Review Article | Published:

Role of biomarker tests for diagnosis of neuroendocrine tumours

Nature Reviews Endocrinologyvolume 14pages656669 (2018) | Download Citation

Abstract

Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.

Key points

  • The diagnosis of gastroenteropancreatic neuroendocrine tumours (NETs) should be made by histological evaluation of tumour tissue, as the diagnostic accuracy of current circulating and imaging biomarkers is insufficient.

  • Clinicians should remain vigilant for the presence of hormonal syndromes in each patient with gastroenteropancreatic NETs, as these can attenuate prognosis, uncover specific biomarkers and facilitate tumour-specific management.

  • Chromogranin A, neuron-specific enolase and pancreatic polypeptide are circulating biomarkers with moderate to poor test characteristics for the diagnosis of gastroenteropancreatic NETs and should not be measured in patients as a means to screen for NET.

  • Circulating transcripts represent an emerging opportunity in the diagnosis of gastroenteropancreatic NETs, but whether they can be used to differentiate NETs from other tumours should be subject to further study, while their availability and cost-effectiveness in clinical practice remain to be determined.

  • PET of the somatostatin receptor and glucose metabolism is key to facilitating the delineation of tumour stage and individual treatment options and should be used in conjunction with anatomical imaging.

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References

  1. 1.

    Dasari, A. et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 3, 1335–1342 (2017).

  2. 2.

    Linan-Rico, A. et al. Mechanosensory signaling in enterochromaffin cells and 5-HT release: potential implications for gut inflammation. Front. Neurosci. 10, 564 (2016).

  3. 3.

    Bellono, N. W. et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170, 185–198 (2017).

  4. 4.

    Gu, X. et al. Chemosensory functions for pulmonary neuroendocrine cells. Am. J. Respir. Cell. Mol. Biol. 50, 637–646 (2014).

  5. 5.

    Wiedenmann, B., Franke, W. W., Kuhn, C., Moll, R. & Gould, V. E. Synaptophysin: a marker protein for neuroendocrine cells and neoplasms. Proc. Natl Acad. Sci. USA 83, 3500–3504 (1986).

  6. 6.

    Eriksson, B. et al. Chromogranins — new sensitive markers for neuroendocrine tumors. Acta Oncol. 28, 325–329 (1989).

  7. 7.

    Duan, K. & Mete, O. Algorithmic approach to neuroendocrine tumors in targeted biopsies: practical applications of immunohistochemical markers. Cancer Cytopathol. 124, 871–884 (2016).

  8. 8.

    Schmitt, A. M., Blank, A., Marinoni, I., Komminoth, P. & Perren, A. Histopathology of NET: current concepts and new developments. Best Pract. Res. Clin. Endocrinol. Metab. 30, 33–43 (2016).

  9. 9.

    Zandee, W. T., Kamp, K., van Adrichem, R. C., Feelders, R. A. & de Herder, W. W. Effect of hormone secretory syndromes on neuroendocrine tumor prognosis. Endocr. Relat. Cancer 24, R261–R274 (2017).

  10. 10.

    Kanakis, G. & Kaltsas, G. Biochemical markers for gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Best Pract. Res. Clin. Gastroenterol. 26, 791–802 (2012).

  11. 11.

    Deftos, L. J. Chromogranin A: its role in endocrine function and as an endocrine and neuroendocrine tumor marker. Endocr. Rev. 12, 181–187 (1991).

  12. 12.

    Sanduleanu, S. et al. Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy. Eur. J. Clin. Invest. 31, 802–811 (2001).

  13. 13.

    Marotta, V. et al. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr. Relat. Cancer 25, R11–R29 (2018).

  14. 14.

    Yang, X. et al. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS ONE 10, e0124884 (2015).

  15. 15.

    Molina, R. et al. Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumour Biol. 32, 13–22 (2011).

  16. 16.

    Raines, D. et al. A prospective evaluation of the effect of chronic proton pump inhibitor use on plasma biomarker levels in humans. Pancreas 41, 508–511 (2012).

  17. 17.

    Calhoun, K., Toth-Fejel, S., Cheek, J. & Pommier, R. Serum peptide profiles in patients with carcinoid tumors. Am. J. Surg. 186, 28–31 (2003).

  18. 18.

    Rustagi, S., Warner, R. R. & Divino, C. M. Serum pancreastatin: the next predictive neuroendocrine tumor marker. J. Surg. Oncol. 108, 126–128 (2013).

  19. 19.

    Stridsberg, M., Oberg, K., Li, Q., Engstrom, U. & Lundqvist, G. Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. J. Endocrinol. 144, 49–59 (1995).

  20. 20.

    Sherman, S. K., Maxwell, J. E., O’Dorisio, M. S., O’Dorisio, T. M. & Howe, J. R. Pancreastatin predicts survival in neuroendocrine tumors. Ann. Surg. Oncol. 21, 2971–2980 (2014).

  21. 21.

    Modlin, I. M., Aslanian, H., Bodei, L., Drozdov, I. & Kidd, M. A. PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors. Endocr. Connect. 3, 215–223 (2014).

  22. 22.

    Sekiya, K. et al. Production of GAWK (chromogranin-B 420–493)-like immunoreactivity by endocrine tumors and its possible diagnostic value. J. Clin. Invest. 83, 1834–1842 (1989).

  23. 23.

    Monaghan, P. J. et al. Routine measurement of plasma chromogranin B has limited clinical utility in the management of patients with neuroendocrine tumours. Clin. Endocrinol. 84, 348–352 (2016).

  24. 24.

    Stridsberg, M., Eriksson, B., Fellstrom, B., Kristiansson, G. & Tiensuu Janson, E. Measurements of chromogranin B can serve as a complement to chromogranin A. Regul. Pept. 139, 80–83 (2007).

  25. 25.

    Pahlman, S., Esscher, T., Bergvall, P. & Odelstad, L. Purification and characterization of human neuron-specific enolase: radioimmunoassay development. Tumour Biol. 5, 127–139 (1984).

  26. 26.

    Baudin, E. et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br. J. Cancer 78, 1102–1107 (1998).

  27. 27.

    Nobels, F. R. et al. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. J. Clin. Endocrinol. Metab. 82, 2622–2628 (1997).

  28. 28.

    Leja, J. et al. Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Mod. Pathol. 22, 261–272 (2009).

  29. 29.

    Melen-Mucha, G. et al. Elevated peripheral blood plasma concentrations of tie-2 and angiopoietin 2 in patients with neuroendocrine tumors. Int. J. Mol. Sci. 13, 1444–1460 (2012).

  30. 30.

    Srirajaskanthan, R. et al. Circulating angiopoietin-2 is elevated in patients with neuroendocrine tumours and correlates with disease burden and prognosis. Endocr. Relat. Cancer 16, 967–976 (2009).

  31. 31.

    Figueroa-Vega, N. et al. The association of the angiopoietin/Tie-2 system with the development of metastasis and leukocyte migration in neuroendocrine tumors. Endocr. Relat. Cancer 17, 897–908 (2010).

  32. 32.

    Detjen, K. M. et al. Angiopoietin-2 promotes disease progression of neuroendocrine tumors. Clin. Cancer Res. 16, 420–429 (2010).

  33. 33.

    Andersson, E. et al. Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets. Mod. Pathol. 29, 616–629 (2016).

  34. 34.

    Karpathakis, A. et al. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clin. Cancer Res. 22, 250–258 (2016).

  35. 35.

    Scarpa, A. et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543, 65–71 (2017).

  36. 36.

    Modlin, I. M. et al. Principal component analysis, hierarchical clustering, and decision tree assessment of plasma mRNA and hormone levels as an early detection strategy for small intestinal neuroendocrine (carcinoid) tumors. Ann. Surg. Oncol. 16, 487–498 (2009).

  37. 37.

    Modlin, I. M., Drozdov, I. & Kidd, M. The identification of gut neuroendocrine tumor disease by multiple synchronous transcript analysis in blood. PLoS ONE 8, e63364 (2013).

  38. 38.

    Modlin, I. M. et al. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. Endocr. Relat. Cancer 21, 615–628 (2014).

  39. 39.

    Modlin, I. M., Kidd, M., Bodei, L., Drozdov, I. & Aslanian, H. The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am. J. Gastroenterol. 110, 1223–1232 (2015).

  40. 40.

    Miller, H. C. et al. MicroRNAs associated with small bowel neuroendocrine tumours and their metastases. Endocr. Relat. Cancer 23, 711–726 (2016).

  41. 41.

    Li, S. C. et al. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod. Pathol. 26, 685–696 (2013).

  42. 42.

    Thorns, C. et al. Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res. 34, 2249–2254 (2014).

  43. 43.

    Lee, Y. S. et al. High expression of microRNA-196a indicates poor prognosis in resected pancreatic neuroendocrine tumor. Medicine 94, e2224 (2015).

  44. 44.

    Ruebel, K. et al. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod. Pathol. 23, 367–375 (2010).

  45. 45.

    Roldo, C. et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J. Clin. Oncol. 24, 4677–4684 (2006).

  46. 46.

    Li, S. C. et al. Somatostatin analogs treated small intestinal neuroendocrine tumor patients circulating microRNAs. PLoS ONE 10, e0125553 (2015).

  47. 47.

    Bowden, M. et al. Profiling of metastatic small intestine neuroendocrine tumors reveals characteristic mi-RNAs detectable in plasma. Oncotarget 8, 54331–54344 (2017).

  48. 48.

    Heverhagen, A. E. et al. Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine. Neuroendocrinology 106, 312–317 (2018).

  49. 49.

    Matsuzaki, J. & Ochiya, T. Circulating microRNAs and extracellular vesicles as potential cancer biomarkers: a systematic review. Int. J. Clin. Oncol. 22, 413–420 (2017).

  50. 50.

    Khan, M. S. et al. Circulating tumor cells and EpCAM expression in neuroendocrine tumors. Clin. Cancer Res. 17, 337–345 (2011).

  51. 51.

    Khan, M. S. et al. Circulating tumor cells as prognostic markers in neuroendocrine tumors. J. Clin. Oncol. 31, 365–372 (2013).

  52. 52.

    Ehlers, M. et al. Circulating tumor cells in patients with neuroendocrine neoplasms. Horm.Metabol. Res. 46, 744–745 (2014).

  53. 53.

    Childs, A. et al. Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours. Br. J. Cancer 115, 1540–1547 (2016).

  54. 54.

    Darmanis, S. et al. Identification of candidate serum proteins for classifying well-differentiated small intestinal neuroendocrine tumors. PLoS ONE 8, e81712 (2013).

  55. 55.

    Kinross, J. M., Drymousis, P., Jimenez, B. & Frilling, A. Metabonomic profiling: a novel approach in neuroendocrine neoplasias. Surgery 154, 1185–1192; discussion 1192–1183 (2013).

  56. 56.

    Erspamer, V. & Asero, B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169, 800–801 (1952).

  57. 57.

    Grahame-Smith, D. G. Progress report: the carcinoid syndrome. Gut 11, 189–192 (1970).

  58. 58.

    Kaltsas, G. A., Besser, G. M. & Grossman, A. B. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr. Rev. 25, 458–511 (2004).

  59. 59.

    Meijer, W. G., Kema, I. P., Volmer, M., Willemse, P. H. & de Vries, E. G. Discriminating capacity of indole markers in the diagnosis of carcinoid tumors. Clin. Chem. 46, 1588–1596 (2000).

  60. 60.

    Scarpa, M. et al. A systematic review of diagnostic procedures to detect midgut neuroendocrine tumors. J. Surg. Oncol. 102, 877–888 (2010).

  61. 61.

    Feldman, J. M. Urinary serotonin in the diagnosis of carcinoid tumors. Clin. Chem. 32, 840–844 (1986).

  62. 62.

    Feldman, J. M. & O’Dorisio, T. M. Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. Am. J. Med. 81, 41–48 (1986).

  63. 63.

    Bajetta, E. et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 86, 858–865 (1999).

  64. 64.

    Zandee, W. T., Kamp, K., van Adrichem, R. C., Feelders, R. A. & de Herder, W. W. Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours. Eur. J. Endocrinol. 175, 361–366 (2016).

  65. 65.

    Turner, G. B. et al. Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours. Gut 55, 1586–1591 (2006).

  66. 66.

    Formica, V. et al. The prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract. Br. J. Cancer 96, 1178–1182 (2007).

  67. 67.

    Seregni, E., Ferrari, L., Bajetta, E., Martinetti, A. & Bombardieri, E. Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann. Oncol. 12 (Suppl. 2), S69–72 (2001).

  68. 68.

    Kema, I. P., Schellings, A. M., Meiborg, G., Hoppenbrouwers, C. J. & Muskiet, F. A. Influence of a serotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin. Chem. 38, 1730–1736 (1992).

  69. 69.

    Tellez, M. R., Mamikunian, G., O’Dorisio, T. M., Vinik, A. I. & Woltering, E. A. A single fasting plasma 5-HIAA value correlates with 24-hour urinary 5-HIAA values and other biomarkers in midgut neuroendocrine tumors (NETs). Pancreas 42, 405–410 (2013).

  70. 70.

    Adaway, J. E. et al. Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement. Ann. Clin. Biochem. 53, 554–560 (2016).

  71. 71.

    Kema, I. P., de Vries, E. G., Schellings, A. M., Postmus, P. E. & Muskiet, F. A. Improved diagnosis of carcinoid tumors by measurement of platelet serotonin. Clin. Chem. 38, 534–540 (1992).

  72. 72.

    Bhattacharyya, S., Toumpanakis, C., Chilkunda, D., Caplin, M. E. & Davar, J. Risk factors for the development and progression of carcinoid heart disease. Am. J. Cardiol. 107, 1221–1226 (2011).

  73. 73.

    Dobson, R. et al. The association of a panel of biomarkers with the presence and severity of carcinoid heart disease: a cross-sectional study. PLoS ONE 8, e73679 (2013).

  74. 74.

    Zuetenhorst, J. M. et al. Carcinoid heart disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-β and fibroblast growth factor. Cancer 97, 1609–1615 (2003).

  75. 75.

    Korse, C. M., Taal, B. G., de Groot, C. A., Bakker, R. H. & Bonfrer, J. M. Chromogranin-A and N-terminal pro-brain natriuretic peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor. J. Clin. Oncol. 27, 4293–4299 (2009).

  76. 76.

    Bhattacharyya, S., Toumpanakis, C., Caplin, M. E. & Davar, J. Usefulness of N-terminal pro-brain natriuretic peptide as a biomarker of the presence of carcinoid heart disease. Am. J. Cardiol. 102, 938–942 (2008).

  77. 77.

    Woltering, E. A. et al. Development of effective prophylaxis against intraoperative carcinoid crisis. J. Clin. Anesth 32, 189–193 (2016).

  78. 78.

    Pernow, B. Substance P. Pharmacol. Rev. 35, 85–141 (1983).

  79. 79.

    Norheim, I., Theodorsson-Norheim, E., Brodin, E. & Oberg, K. Tachykinins in carcinoid tumors: their use as a tumor marker and possible role in the carcinoid flush. J. Clin. Endocrinol. Metab. 63, 605–612 (1986).

  80. 80.

    Oates, J. A., Melmon, K., Sjoerdsma, A., Gillespie, L. & Mason, D. T. Release of a kinin peptide in the carcinoid syndrome. Lancet 1, 514–517 (1964).

  81. 81.

    Whipple, A. The surgical therapy of hyperinsulinism. J. Int. Chir 3, 237–276 (1938).

  82. 82.

    Cryer, P. E. et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 94, 709–728 (2009).

  83. 83.

    Hirshberg, B. et al. Forty-eight-hour fast: the diagnostic test for insulinoma. J. Clin. Endocrinol. Metab. 85, 3222–3226 (2000).

  84. 84.

    Service, F. J. & Natt, N. The prolonged fast. J. Clin. Endocrinol. Metab. 85, 3973–3974 (2000).

  85. 85.

    van Bon, A. C., Benhadi, N., Endert, E., Fliers, E. & Wiersinga, W. M. Evaluation of endocrine tests. D: the prolonged fasting test for insulinoma. Neth. J. Med. 67, 274–278 (2009).

  86. 86.

    Dizon, A. M., Kowalyk, S. & Hoogwerf, B. J. Neuroglycopenic and other symptoms in patients with insulinomas. Am. J. Med. 106, 307–310 (1999).

  87. 87.

    Eldor, R. et al. Glucagonoma and the glucagonoma syndrome — cumulative experience with an elusive endocrine tumour. Clin. Endocrinol. 74, 593–598 (2011).

  88. 88.

    Stacpoole, P. W. The glucagonoma syndrome: clinical features, diagnosis, and treatment. Endocr. Rev. 2, 347–361 (1981).

  89. 89.

    Soga, J. & Yakuwa, Y. Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. J. Hepatobiliary Pancreat. Surg. 5, 312–319 (1999).

  90. 90.

    Said, S. I. & Mutt, V. Potent peripheral and splanchnic vasodilator peptide from normal gut. Nature 225, 863–864 (1970).

  91. 91.

    Barbezat, G. O. & Grossman, M. I. Intestinal secretion: stimulation by peptides. Science 174, 422–424 (1971).

  92. 92.

    Holst, J. J. et al. Vasoactive intestinal polypeptide (VIP) in the pig pancreas: role of VIPergic nerves in control of fluid and bicarbonate secretion. Regul. Pept. 8, 245–259 (1984).

  93. 93.

    Robberecht, P., Conlon, T. P. & Gardner, J. D. Interaction of porcine vasoactive intestinal peptide with dispersed pancreatic acinar cells from the guinea pig. Structural requirements for effects of vasoactive intestinal peptide and secretin on cellular adenosine 3’:5’-monophosphate. J. Biol. Chem. 251, 4635–4639 (1976).

  94. 94.

    Larsson, L. I. et al. Localization of vasoactive intestinal polypeptide (VIP) to central and peripheral neurons. Proc. Natl Acad. Sci. USA 73, 3197–3200 (1976).

  95. 95.

    Bloom, S. R. Vasoactive intestinal peptide, the major mediator of the WDHA (pancreatic cholera) syndrome: value of measurement in diagnosis and treatment. Am. J. Dig. Dis. 23, 373–376 (1978).

  96. 96.

    Ekblad, E. & Sundler, F. Distribution of pancreatic polypeptide and peptide YY. Peptides 23, 251–261 (2002).

  97. 97.

    Wang, X. et al. Quantitative analysis of pancreatic polypeptide cell distribution in the human pancreas. PLoS ONE 8, e55501 (2013).

  98. 98.

    Friesen, S. R., Kimmel, J. R. & Tomita, T. Pancreatic polypeptide as screening marker for pancreatic polypeptide apudomas in multiple endocrinopathies. Am. J. Surg. 139, 61–72 (1980).

  99. 99.

    Maxwell, J. E., O’Dorisio, T. M., Bellizzi, A. M. & Howe, J. R. Elevated pancreatic polypeptide levels in pancreatic neuroendocrine tumors and diabetes mellitus: causation or association? Pancreas 43, 651–656 (2014).

  100. 100.

    Adrian, T. E., Uttenthal, L. O., Williams, S. J. & Bloom, S. R. Secretion of pancreatic polypeptide in patients with pancreatic endocrine tumors. N. Engl. J. Med. 315, 287–291 (1986).

  101. 101.

    Panzuto, F. et al. Utility of combined use of plasma levels of chromogranin A and pancreatic polypeptide in the diagnosis of gastrointestinal and pancreatic endocrine tumors. J. Endocrinol. Invest. 27, 6–11 (2004).

  102. 102.

    Walter, T. et al. Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours? Eur. J. Cancer 48, 1766–1773 (2012).

  103. 103.

    de Laat, J. M. et al. Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients. J. Clin. Endocrinol. Metab. 98, 4143–4151 (2013).

  104. 104.

    Qiu, W. et al. Utility of chromogranin A, pancreatic polypeptide, glucagon and gastrin in the diagnosis and follow-up of pancreatic neuroendocrine tumours in multiple endocrine neoplasia type 1 patients. Clin. Endocrinol. 85, 400–407 (2016).

  105. 105.

    Zollinger, R. M. & Ellison, E. H. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann. Surg. 142, 709–723 (1955).

  106. 106.

    Oberg, K. et al. ENETS Consensus Guidelines for standard of care in neuroendocrine tumours: biochemical markers. Neuroendocrinology 105, 201–211 (2017).

  107. 107.

    Varro, A. & Ardill, J. E. Gastrin: an analytical review. Ann. Clin. Biochem. 40, 472–480 (2003).

  108. 108.

    Poitras, P., Gingras, M. H. & Rehfeld, J. F. The Zollinger-Ellison syndrome: dangers and consequences of interrupting antisecretory treatment. Clin. Gastroenterol. Hepatol. 10, 199–202 (2012).

  109. 109.

    Ito, T., Cadiot, G. & Jensen, R. T. Diagnosis of Zollinger-Ellison syndrome: increasingly difficult. World J. Gastroenterol. 18, 5495–5503 (2012).

  110. 110.

    Berna, M. J., Hoffmann, K. M., Serrano, J., Gibril, F. & Jensen, R. T. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine 85, 295–330 (2006).

  111. 111.

    Berna, M. J. et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine 85, 331–364 (2006).

  112. 112.

    Krejs, G. J. et al. Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N. Engl. J. Med. 301, 285–292 (1979).

  113. 113.

    Larsson, L. I. et al. Pancreatic somatostatinoma. Clinical features and physiological implications. Lancet 1, 666–668 (1977).

  114. 114.

    Tanaka, S. et al. Duodenal somatostatinoma: a case report and review of 31 cases with special reference to the relationship between tumor size and metastasis. Pathol. Int. 50, 146–152 (2000).

  115. 115.

    Wajchenberg, B. L. et al. Ectopic ACTH syndrome. J. Steroid Biochem. Mol. Biol. 53, 139–151 (1995).

  116. 116.

    Howlett, T. A. et al. Diagnosis and management of ACTH-dependent Cushing’s syndrome: comparison of the features in ectopic and pituitary ACTH production. Clin. Endocrinol. 24, 699–713 (1986).

  117. 117.

    Kamp, K. et al. Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors. Eur. J. Endocrinol. 174, 271–280 (2016).

  118. 118.

    Nieman, L. K. et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008).

  119. 119.

    Lacroix, A., Feelders, R. A., Stratakis, C. A. & Nieman, L. K. Cushing’s syndrome. Lancet 386, 913–927 (2015).

  120. 120.

    Deftos, L. J., Gazdar, A. F., Ikeda, K. & Broadus, A. E. The parathyroid hormone-related protein associated with malignancy is secreted by neuroendocrine tumors. Mol. Endocrinol. 3, 503–508 (1989).

  121. 121.

    Kamp, K. et al. Parathyroid hormone-related peptide (PTHrP) secretion by gastroenteropancreatic neuroendocrine tumors (GEP-NETs): clinical features, diagnosis, management, and follow-up. J. Clin. Endocrinol. Metab. 99, 3060–3069 (2014).

  122. 122.

    Burtis, W. J. Parathyroid hormone-related protein: structure, function, and measurement. Clin. Chem. 38, 2171–2183 (1992).

  123. 123.

    Gola, M. et al. Neuroendocrine tumors secreting growth hormone-releasing hormone: pathophysiological and clinical aspects. Pituitary 9, 221–229 (2006).

  124. 124.

    Ghazi, A. A. et al. Ectopic acromegaly due to growth hormone releasing hormone. Endocrine 43, 293–302 (2013).

  125. 125.

    Melmed, S., Ezrin, C., Kovacs, K., Goodman, R. S. & Frohman, L. A. Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor. N. Engl. J. Med. 312, 9–17 (1985).

  126. 126.

    Herrera, M. F. et al. AACE/ACE disease state clinical review: pancreatic neuroendocrine incidentalomas. Endocr. Pract. 21, 546–553 (2015).

  127. 127.

    Sundin, A. et al. ENETS Consensus Guidelines for the standards of care in neuroendocrine tumors: radiological, nuclear medicine and hybrid imaging. Neuroendocrinology 105, 212–244 (2017).

  128. 128.

    Blazevic, A., Hofland, J., Hofland, L. J., Feelders, R. A. & de Herder, W. W. Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum. Endocr. Relat. Cancer 25, R115–R130 (2018).

  129. 129.

    Nijssen, E. C. et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 389, 1312–1322 (2017).

  130. 130.

    Elias, D. et al. Hepatic metastases from neuroendocrine tumors with a “thin slice” pathological examination: they are many more than you think. Ann. Surg. 251, 307–310 (2010).

  131. 131.

    Ricke, J., Klose, K. J., Mignon, M., Oberg, K. & Wiedenmann, B. Standardisation of imaging in neuroendocrine tumours: results of a European delphi process. Eur. J. Radiol. 37, 8–17 (2001).

  132. 132.

    Hofland, L. J. & Lamberts, S. W. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr. Rev. 24, 28–47 (2003).

  133. 133.

    Krenning, E. P. et al. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1, 242–244 (1989).

  134. 134.

    Lamberts, S. W., Reubi, J. C. & Krenning, E. P. Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors. Acta Oncol. 32, 167–170 (1993).

  135. 135.

    Namwongprom, S., Wong, F. C., Tateishi, U., Kim, E. E. & Boonyaprapa, S. Correlation of chromogranin A levels and somatostatin receptor scintigraphy findings in the evaluation of metastases in carcinoid tumors. Ann. Nuclear Med. 22, 237–243 (2008).

  136. 136.

    Rodrigues, M. et al. Concordance between results of somatostatin receptor scintigraphy with 111In-DOTA-DPhe 1-Tyr 3-octreotide and chromogranin A assay in patients with neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imag. 35, 1796–1802 (2008).

  137. 137.

    Tirosh, A. et al. Association between neuroendocrine tumors biomarkers and primary tumor site and disease type based on total 68Ga-DOTATATE-Avid tumor volume measurements. Eur. J. Endocrinol. 176, 575–582 (2017).

  138. 138.

    Rahmim, A. & Zaidi, H. PET versus SPECT: strengths, limitations and challenges. Nucl. Med. Commun. 29, 193–207 (2008).

  139. 139.

    Geijer, H. & Breimer, L. H. Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis. Eur. J. Nucl. Med. Mol. Imag. 40, 1770–1780 (2013).

  140. 140.

    Sadowski, S. M. et al. Prospective Study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J. Clin. Oncol. 34, 588–596 (2016).

  141. 141.

    Naswa, N. et al. Metastatic neuroendocrine carcinoma presenting as a “Superscan” on 68Ga-DOTANOC somatostatin receptor PET/CT. Clin. Nucl. Med. 37, 892–894 (2012).

  142. 142.

    Sharma, P. et al. Somatostatin receptor based PET/CT imaging with 68Ga-DOTA-Nal3-octreotide for localization of clinically and biochemically suspected insulinoma. Q. J. Nucl. Med. Mol. Imag. 60, 69–76 (2016).

  143. 143.

    Barrio, M. et al. The impact of somatostatin receptor-directed PET/CT on the management of patients with neuroendocrine tumor: a systematic review and meta-analysis. J. Nucl. Med. 58, 756–761 (2017).

  144. 144.

    Graham, M. M., Gu, X., Ginader, T., Breheny, P. & Sunderland, J. J. 68Ga-DOTATOC imaging of neuroendocrine tumors: a systematic review and metaanalysis. J. Nucl. Med. 58, 1452–1458 (2017).

  145. 145.

    Hope, T. A. et al. Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors. J. Nucl. Med. 59, 66–74 (2018).

  146. 146.

    Binderup, T. et al. Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET. J. Nucl. Med. 51, 704–712 (2010).

  147. 147.

    Has Simsek, D. et al. Can complementary 68Ga-DOTATATE and 18F-FDG PET/CT establish the missing link between histopathology and therapeutic approach in gastroenteropancreatic neuroendocrine tumors? J. Nucl. Med. 55, 1811–1817 (2014).

  148. 148.

    Squires, M. H. 3rd et al. Octreoscan versus FDG-PET for neuroendocrine tumor staging: a biological approach. Ann. Surg. Oncol. 22, 2295–2301 (2015).

  149. 149.

    Modlin, I. M. et al. Gastrointestinal carcinoids: the evolution of diagnostic strategies. J. Clin. Gastroenterol. 40, 572–582 (2006).

  150. 150.

    Kaltsas, G. et al. Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J. Clin. Endocrinol. Metab. 86, 895–902 (2001).

  151. 151.

    Jager, P. L. et al. 6-L-18F-fluorodihydroxyphenylalanine PET in neuroendocrine tumors: basic aspects and emerging clinical applications. J. Nucl. Med. 49, 573–586 (2008).

  152. 152.

    Balogova, S. et al. 18F-fluorodihydroxyphenylalanine versus other radiopharmaceuticals for imaging neuroendocrine tumours according to their type. Eur. J. Nucl. Med. Mol. Imag. 40, 943–966 (2013).

  153. 153.

    Koopmans, K. P. et al. Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography. J. Clin. Oncol. 26, 1489–1495 (2008).

  154. 154.

    Haug, A. et al. Intraindividual comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in patients with well-differentiated metastatic neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imag. 36, 765–770 (2009).

  155. 155.

    Sundin, A. et al. Demonstration of [11C] 5-hydroxy-L-tryptophan uptake and decarboxylation in carcinoid tumors by specific positioning labeling in positron emission tomography. Nuclear Med. Biol. 27, 33–41 (2000).

  156. 156.

    Orlefors, H. et al. Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors. J. Clin. Oncol. 16, 2534–2541 (1998).

  157. 157.

    Orlefors, H. et al. PET-guided surgery — high correlation between positron emission tomography with 11C-5-hydroxytryptophane (5-HTP) and surgical findings in abdominal neuroendocrine tumours. Cancers 4, 100–112 (2012).

  158. 158.

    Orlefors, H. et al. Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. J. Clin. Endocrinol. Metab. 90, 3392–3400 (2005).

  159. 159.

    Christ, E. et al. Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J. Clin. Endocrinol. Metab. 94, 4398–4405 (2009).

  160. 160.

    Christ, E. et al. Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabetes Endocrinol. 1, 115–122 (2013).

  161. 161.

    Wild, D. et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J. Nucl. Med. 52, 1073–1078 (2011).

  162. 162.

    Kaemmerer, D. et al. Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms. Oncotarget 6, 3346–3358 (2015).

  163. 163.

    Kaemmerer, D. et al. Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget 6, 27566–27579 (2015).

  164. 164.

    Lapa, C. et al. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer — initial experience. Oncotarget 7, 9288–9295 (2016).

  165. 165.

    Werner, R. A. et al. Imaging of chemokine receptor 4 expression in neuroendocrine tumors — a triple tracer comparative approach. Theranostics 7, 1489–1498 (2017).

  166. 166.

    Kuiper, P. et al. Expression and ligand binding of bombesin receptors in pulmonary and intestinal carcinoids. J. Endocrinol. Invest. 34, 665–670 (2011).

  167. 167.

    Dalm, S. U. et al. 68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology. J. Nucl. Med. 58, 293–299 (2017).

  168. 168.

    Nock, B. A. et al. Theranostic perspectives in prostate cancer with the gastrin-releasing peptide receptor antagonist NeoBOMB1: preclinical and first clinical results. J. Nucl. Med. 58, 75–80 (2017).

  169. 169.

    Bossuyt, P. M. et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for reporting of diagnostic accuracy. Clin. Chem. 49, 1–6 (2003).

  170. 170.

    Miekus, N. & Baczek, T. Non-invasive screening for neuroendocrine tumors — Biogenic amines as neoplasm biomarkers and the potential improvement of “gold standards”. J. Pharm. Biomed. Analysis 130, 194–201 (2016).

  171. 171.

    Carreira, S. et al. Tumor clone dynamics in lethal prostate cancer. Sci. Transl Med. 6, 254ra125 (2014).

  172. 172.

    Lehmann-Werman, R. et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc. Natl Acad. Sci. USA 113, E1826–E1834 (2016).

  173. 173.

    Salvianti, F. et al. Tumor-related methylated cell-free DNA and circulating tumor cells in melanoma. Front. Mol. Biosciences 2, 76 (2015).

  174. 174.

    Johnbeck, C. B. et al. Head-to-head comparison of (64)Cu-DOTATATE and (68)Ga-DOTATOC PET/CT: a prospective study of 59 patients with neuroendocrine tumors. J. Nucl. Med. 58, 451–457 (2017).

  175. 175.

    Cescato, R., Waser, B., Fani, M. & Reubi, J. C. Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. J. Nucl. Med. 52, 1886–1890 (2011).

  176. 176.

    Nicolas, G. P. et al. Comparison of (68)Ga-OPS202 ((68)Ga-NODAGA-JR11) and (68)Ga-DOTATOC ((68)Ga-Edotreotide) PET/CT in patients with gastroenteropancreatic neuroendocrine tumors: evaluation of sensitivity in a prospective phase ii imaging study. J. Nucl. Med. 59, 915–921 (2018).

  177. 177.

    Pandit-Taskar, N. et al. Biodistribution and dosimetry of 18F-Meta Fluorobenzyl Guanidine (MFBG): a first-in-human PET-CT imaging study of patients with neuroendocrine malignancies. J. Nucl. Med. 59, 147–153 (2018).

  178. 178.

    Carr, J. C. et al. Overexpression of membrane proteins in primary and metastatic gastrointestinal neuroendocrine tumors. Ann. Surg. Oncol. 20 (Suppl. 3), S739–S746 (2013).

  179. 179.

    Strosberg, J. et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 376, 125–135 (2017).

  180. 180.

    Arlt, W. et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J. Clin. Endocrinol. Metab. 96, 3775–3784 (2011).

  181. 181.

    Han, X. et al. The value of serum chromogranin A as a predictor of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors with liver metastases. Eur. J. Gastroenterol. Hepatol. 27, 527–535 (2015).

  182. 182.

    Modlin, I. M. et al. A nomogram to assess small-intestinal neuroendocrine tumor (‘carcinoid’) survival. Neuroendocrinology 92, 143–157 (2010).

  183. 183.

    Ellison, T. A. et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann. Surg. 259, 204–212 (2014).

  184. 184.

    Biomarkers Definitions Working, G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).

  185. 185.

    Janson, E. T. et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann. Oncol. 8, 685–690 (1997).

  186. 186.

    Eriksson, B., Oberg, K. & Stridsberg, M. Tumor markers in neuroendocrine tumors. Digestion 62 (Suppl. 1), 33–38 (2000).

  187. 187.

    Chou, W. C. et al. Chromogranin A is a reliable biomarker for gastroenteropancreatic neuroendocrine tumors in an Asian population of patients. Neuroendocrinology 95, 344–350 (2012).

  188. 188.

    van Adrichem, R. C. et al. Serum neuron-specific enolase level is an independent predictor of overall survival in patients with gastroenteropancreatic neuroendocrine tumors. Ann. Oncol. 27, 746–747 (2016).

  189. 189.

    Wiese, D. et al. C-reactive protein as a new prognostic factor for survival in patients with pancreatic neuroendocrine neoplasia. J. Clin. Endocrinol. Metab. 101, 937–944 (2016).

  190. 190.

    Salman, T. et al. Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for patients with neuroendocrine tumors: an Izmir Oncology Group Study. Chemotherapy 61, 281–286 (2016).

  191. 191.

    Cao, L. L. et al. A novel predictive model based on preoperative blood neutrophil-to-lymphocyte ratio for survival prognosis in patients with gastric neuroendocrine neoplasms. Oncotarget 7, 42045–42058 (2016).

  192. 192.

    Luo, G. et al. Neutrophil-lymphocyte ratio predicts survival in pancreatic neuroendocrine tumors. Oncol. Lett. 13, 2454–2458 (2017).

  193. 193.

    Okui, M. et al. Prognostic significance of neutrophil-lymphocyte ratios in large cell neuroendocrine carcinoma. Gen. Thorac. Cardiovasc. Surg. 65, 633–639 (2017).

  194. 194.

    Cui, T. et al. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors. PLoS ONE 5, e16010 (2010).

  195. 195.

    Modlin, I. M. et al. Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies. Surgery 159, 336–347 (2016).

  196. 196.

    Cwikla, J. B. et al. Circulating transcript analysis (NETest) in GEP-NETs treated with somatostatin analogs defines therapy. J. Clin. Endocrinol. Metab. 100, E1437–E1445 (2015).

  197. 197.

    Bodei, L. et al. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors. Eur. J. Nucl. Med. Mol. Imag. 43, 839–851 (2016).

  198. 198.

    Pavel, M. et al. NET blood transcript analysis defines the crossing of the clinical rubicon: when stable disease becomes progressive. Neuroendocrinology 104, 170–182 (2017).

  199. 199.

    Khan, M. S. et al. Early changes in circulating tumor cells are associated with response and survival following treatment of metastatic neuroendocrine neoplasms. Clin. Cancer Res. 22, 79–85 (2016).

  200. 200.

    van der Horst-Schrivers, A. N. et al. Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours. Eur. J. Cancer 43, 2651–2657 (2007).

  201. 201.

    Diebold, A. E. et al. Neurokinin A levels predict survival in patients with stage IV well differentiated small bowel neuroendocrine neoplasms. Surgery 152, 1172–1176 (2012).

  202. 202.

    Ardill, J. E., McCance, D. R., Stronge, W. V. & Johnston, B. T. Raised circulating Neurokinin A predicts prognosis in metastatic small bowel neuroendocrine tumours. Lowering Neurokinin A indicates improved prognosis. Ann. Clin. Biochem. 53, 259–264 (2016).

  203. 203.

    Shi, W. et al. The octreotide suppression test and [111In-DTPA-D-Phe1]-octreotide scintigraphy in neuroendocrine tumours correlate with responsiveness to somatostatin analogue treatment. Clin. Endocrinol. 48, 303–309 (1998).

  204. 204.

    Mehta, S. et al. Somatostatin receptor SSTR-2a expression is a stronger predictor for survival than Ki-67 in pancreatic neuroendocrine tumors. Medicine 94, e1281 (2015).

  205. 205.

    Haug, A. R. et al. 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J. Nucl. Med. 51, 1349–1356 (2010).

  206. 206.

    Ezziddin, S. et al. Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system. J. Nucl. Med. 55, 1260–1266 (2014).

  207. 207.

    Chan, D. L. et al. Dual somatostatin receptor/FDG PET/CT imaging in metastatic neuroendocrine tumours: proposal for a novel grading scheme with prognostic significance. Theranostics 7, 1149–1158 (2017).

  208. 208.

    Severi, S. et al. Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imag. 40, 881–888 (2013).

  209. 209.

    Atkins, D. et al. Grading quality of evidence and strength of recommendations. BMJ 328, 1490 (2004).

  210. 210.

    van Haard, P. M. Chromatography of urinary indole derivatives. J. Chromatogr. 429, 59–94 (1988).

  211. 211.

    Carling, R. S., Degg, T. J., Allen, K. R., Bax, N. D. & Barth, J. H. Evaluation of whole blood serotonin and plasma and urine 5-hydroxyindole acetic acid in diagnosis of carcinoid disease. Ann. Clin. Biochem. 39, 577–582 (2002).

  212. 212.

    Wermers, R. A., Fatourechi, V., Wynne, A. G., Kvols, L. K. & Lloyd, R. V. The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Medicine 75, 53–63 (1996).

  213. 213.

    Katznelson, L. et al. Acromegaly: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 3933–3951 (2014).

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Review criteria

For our literature search, the National Center for Biotechnology Information PubMed online database was queried on 21 August 2017 with the following key words: “neuroendocrine” AND “biomarker”, yielding 6,779 papers. After screening of titles for biomarkers in gastroenteropancreatic neuroendocrine tumours, 421 original studies were left for abstract and, if available, full-text evaluation. Through cross-references, relevant studies that were not obtained through the original search were also included.

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  1. ENETS Center of Excellence, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands

    • Johannes Hofland
    • , Wouter T. Zandee
    •  & Wouter W. de Herder

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All authors researched data for the article, provided substantial contributions to discussions of the content, contributed equally to the writing of the article and reviewed and/or edited the manuscript before its submission.

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The authors declare no competing interests.

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Correspondence to Johannes Hofland.

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https://doi.org/10.1038/s41574-018-0082-5