Table Info

Table 1.

Regulation of synthesis and secretion of adrenal medullary hormones

Feature	Adrenal medulla	Sympathetic ganglia
Primary hormones produced	Epinephrine and norepinephrine	Norepinephrine
Enzymes involved	TH	TH
	DDC	DDC
	DBH	DBH
	PNMT	PNMT is not significantly expressed
Key regulatory genes	TH gene	TH gene
	DDC gene	DDC gene
	DBH gene	DBH gene
	PNMT gene	Not significant
Regulatory mechanisms	Negative feedback by catecholamines	Negative feedback by catecholamines
	Neural control	Neural control
	Hormonal control (e.g., glucocorticoids)	Hormonal influence might be less pronounced

Declarations

Author contributions

MSJ and NM: Resources, Writing—original draft, Writing—review & editing. CFJ and JMP: Conceptualization, Supervision, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol. 2022;33:90–114. [DOI] [PubMed]

Lenders JWM, Kerstens MN, Amar L, Prejbisz A, Robledo M, Taieb D, et al. Genetics, diagnosis, management, and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens. 2020;38:1443–56. [DOI] [PubMed] [PMC]

Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, et al. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev. 2022;43:199–239. Erratum in: Endocr Rev. 2022;43:440. Erratum in: Endocr Rev. 2022;43:437–9. [DOI] [PubMed] [PMC]

Richter S, Garrett TJ, Bechmann N, Clifton-Bligh RJ, Ghayee HK. Metabolomics in paraganglioma: applications and perspectives from genetics to therapy. Endocr Relat Cancer. 2023;30:e220376. [DOI] [PubMed] [PMC]

Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–9. [DOI] [PubMed]

Dwight T, Kim E, Novos T, Clifton-Bligh RJ. Metabolomics in the diagnosis of pheochromocytoma and paraganglioma. Horm Metab Res. 2019;51:443–50. [DOI] [PubMed]

Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013;123:3652–8. [DOI] [PubMed] [PMC]

Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483:479–83. [DOI] [PubMed] [PMC]

Lopez AG, Fraissinet F, Lefebvre H, Brunel V, Ziegler F. Pharmacological and analytical interference in hormone assays for diagnosis of adrenal incidentaloma. Ann Endocrinol (Paris). 2019;80:250–8. [DOI] [PubMed]

10.

Jochmanova I, Pacak K. Pheochromocytoma: the first metabolic endocrine cancer. Clin Cancer Res. 2016;22:5001–11. [DOI] [PubMed] [PMC]

11.

Richter S, Gieldon L, Pang Y, Peitzsch M, Huynh T, Leton R, et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019;21:705–17. [DOI] [PubMed] [PMC]

12.

Berends AMA, Eisenhofer G, Fishbein L, Horst-Schrivers ANAVD, Kema IP, Links TP, et al. Intricacies of the molecular machinery of catecholamine biosynthesis and secretion by chromaffin cells of the normal adrenal medulla and in pheochromocytoma and paraganglioma. Cancers (Basel). 2019;11:1121. [DOI] [PubMed] [PMC]

13.

Koopmans KP, Neels ON, Kema IP, Elsinga PH, Links TP, de Vries EG, et al. Molecular imaging in neuroendocrine tumors: molecular uptake mechanisms and clinical results. Crit Rev Oncol Hematol. 2009;71:199–213. [DOI] [PubMed]

14.

Wolf ME, LeWitt PA, Bannon MJ, Dragovic LJ, Kapatos G. Effect of aging on tyrosine hydroxylase protein content and the relative number of dopamine nerve terminals in human caudate. J Neurochem. 1991;56:1191–200. [DOI] [PubMed]

15.

Eisenhofer G, Rundquist B, Aneman A, Friberg P, Dakak N, Kopin IJ, et al. Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines. J Clin Endocrinol Metab. 1995;80:3009–17. [DOI] [PubMed]

16.

Rao F, Zhang K, Zhang L, Rana BK, Wessel J, Fung MM, et al. Human tyrosine hydroxylase natural allelic variation: influence on autonomic function and hypertension. Cell Mol Neurobiol. 2010;30:1391–4. [DOI] [PubMed] [PMC]

17.

Lehnert H. Regulation of catecholamine synthesizing enzyme gene expression in human pheochromocytoma. Eur J Endocrinol. 1998;138:363–7. [DOI] [PubMed]

18.

Daubner SC, Le T, Wang S. Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys. 2011;508:1–12. [DOI] [PubMed] [PMC]

19.

Kennedy B, Bigby TD, Ziegler MG. Nonadrenal epinephrine-forming enzymes in humans. Characteristics, distribution, regulation, and relationship to epinephrine levels. J Clin Invest. 1995;95:2896–902. [DOI] [PubMed] [PMC]

20.

Winkler H, Apps DK, Fischer-Colbrie R. The molecular function of adrenal chromaffin granules: established facts and unresolved topics. Neuroscience. 1986;18:261–90. [DOI] [PubMed]

21.

Wong DL. Why is the adrenal adrenergic? Endocr Pathol. 2003;14:25–36. [DOI] [PubMed]

22.

Kimura N, Togo A, Sugimoto T, Nata K, Okamoto H, Nagatsu I, et al. Deficiency of phenylethanolamine N-methyltransferase in norepinephrine-producing pheochromocytoma. Endocr Pathol. 1996;7:131–6. [DOI] [PubMed]

23.

Lee SE, Oh E, Lee B, Kim YJ, Oh DY, Jung K, et al. Phenylethanolamine N-methyltransferase downregulation is associated with malignant pheochromocytoma/paraganglioma. Oncotarget. 2016;7:24141–53. [DOI] [PubMed] [PMC]

24.

Gruber LM, Jasim S, Ducharme-Smith A, Weingarten T, Young WF, Bancos I. The role for metyrosine in the treatment of patients with pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2021;106:e2393–401. [DOI] [PubMed] [PMC]

25.

Naruse M, Satoh F, Tanabe A, Okamoto T, Ichihara A, Tsuiki M, et al. Efficacy and safety of metyrosine in pheochromocytoma/paraganglioma: a multi-center trial in Japan. Endocr J. 2018;65:359–71. [DOI] [PubMed]

26.

Wachtel H, Kennedy EH, Zaheer S, Bartlett EK, Fishbein L, Roses RE, et al. Preoperative metyrosine improves cardiovascular outcomes for patients undergoing surgery for pheochromocytoma and paraganglioma. Ann Surg Oncol. 2015;22:S646–54. [DOI] [PubMed]

27.

Garg MK, Kharb S, Brar KS, Gundgurthi A, Mittal R. Medical management of pheochromocytoma: role of the endocrinologist. Indian J Endocrinol Metab. 2011;15:S329–36. [DOI] [PubMed] [PMC]

28.

Estevez-Herrera J, Pardo MR, Dominguez N, Pereda D, Machado JD, Borges R. The role of chromogranins in the secretory pathway. Biomol Concepts. 2013;4:605–9. [DOI] [PubMed]

29.

Zudaire E, Martínez A, Cuttitta F. Adrenomedullin and cancer. Regul Pept. 2003;112:175–83. [DOI] [PubMed]

30.

Shimosawa T, Fujita T. Adrenomedullin and its related peptide. Endocr J. 2005;52:1–10. [DOI] [PubMed]

31.

Hu W, Shi L, Zhou PH, Zhang XB. Plasma concentrations of adrenomedullin and atrial and brain natriuretic peptides in patients with adrenal pheochromocytoma. Oncol Lett. 2015;10:3163–70. [DOI] [PubMed] [PMC]

32.

Smith CB, Eiden LE. Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J Mol Neurosci. 2012;48:403–12. [DOI] [PubMed] [PMC]

33.

Crivellato E, Nico B, Ribatti D. The chromaffin vesicle: advances in understanding the composition of a versatile, multifunctional secretory organelle. Anat Rec (Hoboken). 2008;291:1587–602. [DOI] [PubMed]

34.

Jiang J, Zhang J, Pang Y, Bechmann N, Li M, Monteagudo M, et al. Sino-European differences in the genetic landscape and clinical presentation of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2020;105:dgaa502. [DOI] [PubMed]

35.

Lymperopoulos A, Brill A, McCrink KA. GPCRs of adrenal chromaffin cells & catecholamines: the plot thickens. Int J Biochem Cell Biol. 2016;77:213–9. [DOI] [PubMed]

36.

Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58:802–4. [PubMed]

37.

Wang K, Crona J, Beuschlein F, Grossman AB, Pacak K, Nölting S. Targeted therapies in pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2022;107:2963–72. [DOI] [PubMed] [PMC]

38.

Gimenez-Roqueplo AP, Robledo M, Dahia PLM. Update on the genetics of paragangliomas. Endocr Relat Cancer. 2023;30:e220373. [DOI] [PubMed] [PMC]

39.

Gieldon L, William D, Hackmann K, Jahn W, Jahn A, Wagner J, et al. Optimizing genetic workup in pheochromocytoma and paraganglioma by integrating diagnostic and research approaches. Cancers (Basel). 2019;11:809. [DOI] [PubMed] [PMC]

40.

Luchetti A, Walsh D, Rodger F, Clark G, Martin T, Irving R, et al. Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis. Int J Endocrinol. 2015;2015:138573. [DOI] [PubMed] [PMC]

41.

van den Berg MF, Kooistra HS, Grinwis GCM, Nicoli S, Golinelli S, Stammeleer L, et al. Whole transcriptome analysis of canine pheochromocytoma and paraganglioma. Front Vet Sci. 2023;10:1155804. [DOI] [PubMed] [PMC]

42.

Lima JV Júnior, Kater CE. The pheochromocytoma/paraganglioma syndrome: an overview on mechanisms, diagnosis and management. Int Braz J Urol. 2023;49:307–19. [DOI] [PubMed] [PMC]

43.

Kantorovich V, Pacak K. New insights on the pathogenesis of paraganglioma and pheochromocytoma. F1000Res. 2018;7:1500. [DOI] [PubMed] [PMC]

44.

Eisenhofer G, Klink B, Richter S, Lenders JW, Robledo M. Metabologenomics of phaeochromocytoma and paraganglioma: an integrated approach for personalised biochemical and genetic testing. Clin Biochem Rev. 2017;38:69–100. [PubMed] [PMC]

45.

Sarkadi B, Saskoi E, Butz H, Patocs A. Genetics of pheochromocytomas and paragangliomas determine the therapeutical approach. Int J Mol Sci. 2022;23:1450. [DOI] [PubMed] [PMC]

46.

Watts D, Jaykar MT, Bechmann N, Wielockx B. Hypoxia signaling pathway: a central mediator in endocrine tumors. Front Endocrinol (Lausanne). 2023;13:1103075. [DOI] [PubMed] [PMC]

47.

Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, et al.; Cancer Genome Atlas Research Network, Pacak K, Nathanson KL, Wilkerson MD. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31:181–93. [DOI] [PubMed] [PMC]

48.

Iverson TM, Singh PK, Cecchini G. An evolving view of complex II-noncanonical complexes, megacomplexes, respiration, signaling, and beyond. J Biol Chem. 2023;299:104761. [DOI] [PubMed] [PMC]

49.

MacFarlane J, Seong KC, Bisambar C, Madhu B, Allinson K, Marker A, et al. A review of the tumour spectrum of germline succinate dehydrogenase gene mutations: beyond phaeochromocytoma and paraganglioma. Clin Endocrinol (Oxf). 2020;93:528–38. [DOI] [PubMed]

50.

Casey R, Neumann HPH, Maher ER. Genetic stratification of inherited and sporadic phaeochromocytoma and paraganglioma: implications for precision medicine. Hum Mol Genet. 2020;29:R128–37. [DOI] [PubMed] [PMC]

51.

Crona J, Delgado Verdugo A, Maharjan R, Stålberg P, Granberg D, Hellman P, et al. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. J Clin Endocrinol Metab. 2013;98:E1266–71. [DOI] [PubMed]

52.

Alrezk R, Suarez A, Tena I, Pacak K. Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging. Front Endocrinol (Lausanne). 2018;9:515. [DOI] [PubMed] [PMC]

53.

Zografos GN, Vasiliadis GK, Zagouri F, Aggeli C, Korkolis D, Vogiaki S, et al. Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends. World J Surg Oncol. 2010;8:14. [DOI] [PubMed] [PMC]

54.

Taïeb D, Wanna GB, Ahmad M, Lussey-Lepoutre C, Perrier ND, Nölting S, et al. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023;11:345–61. [DOI] [PubMed] [PMC]

55.

Khatami F, Mohammadamoli M, Tavangar SM. Genetic and epigenetic differences of benign and malignant pheochromocytomas and paragangliomas (PPGLs). Endocr Regul. 2018;52:41–54. [DOI] [PubMed]

56.

Kumar S, Lila AR, Memon SS, Sarathi V, Patil VA, Menon S, et al. Metastatic cluster 2-related pheochromocytoma/paraganglioma: a single-center experience and systematic review. Endocr Connect. 2021;10:1463–76. [DOI] [PubMed] [PMC]

57.

Fliedner SMJ, Brabant G, Lehnert H. Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype. Cell Tissue Res. 2018;372:347–65. [DOI] [PubMed]

58.

Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and paraganglioma. N Engl J Med. 2019;381:552–65. [DOI] [PubMed]

59.

Li M, Prodanov T, Meuter L, Kerstens MN, Bechmann N, Prejbisz A, et al. Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2023;108:397–404. [DOI] [PubMed] [PMC]

60.

Boedeker CC, Neumann HP, Maier W, Bausch B, Schipper J, Ridder GJ. Malignant head and neck paragangliomas in SDHB mutation carriers. Otolaryngol Head Neck Surg. 2007;137:126–9. [DOI] [PubMed]

61.

Peng S, Zhang J, Tan X, Huang Y, Xu J, Silk N, et al. The VHL/HIF axis in the development and treatment of pheochromocytoma/paraganglioma. Front Endocrinol (Lausanne). 2020;11:586857. [DOI] [PubMed] [PMC]

62.

Welander J, Söderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011;18:R253–76. [DOI] [PubMed]

63.

Neumann HP, Young WF Jr, Krauss T, Bayley JP, Schiavi F, Opocher G, et al. 65 years of the double helix: Genetics informs precision practice in the diagnosis and management of pheochromocytoma. Endocr Relat Cancer. 2018;25:T201–19. [DOI] [PubMed]

64.

Liu Y, Liu L, Zhu F. Therapies targeting the signal pathways of pheochromocytoma and paraganglioma. Onco Targets Ther. 2019;12:7227–41. [DOI] [PubMed] [PMC]

65.

Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al.; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–42. Erratum in: J Clin Endocrinol Metab. 2023;108:e200. [DOI] [PubMed]

66.

Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23:2440–6. [DOI] [PubMed]

67.

Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–7. [DOI] [PubMed]

68.

Kimura N, Takekoshi K, Naruse M. Risk stratification on pheochromocytoma and paraganglioma from laboratory and clinical medicine. J Clin Med. 2018;7:242. [DOI] [PubMed] [PMC]

69.

Buffet A, Morin A, Castro-Vega LJ, Habarou F, Lussey-Lepoutre C, Letouzé E, et al. Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas. Cancer Res. 2018;78:1914–22. [DOI] [PubMed]

70.

Liu T, Brown TC, Juhlin CC, Andreasson A, Wang N, Bäckdahl M, et al. The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors. Endocr Relat Cancer. 2014;21:427–34. [DOI] [PubMed] [PMC]

71.

Dwight T, Flynn A, Amarasinghe K, Benn DE, Lupat R, Li J, et al. TERT structural rearrangements in metastatic pheochromocytomas. Endocr Relat Cancer. 2018;25:1–9. [DOI] [PubMed]

72.

Cascón A, Calsina B, Monteagudo M, Mellid S, Díaz-Talavera A, Currás-Freixes M, et al. Genetic bases of pheochromocytoma and paraganglioma. J Mol Endocrinol. 2023;70:e220167. [DOI] [PubMed]

73.

Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D’Andrea K, Merrill S, et al. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6140. [DOI] [PubMed] [PMC]

74.

Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, et al. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes Chromosomes Cancer. 2015;54:542–54. [DOI] [PubMed] [PMC]

75.

Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11:101–11. [DOI] [PubMed]

76.

Ryder SJ, Love AJ, Duncan EL, Pattison DA. PET detectives: molecular imaging for phaeochromocytomas and paragangliomas in the genomics era. Clin Endocrinol (Oxf). 2021;95:13–28. [DOI] [PubMed]

77.

Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, et al. European association of nuclear medicine practice guideline/society of nuclear medicine and molecular imaging procedure standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2019;46:2112–37. [DOI] [PubMed] [PMC]

78.

Jha A, Ling A, Millo C, Gupta G, Viana B, Lin FI, et al. Superiority of ⁶⁸Ga-DOTATATE over ¹⁸F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx)-related pheochromocytoma and paraganglioma in the pediatric population. Eur J Nucl Med Mol Imaging. 2018;45:787–97. [DOI] [PubMed] [PMC]

79.

Janssen I, Chen CC, Taieb D, Patronas NJ, Millo CM, Adams KT, 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;57:186–91. [DOI] [PubMed] [PMC]

80.

Taïeb D, Pacak K. New insights into the nuclear imaging phenotypes of cluster 1 pheochromocytoma and paraganglioma. Trends Endocrinol Metab. 2017;28:807–17. [DOI] [PubMed] [PMC]

81.

Därr R, Nambuba J, Del Rivero J, Janssen I, Merino M, Todorovic M, et al. Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome. Endocr Relat Cancer. 2016;23:899–908. [DOI] [PubMed] [PMC]

82.

Janssen I, Chen CC, Zhuang Z, Millo CM, Wolf KI, Ling A, et al. Functional imaging signature of patients presenting with polycythemia/paraganglioma syndromes. J Nucl Med. 2017;58:1236–42. [DOI] [PubMed] [PMC]

83.

Taïeb D, Timmers HJ, Hindié E, Guillet BA, Neumann HP, Walz MK, et al.; European Association of Nuclear Medicine. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2012;39:1977–95. [DOI] [PubMed] [PMC]

84.

Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas. 2021;50:469–93. [DOI] [PubMed]

85.

Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, Hignette C, Hernigou A, Halimi P, 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. 2013;98:E162–73. [DOI] [PubMed]

86.

Kaji P, Carrasquillo JA, Linehan WM, Chen CC, Eisenhofer G, Pinto PA, et al. The role of 6-[¹⁸F]fluorodopamine positron emission tomography in the localization of adrenal pheochromocytoma associated with von Hippel–Lindau syndrome. Eur J Endocrinol. 2007;156:483–7. [DOI] [PubMed]

87.

Kroiss AS, Uprimny C, Shulkin BL, Frech A, Tilg H, Gasser RW, et al. Compared to ¹²³I-MIBG SPECT/CT, ¹⁸F-DOPA PET/CT provides accurate tumor extent in patients with extra-adrenal paraganglioma. Ann Nucl Med. 2017;31:357–65. [DOI] [PubMed]

88.

Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, et al.; ESMO Guidelines Committee. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:1476–90. Erratum in: Ann Oncol. 2023;34:631. [DOI] [PubMed]

89.

Eid M, Foukal J, Sochorová D, Tuček Š, Starý K, Kala Z, et al. Management of pheochromocytomas and paragangliomas: review of current diagnosis and treatment options. Cancer Med. 2023;12:13942–57. [DOI] [PubMed] [PMC]

90.

Buitenwerf E, Osinga TE, Timmers HJLM, Lenders JWM, Feelders RA, Eekhoff EMW, et al. Efficacy of α-blockers on hemodynamic control during pheochromocytoma resection: a randomized controlled trial. J Clin Endocrinol Metab. 2020;105:2381–91. [DOI] [PubMed] [PMC]

91.

Livingstone M, Duttchen K, Thompson J, Sunderani Z, Hawboldt G, Sarah Rose M, et al. Hemodynamic stability during pheochromocytoma resection: lessons learned over the last two decades. Ann Surg Oncol. 2015;22:4175–80. [DOI] [PubMed]

92.

Kinney MA, Narr BJ, Warner MA. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth. 2002;16:359–69. [DOI] [PubMed]

93.

Lo CY, Lam KY, Wat MS, Lam KS. Adrenal pheochromocytoma remains a frequently overlooked diagnosis. Am J Surg. 2000;179:212–5. [DOI] [PubMed]

94.

van der Zee PA, de Boer A. Pheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin. Neth J Med. 2014;72:190–201. [PubMed]

95.

Shah MH, Goldner WS, Benson AB, Bergsland E, Blaszkowsky LS, Brock P, et al. Neuroendocrine and adrenal tumors, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19:839–68. [DOI] [PubMed]

96.

Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92:4069–79. [DOI] [PubMed]

97.

Tian J, Bao Z, Yuan Y, Fang D, Zhan Y, Wang T, et al. The duration of preoperative administration of single α-receptor blocker phenoxybenzamine before adrenalectomy for pheochromocytoma: 18 years of clinical experience from nationwide high-volume center. Biomed Res Int. 2019;2019:2613137. [DOI] [PubMed] [PMC]

98.

Bai S, Yao Z, Zhu X, Li Z, Jiang Y, Wang R, et al. Comparison of transperitoneal laparoscopic versus open adrenalectomy for large pheochromocytoma: a retrospective propensity score-matched cohort study. Int J Surg. 2019;61:26–32. [DOI] [PubMed]

99.

Fu SQ, Wang SY, Chen Q, Liu YT, Li ZL, Sun T. Laparoscopic versus open surgery for pheochromocytoma: a meta-analysis. BMC Surg. 2020;20:167. [DOI] [PubMed] [PMC]

100.

Rossitti HM, Söderkvist P, Gimm O. Extent of surgery for phaeochromocytomas in the genomic era. Br J Surg. 2018;105:e84–98. [DOI] [PubMed]

101.

Jackson RS, Myhill JA, Padhya TA, McCaffrey JC, McCaffrey TV, Mhaskar RS. The effects of preoperative embolization on carotid body paraganglioma surgery: a systematic review and meta-analysis. Otolaryngol Head Neck Surg. 2015;153:943–50. [DOI] [PubMed]

102.

Lin EP, Chin BB, Fishbein L, Moritani T, Montoya SP, Ellika S, et al. Head and neck paragangliomas: an update on the molecular classification, state-of-the-art imaging, and management recommendations. Radiol Imaging Cancer. 2022;4:e210088. [DOI] [PubMed] [PMC]

103.

Nölting S, Ullrich M, Pietzsch J, Ziegler CG, Eisenhofer G, Grossman A, et al. Current management of pheochromocytoma/paraganglioma: a guide for the practicing clinician in the era of precision medicine. Cancers (Basel). 2019;11:1505. [DOI] [PubMed] [PMC]

104.

Ellis RJ, Patel D, Prodanov T, Sadowski S, Nilubol N, Adams K, et al. Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted? J Am Coll Surg. 2013;217:489–96. [DOI] [PubMed] [PMC]

105.

Roman-Gonzalez A, Zhou S, Ayala-Ramirez M, Shen C, Waguespack SG, Habra MA, et al. Impact of surgical resection of the primary tumor on overall survival in patients with metastatic pheochromocytoma or sympathetic paraganglioma. Ann Surg. 2018;268:172–8. [DOI] [PubMed]

106.

Strajina V, Dy BM, Farley DR, Richards ML, McKenzie TJ, Bible KC, et al. Surgical treatment of malignant pheochromocytoma and paraganglioma: retrospective case series. Ann Surg Oncol. 2017;24:1546–50. [DOI] [PubMed]

107.

Hamidi O, Young WF Jr, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, et al. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab. 2017;102:3296–305. [DOI] [PubMed] [PMC]

108.

Ayala-Ramirez M, Feng L, Habra MA, Rich T, Dickson PV, Perrier N, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer. 2012;118:2804–12. [DOI] [PubMed] [PMC]

109.

Nockel P, El Lakis M, Gaitanidis A, Yang L, Merkel R, Patel D, et al. Preoperative genetic testing in pheochromocytomas and paragangliomas influences the surgical approach and the extent of adrenal surgery. Surgery. 2018;163:191–6. [DOI] [PubMed] [PMC]

110.

Taïeb D, Kaliski A, Boedeker CC, Martucci V, Fojo T, Adler JR Jr, et al. Current approaches and recent developments in the management of head and neck paragangliomas. Endocr Rev. 2014;35:795–819. [DOI] [PubMed] [PMC]

111.

Capatina C, Ntali G, Karavitaki N, Grossman AB. The management of head-and-neck paragangliomas. Endocr Relat Cancer. 2013;20:R291–305. [DOI] [PubMed]

112.

Moore MG, Netterville JL, Mendenhall WM, Isaacson B, Nussenbaum B. Head and neck paragangliomas: an update on evaluation and management. Otolaryngol Head Neck Surg. 2016;154:597–605. [DOI] [PubMed]

113.

Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, et al. SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery. 2017;161:230–9. [DOI] [PubMed] [PMC]

114.

Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, 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;48:1739–49. [DOI] [PubMed] [PMC]

115.

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;90:2110–6. [DOI] [PubMed]

116.

King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, et al. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011;29:4137–42. [DOI] [PubMed] [PMC]

117.

Grossman A, Pacak K, Sawka A, Lenders JW, Harlander D, Peaston RT, et al. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci. 2006;1073:332–47. [DOI] [PubMed]

118.

Korevaar TI, Grossman AB. Pheochromocytomas and paragangliomas: assessment of malignant potential. Endocrine. 2011;40:354–65. [DOI] [PubMed]

119.

Castinetti F, Qi XP, Walz MK, Maia AL, Sansó G, Peczkowska M, et al. Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol. 2014;15:648–55. [DOI] [PubMed]

120.

Neumann HPH, Tsoy U, Bancos I, Amodru V, Walz MK, Tirosh A, et al.; International Bilateral-Pheochromocytoma-Registry Group. Comparison of pheochromocytoma-specific morbidity and mortality among adults with bilateral pheochromocytomas undergoing total adrenalectomy vs cortical-sparing adrenalectomy. JAMA Netw Open. 2019;2:e198898. [DOI] [PubMed] [PMC]

121.

Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, et al.; French group of Endocrine and Adrenal tumors (Groupe des Tumeurs Endocrines-REseau NAtional des Tumeurs ENdocrines and COrtico-MEdullo Tumeurs Endocrines networks). One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98:4006–12. [DOI] [PubMed]

122.

Vogel J, Atanacio AS, Prodanov T, Turkbey BI, Adams K, Martucci V, et al. External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma. Front Oncol. 2014;4:166. [DOI] [PubMed] [PMC]

123.

Breen W, Bancos I, Young WF Jr, Bible KC, Laack NN, Foote RL, et al. External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma. Adv Radiat Oncol. 2017;3:25–9. [DOI] [PubMed] [PMC]

124.

Kohlenberg J, Welch B, Hamidi O, Callstrom M, Morris J, Sprung J, et al. Efficacy and safety of ablative therapy in the treatment of patients with metastatic pheochromocytoma and paraganglioma. Cancers (Basel). 2019;11:195. [DOI] [PubMed] [PMC]

125.

Nölting S, Grossman A, Pacak K. Metastatic phaeochromocytoma: spinning towards more promising treatment options. Exp Clin Endocrinol Diabetes. 2019;127:117–28. [DOI] [PubMed] [PMC]

126.

Hescot S, Curras-Freixes M, Deutschbein T, van Berkel A, Vezzosi D, Amar L, et al.; European Network for the Study of Adrenal Tumors (ENS@T). Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono study): a European Network for the Study of Adrenal Tumors retrospective study. J Clin Endocrinol Metab. 2019;104:2367–74. [DOI] [PubMed]

127.

Crona J, Lamarca A, Ghosal S, Welin S, Skogseid B, Pacak K. Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocr Relat Cancer. 2019;26:539–50. [DOI] [PubMed] [PMC]

128.

Fankhauser M, Bechmann N, Lauseker M, Goncalves J, Favier J, Klink B, et al. Synergistic highly potent targeted drug combinations in different pheochromocytoma models including human tumor cultures. Endocrinology. 2019;160:2600–17. [DOI] [PubMed] [PMC]

129.

Nölting S, Giubellino A, Tayem Y, Young K, Lauseker M, Bullova P, et al. Combination of 13-Cis retinoic acid and lovastatin: marked antitumor potential in vivo in a pheochromocytoma allograft model in female athymic nude mice. Endocrinology. 2014;155:2377–90. [DOI] [PubMed] [PMC]

130.

Nölting S, Garcia E, Alusi G, Giubellino A, Pacak K, Korbonits M, et al. Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. J Mol Endocrinol. 2012;49:79–96. [DOI] [PubMed] [PMC]

131.

Noto RB, Pryma DA, Jensen J, Lin T, Stambler N, Strack T, et al. Phase 1 study of high-specific-activity I-131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2018;103:213–20. [DOI] [PubMed]

132.

van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EP. ¹³¹I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf). 2014;80:487–501. [DOI] [PubMed]

133.

Nastos K, Cheung VTF, Toumpanakis C, Navalkissoor S, Quigley AM, Caplin M, et al. Peptide receptor radionuclide treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas. J Surg Oncol. 2017;115:425–34. [DOI] [PubMed]

134.

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 Invest. 1997;20:648–58. [DOI] [PubMed]

135.

Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, et al. Phase II study of high-dose [¹³¹I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol. 2009;27:4162–8. [DOI] [PubMed] [PMC]

136.

Thorpe MP, Kane A, Zhu J, Morse MA, Wong T, Borges-Neto S. Long-term outcomes of 125 patients with metastatic pheochromocytoma or paraganglioma treated with 131-I MIBG. J Clin Endocrinol Metab. 2020;105:e494–501. [DOI] [PubMed] [PMC]

137.

Wakabayashi H, Inaki A, Yoshimura K, Murayama T, Imai Y, Higuchi T, et al. Author correction: A phase I clinical trial for [¹³¹I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma. Sci Rep. 2022;12:1347. Erratum in: Sci Rep. 2019;9:7625. [DOI] [PubMed] [PMC]

138.

Fonte JS, Robles JF, Chen CC, Reynolds J, Whatley M, Ling A, et al. False-negative ¹²³I-MIBG SPECT is most commonly found in SDHB-related pheochromocytoma or paraganglioma with high frequency to develop metastatic disease. Endocr Relat Cancer. 2012;19:83–93. [DOI] [PubMed] [PMC]

139.

Job S, Draskovic I, Burnichon N, Buffet A, Cros J, Lépine C, et al. Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma. Clin Cancer Res. 2019;25:760–70. [DOI] [PubMed]

140.

van Essen M, Krenning EP, Kooij PP, Bakker WH, Feelders RA, de Herder WW, et al. Effects of therapy with [¹⁷⁷Lu-DOTA⁰, Tyr³]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med. 2006;47:1599–606. [PubMed]

141.

Zovato S, Kumanova A, Demattè S, Sansovini M, Bodei L, Di Sarra D, et al. Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE in individuals with neck or mediastinal paraganglioma (PGL). Horm Metab Res. 2012;44:411–4. [DOI] [PubMed]

142.

Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging. 2008;52:334–40. [PubMed]

143.

Kong G, Grozinsky-Glasberg S, Hofman MS, Callahan J, Meirovitz A, Maimon O, et al. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. J Clin Endocrinol Metab. 2017;102:3278–87. [DOI] [PubMed]

144.

Pinato DJ, Black JR, Ramaswami R, Tan TM, Adjogatse D, Sharma R. Peptide receptor radionuclide therapy for metastatic paragangliomas. Med Oncol. 2016;33:47. [DOI] [PubMed]

145.

Zandee WT, Feelders RA, Smit Duijzentkunst DA, Hofland J, Metselaar RM, Oldenburg RA, et al. Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using ¹⁷⁷Lu-DOTATATE. Eur J Endocrinol. 2019;181:45–53. [DOI] [PubMed]

146.

Satapathy S, Mittal BR, Bhansali A. ‘Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: a systematic review and meta-analysis’. Clin Endocrinol (Oxf). 2019;91:718–27. [DOI] [PubMed]

147.

Jaiswal SK, Sarathi V, Memon SS, Garg R, Malhotra G, Verma P, et al. ¹⁷⁷Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma. Endocr Connect. 2020;9:864–73. [DOI] [PubMed] [PMC]

148.

Pryma DA, Chin BB, Noto RB, Dillon JS, Perkins S, Solnes L, et al. Efficacy and safety of high-specific-activity ¹³¹I-MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. J Nucl Med. 2019;60:623–30. [DOI] [PubMed] [PMC]

149.

Baudin E, Habra MA, Deschamps F, Cote G, Dumont F, Cabanillas M, et al. Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma. Eur J Endocrinol. 2014;171:R111–22. [DOI] [PubMed]

150.

Jawed I, Velarde M, Därr R, Wolf KI, Adams K, Venkatesan AM, et al. Continued tumor reduction of metastatic pheochromocytoma/paraganglioma harboring succinate dehydrogenase subunit B mutations with cyclical chemotherapy. Cell Mol Neurobiol. 2018;38:1099–106. [DOI] [PubMed] [PMC]

151.

Hadoux J, Favier J, Scoazec JY, Leboulleux S, Al Ghuzlan A, Caramella C, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014;135:2711–20. [DOI] [PubMed]

152.

Bravo EL, Kalmadi SR, Gill I. Clinical utility of temozolomide in the treatment of malignant paraganglioma: a preliminary report. Horm Metab Res. 2009;41:703–6. [DOI] [PubMed]

153.

Toledo R, Jimenez C. Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors. F1000Res. 2018;7:1148. [DOI] [PubMed] [PMC]

154.

Cassol CA, Winer D, Liu W, Guo M, Ezzat S, Asa SL. Tyrosine kinase receptors as molecular targets in pheochromocytomas and paragangliomas. Mod Pathol. 2014;27:1050–62. [DOI] [PubMed] [PMC]

155.

Salmenkivi K, Heikkilä P, Liu J, Haglund C, Arola J. VEGF in 105 pheochromocytomas: enhanced expression correlates with malignant outcome. APMIS. 2003;111:458–64. [DOI] [PubMed]

156.

O’Kane GM, Ezzat S, Joshua AM, Bourdeau I, Leibowitz-Amit R, Olney HJ, et al. A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial. Br J Cancer. 2019;120:1113–9. [DOI] [PubMed] [PMC]

157.

Jimenez C, Habra MA, Campbell MT, Tamsen G, Cruz-Goldberg D, Long J, et al. A phase 2 clinical trial of cabozantinib in patients with unresectable and progressive metastatic pheochromocytoma or paraganglioma: The NATALIE trial. Endocr Abstr. 2023;98:C5. [DOI]

158.

Hassan Nelson L, Fuentes-Bayne H, Yin J, Asmus E, Ryder M, Morris JC, et al. Lenvatinib as a therapeutic option in unresectable metastatic pheochromocytoma and paragangliomas. J Endocr Soc. 2022;6:bvac044. [DOI] [PubMed] [PMC]

159.

Jasim S, Suman VJ, Jimenez C, Harris P, Sideras K, Burton JK, et al. Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma. Endocrine. 2017;57:220–5. [DOI] [PubMed]

160.

Jimenez C, Subbiah V, Stephen B, Ma J, Milton D, Xu M, et al. Phase II clinical trial of pembrolizumab in patients with progressive metastatic pheochromocytomas and paragangliomas. Cancers (Basel). 2020;12:2307. [DOI] [PubMed] [PMC]

161.

Naing A, Meric-Bernstam F, Stephen B, Karp DD, Hajjar J, Rodon Ahnert J, et al. Phase 2 study of pembrolizumab in patients with advanced rare cancers. J Immunother Cancer. 2020;8:e000347. Erratum in: J Immunother Cancer. 2020;8:e000347corr1. [DOI] [PubMed] [PMC]

162.

Fanciulli G, Di Molfetta S, Dotto A, Florio T, Feola T, Rubino M, et al. Emerging therapies in pheochromocytoma and paraganglioma: immune checkpoint inhibitors in the starting blocks. J Clin Med. 2020;10:88. [DOI] [PubMed] [PMC]