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Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine tumors (islet-cell tumors)

Jonathan R Strosberg, MD
Section Editors
David M Nathan, MD
David C Whitcomb, MD, PhD
Richard M Goldberg, MD
Deputy Editors
Diane MF Savarese, MD
Shilpa Grover, MD, MPH, AGAF


Pancreatic neuroendocrine tumors (pancreatic NETs), also known as islet cell tumors, are rare neoplasms that arise in the endocrine tissues of the pancreas (picture 1). They can secrete a variety of peptide hormones, including insulin, gastrin, glucagon, and vasoactive intestinal peptide (VIP), resulting in myriad clinical syndromes. In modern clinical series, however, between 50 and 75 percent of pancreatic NETs are nonfunctioning (ie, unassociated with a hormonal syndrome).

This topic review will cover the classification, clinical presentation, localization and staging of well-differentiated pancreatic NETs. A discussion of surgical management of sporadic pancreatic NETs, clinical features, diagnostic evaluation and treatment of high-grade gastroenteropancreatic neuroendocrine carcinomas, and specific topics that address the presentation and management of functioning pancreatic NETs and neuroendocrine neoplasms of unknown primary site are all presented elsewhere.

(See "Surgical resection of sporadic pancreatic neuroendocrine tumors".)

(See "High-grade gastroenteropancreatic neuroendocrine carcinoma".)

(See "Insulinoma".)

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Literature review current through: Nov 2017. | This topic last updated: Oct 20, 2017.
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  1. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours of the Digestive System, 4th ed, Bosman TF, Carneiro F, Hruban RH, Theise ND (Eds), International Agency for Research on cancer (IARC), Lyon 2010. p.13.
  2. Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 2014; 120:2814.
  3. American Joint Committee on Cancer Staging Manual, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010.
  4. Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 2004; 1014:13.
  5. Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol 2007; 20 Suppl 1:S94.
  6. Hallet J, Law CH, Cukier M, et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015; 121:589.
  7. Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol 2017; 3:1335.
  8. Fesinmeyer MD, Austin MA, Li CI, et al. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2005; 14:1766.
  9. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008; 135:1469.
  10. Leoncini E, Carioli G, La Vecchia C, et al. Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann Oncol 2016; 27:68.
  11. Capurso G, Falconi M, Panzuto F, et al. Risk factors for sporadic pancreatic endocrine tumors: a case-control study of prospectively evaluated patients. Am J Gastroenterol 2009; 104:3034.
  12. Hassan MM, Phan A, Li D, et al. Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study. Int J Cancer 2008; 123:867.
  13. Halfdanarson TR, Bamlet WR, McWilliams RR, et al. Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study. Pancreas 2014; 43:1219.
  14. Solcia E, Kloppel G, Sobin LH.. Histological typing on endocrine tumors. In: WHO International Classification of Tumors, 2nd, Springer, Berlin, Germany 2000.
  15. Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002; 20:2633.
  16. WHO Classification of Tumours of the Digestive System, Bosman F, Carneiro F, Hruban R, Thiese N (Eds), IARC Press, Lyon, France 2010.
  17. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39:707.
  18. Zerbi A, Falconi M, Rindi G, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol 2010; 105:1421.
  19. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 2008; 19:1727.
  20. Falconi M, Plockinger U, Kwekkeboom DJ, et al. Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology 2006; 84:196.
  21. Ito T, Tanaka M, Sasano H, et al. Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors. J Gastroenterol 2007; 42:497.
  22. Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 2005; 12:1083.
  23. Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2011; 61:113.
  24. Kasumova GG, Tabatabaie O, Eskander MF, et al. National Rise of Primary Pancreatic Carcinoid Tumors: Comparison to Functional and Nonfunctional Pancreatic Neuroendocrine Tumors. J Am Coll Surg 2017; 224:1057.
  25. de Mestier L, Hentic O, Cros J, et al. Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. Ann Intern Med 2015; 162:682.
  26. Vagefi PA, Razo O, Deshpande V, et al. Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. Arch Surg 2007; 142:347.
  27. Li J, Luo G, Fu D, et al. Preoperative diagnosis of nonfunctioning pancreatic neuroendocrine tumors. Med Oncol 2011; 28:1027.
  28. Nomura N, Fujii T, Kanazumi N, et al. Nonfunctioning neuroendocrine pancreatic tumors: our experience and management. J Hepatobiliary Pancreat Surg 2009; 16:639.
  29. Cheema A, Weber J, Strosberg JR. Incidental detection of pancreatic neuroendocrine tumors: an analysis of incidence and outcomes. Ann Surg Oncol 2012; 19:2932.
  30. Cheslyn-Curtis S, Sitaram V, Williamson RC. Management of non-functioning neuroendocrine tumours of the pancreas. Br J Surg 1993; 80:625.
  31. Madura JA, Cummings OW, Wiebke EA, et al. Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort. Am Surg 1997; 63:573.
  32. Matthews BD, Heniford BT, Reardon PR, et al. Surgical experience with nonfunctioning neuroendocrine tumors of the pancreas. Am Surg 2000; 66:1116.
  33. Chu QD, Hill HC, Douglass HO Jr, et al. Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas. Ann Surg Oncol 2002; 9:855.
  34. Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol 2005; 16:1806.
  35. Pape UF, Jann H, Müller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008; 113:256.
  36. Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010; 21:1794.
  37. Riihimäki M, Hemminki A, Sundquist K, et al. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer 2016; 139:2679.
  38. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas 2009; 38:255.
  39. Sadowski SM, Neychev V, Millo C, 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 2016; 34:588.
  40. Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg 2008; 247:165.
  41. Paulson EK, McDermott VG, Keogan MT, et al. Carcinoid metastases to the liver: role of triple-phase helical CT. Radiology 1998; 206:143.
  42. Legmann P, Vignaux O, Dousset B, et al. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. AJR Am J Roentgenol 1998; 170:1315.
  43. Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc 2011; 73:691.
  44. Dromain C, de Baere T, Baudin E, et al. MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques. AJR Am J Roentgenol 2003; 180:121.
  45. King CM, Reznek RH, Dacie JE, Wass JA. Imaging islet cell tumours. Clin Radiol 1994; 49:295.
  46. Wang SC, Parekh JR, Zuraek MB, et al. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg 2010; 145:276.
  47. Thoeni RF, Mueller-Lisse UG, Chan R, et al. Detection of small, functional islet cell tumors in the pancreas: selection of MR imaging sequences for optimal sensitivity. Radiology 2000; 214:483.
  48. Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med 1996; 125:26.
  49. Pisegna JR, Doppman JL, Norton JA, et al. Prospective comparative study of ability of MR imaging and other imaging modalities to localize tumors in patients with Zollinger-Ellison syndrome. Dig Dis Sci 1993; 38:1318.
  50. Dromain C, de Baere T, Lumbroso J, et al. Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol 2005; 23:70.
  51. Vinik AI, Delbridge L, Moattari R, et al. Transhepatic portal vein catheterization for localization of insulinomas: a ten-year experience. Surgery 1991; 109:1.
  52. Rösch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med 1992; 326:1721.
  53. Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol 2000; 95:2271.
  54. Hellman P, Hennings J, Akerström G, Skogseid B. Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1. Br J Surg 2005; 92:1508.
  55. James PD, Tsolakis AV, Zhang M, et al. Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis. Gastrointest Endosc 2015; 81:848.
  56. Kann PH, Kann B, Fassbender WJ, et al. Small neuroendocrine pancreatic tumors in multiple endocrine neoplasia type 1 (MEN1): least significant change of tumor diameter as determined by endoscopic ultrasound (EUS) imaging. Exp Clin Endocrinol Diabetes 2006; 114:361.
  57. Cadiot G, Lebtahi R, Sarda L, et al. Preoperative detection of duodenal gastrinomas and peripancreatic lymph nodes by somatostatin receptor scintigraphy. Groupe D'etude Du Syndrome De Zollinger-Ellison. Gastroenterology 1996; 111:845.
  58. Chatzipantelis P, Salla C, Konstantinou P, et al. Endoscopic ultrasound-guided fine-needle aspiration cytology of pancreatic neuroendocrine tumors: a study of 48 cases. Cancer 2008; 114:255.
  59. Atiq M, Bhutani MS, Bektas M, et al. EUS-FNA for pancreatic neuroendocrine tumors: a tertiary cancer center experience. Dig Dis Sci 2012; 57:791.
  60. Modlin IM, Tang LH. Approaches to the diagnosis of gut neuroendocrine tumors: the last word (today). Gastroenterology 1997; 112:583.
  61. Lamberts SW, Bakker WH, Reubi JC, Krenning EP. Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med 1990; 323:1246.
  62. Modlin IM, Cornelius E, Lawton GP. Use of an isotopic somatostatin receptor probe to image gut endocrine tumors. Arch Surg 1995; 130:367.
  63. Fjällskog ML, Ludvigsen E, Stridsberg M, et al. Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors. Med Oncol 2003; 20:59.
  64. Kimura N, Pilichowska M, Date F, et al. Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine tumors. Clin Cancer Res 1999; 5:3483.
  65. Papotti M, Bongiovanni M, Volante M, et al. Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch 2002; 440:461.
  66. Zimmer T, Stölzel U, Bäder M, et al. Endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localisation of insulinomas and gastrinomas. Gut 1996; 39:562.
  67. Reidy-Lagunes DL, Gollub MJ, Saltz LB. Addition of octreotide functional imaging to cross-sectional computed tomography or magnetic resonance imaging for the detection of neuroendocrine tumors: added value or an anachronism? J Clin Oncol 2011; 29:e74.
  68. Shaverdian N, Pinchot SN, Zarebczan B, et al. Utility of ¹¹¹indium-pentetreotide scintigraphy in patients with neuroendocrine tumors. Ann Surg Oncol 2013; 20:640.
  69. Janson ET, Westlin JE, Eriksson B, et al. [111In-DTPA-D-Phe1]octreotide scintigraphy in patients with carcinoid tumours: the predictive value for somatostatin analogue treatment. Eur J Endocrinol 1994; 131:577.
  70. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26:2124.
  71. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504524.htm (Accessed on June 07, 2016).
  72. Thom AK, Norton JA, Doppman JL, et al. Prospective study of the use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery 1992; 112:1002.
  73. Doppman JL, Miller DL, Chang R, et al. Insulinomas: localization with selective intraarterial injection of calcium. Radiology 1991; 178:237.
  74. Pereira PL, Roche AJ, Maier GW, et al. Insulinoma and islet cell hyperplasia: value of the calcium intraarterial stimulation test when findings of other preoperative studies are negative. Radiology 1998; 206:703.
  75. Abboud B, Boujaoude J. Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol 2008; 14:657.
  76. Frucht H, Norton JA, London JF, et al. Detection of duodenal gastrinomas by operative endoscopic transillumination. A prospective study. Gastroenterology 1990; 99:1622.
  77. Huai JC, Zhang W, Niu HO, et al. Localization and surgical treatment of pancreatic insulinomas guided by intraoperative ultrasound. Am J Surg 1998; 175:18.
  78. Modlin IM, Gustafsson BI, Moss SF, et al. Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol 2010; 17:2427.
  79. Peracchi M, Conte D, Gebbia C, et al. Plasma chromogranin A in patients with sporadic gastro-entero-pancreatic neuroendocrine tumors or multiple endocrine neoplasia type 1. Eur J Endocrinol 2003; 148:39.
  80. O'Toole D, Grossman A, Gross D, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology 2009; 90:194.
  81. O'Connor DT, Deftos LJ. Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986; 314:1145.
  82. Panzuto F, Severi C, Cannizzaro R, 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 2004; 27:6.
  83. Wang YH, Yang QC, Lin Y, et al. Chromogranin A as a marker for diagnosis, treatment, and survival in patients with gastroenteropancreatic neuroendocrine neoplasm. Medicine (Baltimore) 2014; 93:e247.
  84. Nikou GC, Marinou K, Thomakos P, et al. Chromogranin a levels in diagnosis, treatment and follow-up of 42 patients with non-functioning pancreatic endocrine tumours. Pancreatology 2008; 8:510.
  85. Campana D, Nori F, Piscitelli L, et al. Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol 2007; 25:1967.
  86. Baudin E, Gigliotti A, Ducreux M, et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer 1998; 78:1102.
  87. Jun E, Kim SC, Song KB, et al. Diagnostic value of chromogranin A in pancreatic neuroendocrine tumors depends on tumor size: A prospective observational study from a single institute. Surgery 2017; 162:120.
  88. Pregun I, Herszényi L, Juhász M, et al. Effect of proton-pump inhibitor therapy on serum chromogranin a level. Digestion 2011; 84:22.
  89. Korse CM, Muller M, Taal BG. Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours. Br J Cancer 2011; 105:1173.
  90. Eriksson B, Oberg K, Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion 2000; 62 Suppl 1:33.
  91. Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449:395.
  92. Strosberg JR, Cheema A, Weber JM, et al. Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications. Ann Surg 2012; 256:321.
  93. Strosberg JR, Cheema A, Weber J, et al. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol 2011; 29:3044.
  94. Cho JH, Ryu JK, Song SY, et al. Prognostic Validity of the American Joint Committee on Cancer and the European Neuroendocrine Tumors Staging Classifications for Pancreatic Neuroendocrine Tumors: A Retrospective Nationwide Multicenter Study in South Korea. Pancreas 2016; 45:941.
  95. Bergsland EK, Woltering EA, Rindo G. Neuroendocrine tumors of the pancreas. In: AJCC Cancer Staging Manual, 8th, Amin MB (Ed), AJCC, Chicago 2017. p.407.
  96. Luo G, Javed A, Strosberg JR, et al. Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems. J Clin Oncol 2017; 35:274.