoma in a young boy. Ann Endocrinol (Paris) 73:37–42, 2012

    Article  Google Scholar 

  57. Kurozumi K, Tabuchi A, Ono Y, et al.: [Pituitary adenoma associated with neurofibromatosis type 1: case report]. No Shinkei Geka 30:741–5, 2002

    PubMed  Google Scholar 

  58. Dwight T, Mann K, Benn DE, et al.: Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab 98:E1103-8, 2013

    Article  PubMed  CAS  Google Scholar 

  59. Stratakis CA, Carney JA: The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 266:43–52, 2009

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Bayley JP, Kunst HP, Cascon A, et al.: SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 11:366–72, 2010

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Qin Y, Yao L, King EE, et al.: Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 42:229–33, 2010

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Burnichon N, Cascon A, Schiavi F, et al.: MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 18:2828–37, 2012

    Article  PubMed  CAS  Google Scholar 

  64. Astuti D, Ricketts CJ, Chowdhury R, et al.: Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. Endocr Relat Cancer 18:73–83, 2011

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Lorenzo FR, Yang C, Ng Tang Fui M, et al.: A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl) 91:507–12, 2013

    Article  CAS  Google Scholar 

  66. Zhuang Z, Yang C, Lorenzo F, et al.: Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 367:922–30, 2012

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Schlisio S, Kenchappa RS, Vredeveld LC, et al.: The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev 22:884–93, 2008

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Maher ER: HIF2 and endocrine neoplasia: an evolving story. Endocr Relat Cancer 20:C5–7, 2013

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA

    Arthur S. Tischler

  2. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, MSC-1583, Bethesda, MD, 20892-1583, USA

    Karel Pacak

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

    Graeme Eisenhofer

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  1. Arthur S. Tischler
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  2. Karel Pacak
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Correspondence to Arthur S. Tischler.

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Tischler, A.S., Pacak, K. & Eisenhofer, G. The Adrenal Medulla and Extra-adrenal Paraganglia: Then and Now. Endocr Pathol 25, 49–58 (2014). https://doi.org/10.1007/s12022-013-9286-3

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