Pancreatic Neuroendocrine Tumors (pNETs)

  • Alessandro Sanguinetti
  • Andrea Polistena
  • Louis Banka Johnson
  • Nicola Avenia


This chapter briefly summarizes the epidemiology, pathophysiology, clinical management, and outcomes of patients with pancreatic neuroendocrine tumors (PNETs) and highlights recent advances in PNET research. PNETs are rare neoplasms, compared with carcinomas arising from pancreatic exocrine tissue. They, like other neuroendocrine tumor types, display variable malignant potential, hormone-related syndromes (functionality), localization, and genetic background. Although tumor origin and molecular pathogenesis remain poorly understood, recently established grading and staging systems facilitate patient risk stratification and thereby directly impact clinical decision-making. Although the optimal clinical management of PNETs involves a multidisciplinary approach, surgery remains the only curative treatment for early-stage disease. Surgery may also have a role in patients with advanced stage disease, including those with hepatic metastases. Alternative therapeutic approaches applied to PNETs, including chemotherapy, radiofrequency ablation, transarterial chemoembolization, biotherapy, polypeptide radionuclide receptor therapy, antiangiogenic therapy, and selective internal radiotherapy, have failed to demonstrate a long-term survival benefit. Surgery remains the primary therapeutic option for patients with PNETs. Research on PNETs is desperately needed to improve the therapeutic options for patients with this disease.


Pancreatic neuroendocrine tumors Insulinoma Gastrinoma VIPoma Glucagonoma Nonfunctioning Multiple endocrine neoplasia syndrome type 1 Mahvash disease 


  1. 1.
    Fraenkel M, Kim MK, Faggiano A, et al. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26:691–703.PubMedCrossRefGoogle Scholar
  2. 2.
    Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40:1–18.CrossRefGoogle Scholar
  3. 3.
    Halfdanarson TR, Rubin J, Farnell MB, et al. Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer. 2008;15:409–27.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine tumors of the pancreas: analysis of autopsy cases. Dig Dis Sci. 1991;36:933–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Halfdanarson TR, Rabe KG, Rubin J, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–33.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007;14:3492–500.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–92.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Rindi G, Bordi C. Highlights of the biology of endocrine tumours of the gut and pancreas. Endocr Relat Cancer. 2003;10:427–36.PubMedCrossRefGoogle Scholar
  10. 10.
    de Wilde RF, Edil BH, Hruban RH, et al. Well differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol. 2012;9:199–208.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Perren A, Anlauf M, Henopp T, et al. Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas. J Clin Endocrinol Metab. 2007;92:1118–28.PubMedCrossRefGoogle Scholar
  12. 12.
    Massironi S, Sciola V, Peracchi M, et al. Neuroendocrine tumors of the gastro-entero-pancreatic system. World J Gastroenterol. 2008;14:5377–84.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Ehehalt F, Saeger HD, Schmidt CM, et al. Neuroendocrine tumors of the pancreas. Oncologist. 2009;14:456–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg. 2006;243:265–72.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Oberg K. Genetics and molecular pathology of neuroendocrine gastrointestinal and pancreatic tumors (gastroenteropancreatic neuroendocrine tumors). Curr Opin Endocrinol Diabetes Obes. 2009;16:72–8.CrossRefGoogle Scholar
  16. 16.
    Alexakis N, Connor S, Ghaneh P, et al. Hereditary pancreatic endocrine tumours. Pancreatology. 2004;4:417–33. discussion 434-5.PubMedCrossRefGoogle Scholar
  17. 17.
    Dean PG, van Heerden JA, Farley DR, et al. Are patients with multiple endocrine neoplasia type I prone to premature death? World J Surg. 2000;24:1437–41.PubMedCrossRefGoogle Scholar
  18. 18.
    Pellegata NS. MENX and MEN4. Clinics (Sao Paulo). 2012;67(Suppl 1):13–8.CrossRefGoogle Scholar
  19. 19.
    Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386:2–15.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Vortmeyer AO, Huang S, Lubensky I, et al. Nonislet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab. 2004;89:1934–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–203.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Heaphy CM, de Wilde RF, Jiao Y, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333:425.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Singh R, Basturk O, Klimstra DS, et al. Lipid-rich variant of pancreatic endocrine neoplasms. Am J Surg Pathol. 2006;30:194–200.PubMedCrossRefGoogle Scholar
  24. 24.
    Marinoni I, Kurrer AS, Vassella E, et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology. 2014;146:453–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Klimsta DS, Armold R, Capella C, et al. Neuroendocrine neoplasms of the pancreas. In: Bosman F, Carneiro F, Hruban RH, et al., editors. WHO classification of tumours of the digestive system. Lyon: IARC Press; 2010. p. 322–6.Google Scholar
  26. 26.
    Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Exocrine and endocrine pancreas. AJCC cancer staging manual. New York, NY: Springer; 2010. p. 241–9.Google Scholar
  28. 28.
    Ellison TA, Wolfgang CL, Shi C, 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. 2014;259:204–12.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Liu TC, Hamilton N, Hawkins W, et al. Comparison of WHO classifications (2004, 2010), the Hochwald grading system, and AJCC and ENETS staging systems in predicting prognosis in locoregional well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2013;37:853–9.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Rindi G, Falconi M, Klersy C, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012;104:764–77.PubMedCrossRefGoogle Scholar
  31. 31.
    Sakurai A, Katai M, Yamashita K, et al. Long term follow-up of patients with multiple endocrine neoplasia type 1. Endocr J. 2007;54:295–302.PubMedCrossRefGoogle Scholar
  32. 32.
    Davì MV, Boninsegna L, Dalle Carbonare L, et al. Presentation and outcome of pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1 syndrome. Neuroendocrinology. 2011;94:58–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Broder LE, Carter SK. Pancreatic islet cell carcinoma. I. Clinical features of 52 patients. Ann Intern Med. 1973;79:101–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Cubilla AL, Hajdu SI. Islet cell carcinoma of the pancreas. Arch Pathol. 1975;99:204–7.PubMedGoogle Scholar
  35. 35.
    La Rosa S, Klersy C, Uccella S, et al. Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol. 2009;40:30–40.PubMedCrossRefGoogle Scholar
  36. 36.
    Schmitt AM, Anlauf M, Rousson V, WHO, et al. Criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors. Am J Surg Pathol. 2004;2007(31):1677–82.Google Scholar
  37. 37.
    Zhu L, Domenico DR, Howard JM. Metastatic pancreatic neuroendocrine carcinoma causing Cushing’s syndrome. ACTH secretion by metastases 3 years after resection of nonfunctioning primary cancer. Int J Pancreatol. 1996;19:205–8.PubMedGoogle Scholar
  38. 38.
    Milanesi A, Yu R, Geller SA, et al. Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1. Pancreas. 2011;40:634–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Miehle K, Tannapfel A, Lamesch P, et al. Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production upon second recurrence. J Clin Endocrinol Metab. 2004;89:3731–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Heik SCW, Klöppel G, Krone W, et al. Hypoglykämie durch Insulinom bei Diabetes mellitus. Dtsch Med Wochenschr. 1988;113:1714–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Mann JR, Rayner PH, Gourevitch A. Insulinoma in childhood. Arch Dis Child. 1969;44:435–42.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lo CY, Lam KY, Kung AW, et al. Pancreatic insulinomas. A 15-year experience. Arch Surg. 1997;132:926–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Sempoux C, Guiot Y, Dahan K, et al. The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. Diabetes. 2003;52:784–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Reinecke-Lüthge A, Koschoreck F, Klöppel G. The molecular basis of persistent hyperinsulinemic hypoglycemia of infancy and its pathologic substrates. Virchows Arch. 2000;436:1–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Keller A, Stone AM, Valderrama E, et al. Pancreatic nesidioblastosis in adults. Report of a patient with hyperinsulinemic hypoglycemia. Am J Surg. 1983;145:412–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Anlauf M, Wieben D, Perren A, et al. Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence and characterization of β-cell changes. Am J Surg Pathol. 2005;29:524–33.PubMedCrossRefGoogle Scholar
  47. 47.
    Miyazaki K, Funakoshi A, Nishihara S, et al. Aberrant insulinoma in the duodenum. Gastroenterology. 1986;90:1280–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Adamson AR, Grahame-Smith DG, Bogomoletz V, et al. Malignant argentaffinoma with carcinoid syndrome and hypoglycaemia. Br Med J. 1971;3:93–4.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Pelletier G, Cortot A, Launay JM, et al. Serotonin-secreting and insulin-secreting ileal carcinoid tumor and the use of in vitro culture of tumoral cells. Cancer. 1984;54:319–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Shames JM, Dhurandhar NR, Blackard WG. Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med. 1968;44:632–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Kiang DT, Bauer GE, Kennedy BJ. Immunoassayable insulin in carcinoma of the cervix associated with hypoglycemia. Cancer. 1973;31:801–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Ashton MA. Strumal carcinoid of the ovary associated with hyperinsulinaemic hypoglycaemia and cutaneous melanosis. Histopathology. 1995;27:463–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Liu TH, Tseng HC, Zhu Y, et al. Insulinoma. An immunohistochemical and morphologic analysis of 95 cases. Cancer. 1985;56:1420–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Roth J, Klöppel G, Madsen OD, et al. Distribution patterns of proinsulin and insulin in human insulinomas: an immunohistochemical analysis in 76 tumors. Virchows Arch B Cell Pathol. 1992;63:51–61.CrossRefGoogle Scholar
  55. 55.
    Paik WH, Ryu JK, Song BJ, et al. Clinical usefulness of plasma chromogranin a in pancreatic neuroendocrine neoplasm. J Korean Med Sci. 2013;28:750–4.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Vinik AI, Silva MP, Woltering EA, et al. Biochemical testing for neuroendocrine tumors. Pancreas. 2009;38:876–89.PubMedCrossRefGoogle Scholar
  57. 57.
    Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer. 1999;86:858–65.PubMedCrossRefGoogle Scholar
  58. 58.
    Oberg K. Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011;18(Suppl 1):S17–25.PubMedCrossRefGoogle Scholar
  59. 59.
    Anders S. Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumors. Best Pract Res Clin Gastroenterol. 2012;26:803–18.CrossRefGoogle Scholar
  60. 60.
    Herwick S, Miller FH, Keppke AL. MRI of islet cell tumors of the pancreas. AJR Am J Roentgenol. 2006;187:W472–80.PubMedCrossRefGoogle Scholar
  61. 61.
    Singhi AD, Chu LC, Tatsas AD, et al. Cystic pancreatic neuroendocrine tumors: a clinicopathologic study. Am J Surg Pathol. 2012;36:1666–73.PubMedCrossRefGoogle Scholar
  62. 62.
    Sundin A, Vullierme MP, Kaltsas G, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: radiological examinations. Neuroendocrinology. 2009;90:167–83.PubMedCrossRefGoogle Scholar
  63. 63.
    Caramella C, Dromain C, De Baere T, et al. Endocrine pancreatic tumors: which are the most useful MRI sequences? Eur Radiol. 2010;20:2618–27.PubMedCrossRefGoogle Scholar
  64. 64.
    Oberg K. Diagnostic work-up of gastroenteropancreatic neuroendocrine tumors. Clinics (Sao Paulo). 2012;67:109–12.CrossRefGoogle Scholar
  65. 65.
    Joseph S, Wang YZ, Boudreaux JP, et al. Neuroendocrine tumors: current recommendations for diagnosis and surgical management. Endocrinol Metab Clin N Am. 2011;40:205–31.CrossRefGoogle Scholar
  66. 66.
    de Herder WW, Kwekkeboom DJ, Valkema R, et al. Neuroendocrine tumors and somatostatin: imaging techniques. J Endocrinol Investig. 2005;28:132–6.Google Scholar
  67. 67.
    Garin E, Le Jeune F, Devillers A, et al. Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. J Nucl Med. 2009;50:858–64.PubMedCrossRefGoogle Scholar
  68. 68.
    Binderup T, Knigge U, Loft A, et al. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res. 2010;16:978–85.PubMedCrossRefGoogle Scholar
  69. 69.
    Gabriel M, Decristoforo C, Kendler D, et al. 68 Ga- DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48:508–18.PubMedCrossRefGoogle Scholar
  70. 70.
    Naswa N, Sharma P, Kumar A, et al. Gallium-68-DOTANOC PET/CT of patients with gastroenteropancreatic neuroendocrine tumors: a prospective single-center study. AJR Am J Roentgenol. 2011;197:1221–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Frilling A, Sotiropoulos GC, Li J, et al. Multimodal management of neuroendocrine liver metastases. HPB (Oxford) 2010;12:361-79. 69. Kim MK. Endoscopic ultrasound in gastroenteropancreatic neuroendocrine tumors. Gut Liver. 2012;6:405–10.CrossRefGoogle Scholar
  72. 72.
    Atiq M, Bhutani MS, Bektas M, et al. EUS-FNA for pancreatic neuroendocrine tumors: a tertiary cancer center experience. Dig Dis Sci. 2012;57:791–800.PubMedCrossRefGoogle Scholar
  73. 73.
    Lennon AM, Newman N, Makary MA, et al. EUS-guided tattooing before laparoscopic distal pancreatic resection (with video). Gastrointest Endosc. 2010;72:1089–94.PubMedCrossRefGoogle Scholar
  74. 74.
    Fendrich V, Waldmann J, Bartsch DK, Langer P. Surgical management of pancreatic endocrine tumors. Nat Rev Clin Oncol. 2009;6(7):419–28.PubMedCrossRefGoogle Scholar
  75. 75.
    Grant CS. Surgical management of malignant islet cell tumors. World J Surg. 1993;17(4):498–503.PubMedCrossRefGoogle Scholar
  76. 76.
    Grama D, Eriksson B, Martensson H, et al. Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes. World J Surg. 1992;16(4):632–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Crippa S, Zerbi A, Boninsegna L, et al. Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg. 2012;147(3):261–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Rothmund M, Angelini L, Brunt LM, et al. Surgery for benign insulinoma: an international review. World J Surg. 1990;14(3):393–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Falconi M, Zerbi A, Crippa S, et al. Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol. 2010;17(6):1621–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhao YP, Zhan HX, Zhang TP, et al. Surgical management of patients with insulinomas: result of 292 cases in a single institution. J Surg Oncol. 2011;103(2):169–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Hirshberg B, Libutti SK, Alexander HR, et al. Blind distal pancreatectomy for occult insulinoma, an inadvisable procedure. J Am Coll Surg. 2002;194(6):761–4.PubMedCrossRefGoogle Scholar
  82. 82.
    Norton JA, Shawker TH, Doppman JL, et al. Localization and surgical treatment of occult insulinomas. Ann Surg. 1990;212(5):615–20.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Wolfe MM, Alexander RW, McGuigan JE. Extrapancreatic, extraintestinal gastrinoma: effective treatment by surgery. N Engl J Med. 1982;306:1533–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Thompson JC, Lewis BG, Wiener I, et al. The role of surgery in the Zollinger–Ellison syndrome. Ann Surg. 1983;197:594–607.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Schwarting H, Osse G, Sippel M, et al. Morphometry of the pancreatic islets in patients with insulinomas and gastrinomas. In: Mutt V, Uvnäs-Moberg K, editors. Regulatory peptides. Abstracts of the 4th international symposium on gastrointestinal hormones. Amsterdam: Elsevier; 1983. p. 129.Google Scholar
  86. 86.
    Martella EM, Ferraro G, Azzoni C, et al. Pancreatic-polypeptide cell hyperplasia associated with pancreatic or duodenal gastrinomas. Hum Pathol. 1997;28:149–53.PubMedCrossRefGoogle Scholar
  87. 87.
    Mallinson CN, Bloom SR, Warin AP, et al. A glucagonoma syndrome. Lancet. 1974;304:1–5.CrossRefGoogle Scholar
  88. 88.
    Fujita J, Seino Y, Ishida H, et al. A functional study of a case of glucagonoma exhibiting typical glucagonoma syndrome. Cancer. 1986;57:860–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Ruttman E, Klöppel G, Bommer G, et al. Pancreatic glucagonoma with and without syndrome. Immunocytochemical study of 5 tumour cases and review of the literature. Virchows Arch A Pathol Anat. 1980;388:51–67.CrossRefGoogle Scholar
  90. 90.
    Bordi C, Ravazzola M, Baetens D, et al. A study of glucagonomas by light and electron microscopy and immunofluorescence. Diabetes. 1979;28:925–36.PubMedCrossRefGoogle Scholar
  91. 91.
    Hamid QA, Bishop AE, Sikri KL, et al. Immunocytochemical characterization of 10 pancreatic tumours, associated with the glucagonoma syndrome, using antibodies to separate regions of the pro-glucagon molecule and other neuroendocrine markers. Histopathology. 1986;10:119–33.PubMedCrossRefGoogle Scholar
  92. 92.
    Trump DL, Livingston JN, Baylin SB. Watery diarrhea syndrome in an adult with ganglioneuroma-pheochromocytoma: identification of vasoactive intestinal peptide, calcitonin, and catecholamines and assessment of their biologic activity. Cancer. 1977;40:1526–32.PubMedCrossRefGoogle Scholar
  93. 93.
    Mendelsohn G, Eggleston JC, Olson JL, et al. Vasoactive intestinal peptide and its relationship to ganglion cell differentiation in neuroblastic tumors. Lab Investig. 1979;41:144–9.PubMedGoogle Scholar
  94. 94.
    Capella C, Polak JM, Buffa R, et al. Morphologic patterns and diagnostic criteria of VIP-producing endocrine tumors. A histologic, histochemical, ultrastructural and biochemical study of 32 cases. Cancer. 1983;52:1860–74.PubMedCrossRefGoogle Scholar
  95. 95.
    Udall JN Jr. Diarrhea due to hormone-secreting tumours. In: Lebenthal E, editor. Textbook of gastroenterology and nutrition in infancy. 2nd ed. New York: Raven; 1989. p. 1193–205.Google Scholar
  96. 96.
    Long RG, Bryant MG, Mitchell SJ, et al. Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas). Br Med J (Clin Res Ed). 1981;282:1767–71.CrossRefGoogle Scholar
  97. 97.
    Verner JV, Morrison AB. Endocrine pancreatic islet disease with diarrhea. Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med. 1974;133:492–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Tomita T, Kimmel JR, Friesen SR, et al. Pancreatic polypeptide cell hyperplasia with and without watery diarrhea syndrome. J Surg Oncol. 1980;14:11–20.PubMedCrossRefGoogle Scholar
  99. 99.
    Ooi A, Kameya T, Tsumuraya M, et al. Pancreatic endocrine tumours associated with WDHA syndrome. An immunohistochemical and electron microscopic study. Virchows Arch A Pathol Anat. 1985;405:311–23.CrossRefGoogle Scholar
  100. 100.
    Krejs GJ, Orci L, Conlon JM, et al. Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N Engl J Med. 1979;301:285–92.PubMedCrossRefGoogle Scholar
  101. 101.
    Vinik AI, Gonzales MR. New and emerging syndromes due to neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:19–63, vii.PubMedCrossRefGoogle Scholar
  102. 102.
    Sessa F, Arcidiaco M, Valenti L, et al. Metastatic psammomatous somatostatinoma of the pancreas causing severe ketoacedotic diabetes cured by surgery. Endocr Pathol. 1997;8:327–33.PubMedCrossRefGoogle Scholar
  103. 103.
    Heitz PU, Klöppel G, Polak JM, et al. Ectopic hormone production by endocrine tumors: localization of hormones at the cellular level by immunocytochemistry. Cancer. 1981;48:2029–37.PubMedCrossRefGoogle Scholar
  104. 104.
    Melmed S, Yamashita S, Kovacs K, et al. Cushing’s syndrome due to ectopic proopiomelanocortin gene expression by islet cell carcinoma of the pancreas. Cancer. 1987;59:772–8.PubMedCrossRefGoogle Scholar
  105. 105.
    Wilander E, El-Salhy M, Willén T, et al. Immunocytochemistry and electron microscopy of an argentaffin endocrine tumor of the pancreas. Virchows Arch A Pathol Anat. 1981;392:263–9.CrossRefGoogle Scholar
  106. 106.
    Sano T, Asa SL, Kovacs K. Growth hormone-releasing hormoneproducing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev. 1988;9:357–73.PubMedCrossRefGoogle Scholar
  107. 107.
    Bostwick DG, Quan R, Hoffman AR, et al. Growth-hormonereleasing factor immunoreactivity in human endocrine tumors. Am J Pathol. 1984;117:167–70.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Rasbach DA, Hammond JM. Pancreatic islet cell carcinoma with hypercalcemia. Primary hyperparathyroidism or humoral hypercalcemia of malignancy. Am J Med. 1985;78:337–42.PubMedCrossRefGoogle Scholar
  109. 109.
    Broadus AE, Mangin M, Ikeda K, et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med. 1988;319:556–63.PubMedCrossRefGoogle Scholar
  110. 110.
    Saeger W, Schulte HM, Klöppel G. Morphology of a GHRH producing pancreatic islet cell tumor causing acromegaly. Virchows Arch A Pathol Anat. 1986;409:547–54.CrossRefGoogle Scholar
  111. 111.
    Cryer PE, Hill GJ. Pancreatic islet cell carcinoma with hypercalcemia and hypergastrinemia: response to streptozotocin. Cancer. 1976;38:2217–21.PubMedCrossRefGoogle Scholar
  112. 112.
    Hammar S, Sale G. Multiple hormone producing islet cell carcinomas of the pancreas. A morphological and biochemical investigation. Hum Pathol. 1975;6:349–62.PubMedCrossRefGoogle Scholar
  113. 113.
    Maton PN, Gardner JD, Jensen RT. Cushing’s syndrome in patients with the Zollinger–Ellison syndrome. N Engl J Med. 1986;315:1–5.PubMedCrossRefGoogle Scholar
  114. 114.
    Sadoff L, Gordon J, Goldman S. Amelioration of hypoglycemia in a patient with malignant insulinoma during the development of the ectopic ACTH syndrome. Diabetes. 1975;24:600–3.PubMedCrossRefGoogle Scholar
  115. 115.
    Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumors. N Engl J Med. 1988;319:605–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Gloor F, Pletscher A, Hardmeier T. Metastasierendes Inselzelladenom des Pankreas mit 5-Hydroxytryptamin- und Insulin-Produktion. Schweiz Med Wochenschr. 1964;94:1476–80.PubMedGoogle Scholar
  117. 117.
    Appleyard TN, Losowsky MS. A pancreatic tumor with carcinoid syndrome and hypoglycemia. Postgrad Med J. 1970;46:159–71.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Ohneda A, Otsuki M, Fujiya H, et al. A malignant insulinoma transformed into a glucagonoma syndrome. Diabetes. 1979;28:962–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Simpson WF, Adams DB, Metcalf JS, et al. Nonfunctioning pancreatic neuroendocrine tumors presenting as pancreatitis: report of four cases. Pancreas. 1988;3:223–31.PubMedCrossRefGoogle Scholar
  120. 120.
    Aabo K, Romond E, Dimitrov NV, et al. Pancreatic islet cell carcinoma associated with multiple hormone secretion and pancytopenia. Evidence of a serum factor suppressing hematopoiesis. Cancer. 1983;51:1691–6.PubMedCrossRefGoogle Scholar
  121. 121.
    Kniffin WD Jr, Spencer SK, Memoli VA, et al. Metastatic islet cell amphicrine carcinoma of the pancreas. Association with an eosinophilic infiltration of the skin. Cancer. 1988;62:1999–204.PubMedCrossRefGoogle Scholar
  122. 122.
    Feurle GE, Helmstaedter V, Tischbirek K, et al. A multihormonal tumor of the pancreas producing neurotensin. Dig Dis Sci. 1981;26:1125–33.PubMedCrossRefGoogle Scholar
  123. 123.
    Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery. 1986;100:978–88.PubMedGoogle Scholar
  124. 124.
    Perrone T, Sibley RK, Rosai J. Duodenal gangliocytic paraganglioma. An immunohistochemical and ultrastructural study and a hypothesis concerning its origin. Am J Surg Pathol. 1985;9:31–41.PubMedCrossRefGoogle Scholar
  125. 125.
    Parekh JR, Wang SC, Bergsland EK, et al. Lymph node sampling rates and predictors of nodal metastasis in pancreatic neuroendocrine tumor resections: the ucsf experience with 149 patients. Pancreas. 2012;41(6):840–4.PubMedCrossRefGoogle Scholar
  126. 126.
    Alumets J, Alm P, Falkmer S, et al. Immunohistochemical evidence of peptide hormones in endocrine tumors of the rectum. Cancer. 1981;48:2409–15.PubMedCrossRefGoogle Scholar
  127. 127.
    Kanavaros P, Hoang C, Le Bodic MF, et al. Serotonin-producing pancreatic endocrine tumour. Histological, ultrastructural and immunohistochemical study of a case. Histol Histopathol. 1990;5:325–8.PubMedGoogle Scholar
  128. 128.
    Padberg B, Schröder S, Capella C, et al. Multiple endocrine neoplasia type 1 (MEN 1) revisited. Virchows Arch. 1995;426:541–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Samaan NA, Ouais S, Ordóñez NG, et al. Multiple endocrine syndrome type I. Clinical, laboratory findings, and management in five families. Cancer. 1989;64:741–52.PubMedCrossRefGoogle Scholar
  130. 130.
    Duh QY, Hybarger CP, Geist R, et al. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg. 1987;154:142–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Anlauf M, Schlenger R, Perren A, et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol. 2006;30:560–74.PubMedCrossRefGoogle Scholar
  132. 132.
    Friesen SR. Tumors of the endocrine pancreas. N Engl J Med. 1982;306:580–90.PubMedCrossRefGoogle Scholar
  133. 133.
    Le Bodic MF, Heymann MF, Lecomte M, et al. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. Am J Surg Pathol. 1996;20:1378–84.PubMedCrossRefGoogle Scholar
  134. 134.
    Warner TF, Block M, Hafez GR, et al. Glucagonomas. Ultrastructure and immunohistochemistry. Cancer. 1983;51:1091–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Grant CS. Insulinoma. Best Pract Res Clin Gastroenterol. 2005;19:783–98.PubMedCrossRefGoogle Scholar
  136. 136.
    Berna MJ, Hoffmann KM, Serrano J, et al. 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 (Baltimore). 2006;85:295–330.CrossRefGoogle Scholar
  137. 137.
    Milan SA, Yeo CJ. Neuroendocrine tumors of the pancreas. Curr Opin Oncol. 2012;24:46–55.PubMedCrossRefGoogle Scholar
  138. 138.
    van Beek AP, de Haas ER, van Vloten WA, et al. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. 2004;151:531–7.PubMedCrossRefGoogle Scholar
  139. 139.
    Mullans EA, Cohen PR. Iatrogenic necrolytic migratory erythema: a case report and review of nonglucagonomaassociated necrolytic migratory erythema. J Am Acad Dermatol. 1998;38:866–73.PubMedCrossRefGoogle Scholar
  140. 140.
    Appetecchia M, Ferretti E, Carducci M, et al. Malignant glucagonoma. New options of treatment. J Exp Clin Cancer Res. 2006;25:135–9.PubMedGoogle Scholar
  141. 141.
    Nikou GC, Toubanakis C, Nikolaou P, et al. VIPomas: an update in diagnosis and management in a series of 11 patients. Hepato-Gastroenterology. 2005;52:1259–65.PubMedGoogle Scholar
  142. 142.
    Ghaferi AA, Chojnacki KA, Long WD, et al. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. 2008;12:382–93.PubMedCrossRefGoogle Scholar
  143. 143.
    Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int. 2010;9(3):234–41.PubMedGoogle Scholar
  144. 144.
    Sa Cunha A, Rault A, Beau C, Collet D, Masson B. Laparoscopic central pancreatectomy: single institution experience of 6 patients. Surgery. 2007;142(3):405–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Ellison EC, Sparks J, Verducci JS, et al. 50-year appraisal of gastrinoma: recommendations for staging and treatment. J Am Coll Surg. 2006;202(6):897–905.PubMedCrossRefGoogle Scholar
  146. 146.
    Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med. 1999;341(9):635–44.PubMedCrossRefGoogle Scholar
  147. 147.
    Norton JA, Alexander HR, Fraker DL, et al. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? Ann Surg. 2004;239(5):617–26.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29(17):2372–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Kinoshita K, Minami T, Ohmori Y, Kanayama S, Yoshikawa K, Tsujimura T. Curative resection of a small cell carcinoma of the pancreas: report of a case of long survival without chemotherapy. J Gastroenterol Hepatol. 2004;19(9):1087–91.PubMedCrossRefGoogle Scholar
  150. 150.
    Reyes CV, Wang T. Undifferentiated small cell carcinoma of the pancreas: a report of five cases. Cancer. 1981;47(10):2500–2.PubMedCrossRefGoogle Scholar
  151. 151.
    Nilsson O, Van Cutsem E, Delle Fave G, et al. Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology. 2007;84(3):212–5.CrossRefGoogle Scholar
  152. 152.
    Kolby L, Nilsson O, Ahlman H. Gastroduodenal endocrine tumours. Scand J Surg. 2004;93(4):317–23.PubMedCrossRefGoogle Scholar
  153. 153.
    Akerstrom G. Management of carcinoid tumors of the stomach, duodenum, and pancreas. World J Surg. 1996;20(2):173–82.PubMedCrossRefGoogle Scholar
  154. 154.
    Abu Hilal M, McPhail MJW, Zeidan BA, Jones CE, Johnson CD, Pearce NW. Aggressive multi-visceral pancreatic resections for locally advanced neuroendocrine tumours. Is it worth it? J Pancreas. 2009;10(3):276–9.Google Scholar
  155. 155.
    Norton JA, Kivlen M, Li M, et al. Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Arch Surg. 2003;138(8):859–66.PubMedCrossRefGoogle Scholar
  156. 156.
    Hellman P, Andersson M, Rastad J, et al. Surgical strategy for large or malignant endocrine pancreatic tumors. World J Surg. 2000;24(11):1353–60.PubMedCrossRefGoogle Scholar
  157. 157.
    Hill JS, McPhee JT, McDade TP, et al. Pancreatic neuroendocrine tumors. Cancer. 2009;115(4):741–51.PubMedCrossRefGoogle Scholar
  158. 158.
    Glazer ES, Tseng JF, Al-Refaie W, et al. Long-term survival after surgical management of neuroendocrine hepatic metastases. HPB. 2010;12(6):427–33.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Bruzoni M, Parikh P, Celis R, et al. Management of the primary tumor in patients with metastatic pancreatic neuroendocrine tumor: a contemporary single-institution review. Am J Surg. 2009;197(3):376–81.PubMedCrossRefGoogle Scholar
  160. 160.
    Cho CS, Labow DM, Tang L, et al. Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms. Cancer. 2008;113(1):126–34.PubMedCrossRefGoogle Scholar
  161. 161.
    Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg. 1998;187(1):88–92.PubMedCrossRefGoogle Scholar
  162. 162.
    Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg. 1995;169(1):36–43.PubMedCrossRefGoogle Scholar
  163. 163.
    Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Fave GD, Falconi M. Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology. 2011;93(4):223–9.PubMedCrossRefGoogle Scholar
  164. 164.
    Mayo SC, De Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010;17(12):3129–36.PubMedCrossRefGoogle Scholar
  165. 165.
    Cusati D, Zhang L, Harmsen WS, et al. Metastatic nonfunctioning pancreatic neuroendocrine carcinoma to liver: surgical treatment and outcomes. J Am Coll Surg. 2012;215(1):117–24.PubMedCrossRefGoogle Scholar
  166. 166.
    Dousset B, Saint-Marc O, Pitre J, Soubrane O, Houssin D, Chapuis Y. Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation. World J Surg. 1996;20(7):908–15.PubMedCrossRefGoogle Scholar
  167. 167.
    Elias D, Lasser P, Ducreux M, et al. Liver resection (and associated extrahepatic resections) for metastatic welldifferentiated endocrine tumors: a 15-year single center prospective study. Surgery. 2003;133(4):375–82.PubMedCrossRefGoogle Scholar
  168. 168.
    Kianmanesh R, Sauvanet A, Hentic O, et al. Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection. Ann Surg. 2008;247(4):659–65.PubMedCrossRefGoogle Scholar
  169. 169.
    Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg. 2003;197(1):29–37.PubMedCrossRefGoogle Scholar
  170. 170.
    Thompson GB, Van Heerden JA, Grant CS, Carney JA, Ilstrup DM. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery. 1988;104(6):1011–7.PubMedGoogle Scholar
  171. 171.
    Grazi GL, Cescon M, Pierangeli F, et al. Highly aggressive policy of hepatic resections for neuroendocrine liver metastases. Hepato-Gastroenterology. 2000;47(32):481–6.PubMedGoogle Scholar
  172. 172.
    Bassi C. Middle segment pancreatectomy: a useful tool in the management of pancreatic neoplasms. J Gastrointest Surg. 2007;11(4):421–4.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Hackert T, Hinz U, Fritz S, et al. Enucleation in pancreatic surgery: indications, technique, and outcome compared to standard pancreatic resections. Langenbeck's Arch Surg. 2011;396:1197–203.CrossRefGoogle Scholar
  174. 174.
    Crippa S, Bassi C, Salvia R, Falconi M, Butturini G, Pederzoli P. Enucleation of pancreatic neoplasms. Br J Surg. 2007;94(10):1254–9.PubMedCrossRefGoogle Scholar
  175. 175.
    Dedieu A, Rault A, Collet D, Masson B, Sa Cunha A. Laparoscopic enucleation of pancreatic neoplasm. Surg Endosc Other Intervent Tech. 2011;25(2):575–6.Google Scholar
  176. 176.
    DiNorcia J, Lee MK, Reavey PL, et al. One hundred thirty resections for pancreatic neuroendocrine tumor: evaluating the impact of minimally invasive and parenchyma-sparing techniques. J Gastrointest Surg. 2010;14(10):1536–46.PubMedCrossRefGoogle Scholar
  177. 177.
    Assalia A, Gagner M. Laparoscopic pancreatic surgery for islet cell tumors of the pancreas. World J Surg. 2004;28(12):1239–47.PubMedCrossRefGoogle Scholar
  178. 178.
    Gagner M, Pomp A, Herrera MF, et al. Early experience with laparoscopic resections of islet cell tumors. Surgery. 1996;120(6):1051–4.PubMedCrossRefGoogle Scholar
  179. 179.
    Limongelli P, Belli A, Russo G, et al. Laparoscopic and open surgical treatment of left-sided pancreatic lesions: clinical outcomes and cost-effectiveness analysis. Surg Endosc Other Intervent Tech. 2012;26(7):1830–6.CrossRefGoogle Scholar
  180. 180.
    Kim SC, Park KT, Hwang JW, et al. Comparative analysis of clinical outcomes for laparoscopic distal pancreatic resection and open distal pancreatic resection at a single institution. Surg Endosc Other Intervent Tech. 2008;22(10):2261–8.CrossRefGoogle Scholar
  181. 181.
    Baker MS, Bentrem DJ, Ujiki MB, Stocker S, Talamonti MS. A prospective single institution comparison of peri-operative outcomes for laparoscopic and open distal pancreatectomy. Surgery. 2009;146(4):635–45.PubMedCrossRefGoogle Scholar
  182. 182.
    Kooby DA, Hawkins WG, Schmidt CM, et al. Curative laparoscopic resection for pancreatic neoplasms: a critical analysis from a single institution. J Am Coll Surg. 2010;210(5):779–85.PubMedCrossRefGoogle Scholar
  183. 183.
    Fernández-Cruz L, Cosa R, Blanco L, Levi S, Lopez-Boado MA, Navarro S. Curative laparoscopic resection for pancreatic neoplasms: a critical analysis from a single institution. J Gastrointest Surg. 2007;11(12):1607–22.PubMedCrossRefGoogle Scholar
  184. 184.
    Butturini G, Inama M, Malleo G, et al. Perioperative and long-term results of laparoscopic spleen-preserving distal pancreatectomy with or without splenic vessels conservation: a retrospective analysis. J Surg Oncol. 2012;105(4):387–92.PubMedCrossRefGoogle Scholar
  185. 185.
    Singh N, Lo CY, Chan WF. Laparoscopic enucleation of a nonfunctioning neuroendocrine tumor at the head of the pancreas. JSLS. 2006;10(2):259–62.PubMedPubMedCentralGoogle Scholar
  186. 186.
    Kim SC, Song KB, Jung YS, et al. Short-term clinical outcomes for 100 consecutive cases of laparoscopic pylorus-preserving pancreatoduodenectomy: improvement with surgical experience. Surg Endosc. 2012;27(1):95–103.PubMedCrossRefGoogle Scholar
  187. 187.
    Fernandez-Cruz L, Cesar-Borges G. Laparoscopic strategies for resection of insulinomas. J Gastrointest Surg. 2006;10(5):752–60.PubMedCrossRefGoogle Scholar
  188. 188.
    Toniato A, Meduri F, Foletto M, Avogaro A, Pelizzo M. Laparoscopic treatment of benign insulinomas localized in the body and tail of the pancreas: a single-center experience. World J Surg. 2006;30(10):1916–9.PubMedCrossRefGoogle Scholar
  189. 189.
    Murakami Y, Uemura K, Sudo T, et al. Number of metastatic lymph nodes, but not lymph node ratio, is an independent prognostic factor after resection of pancreatic carcinoma. J Am Coll Surg. 2010;211(2):196–204.PubMedCrossRefGoogle Scholar
  190. 190.
    Pomianowska E, Westgaard A, Mathisen O, et al. Prognostic relevance of number and ratio of metastatic lymph nodes in resected pancreatic, ampullary, and distal bile duct carcinomas. Ann Surg Oncol. 2012;20(1):233–41.PubMedCrossRefGoogle Scholar
  191. 191.
    Boninsegna L, Panzuto F, Partelli S, et al. Malignant pancreatic neuroendocrine tumour: lymph node ratio and Ki67 are predictors of recurrence after curative resections. Eur J Cancer. 2012;48(11):1608–15.PubMedCrossRefGoogle Scholar
  192. 192.
    Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005;16(11):1806–10.PubMedCrossRefGoogle Scholar
  193. 193.
    Ouaissi M, Hubert C, Verhelst R, et al. Vascular reconstruction during pancreatoduodenectomy for ductal adenocarcinoma of the pancreas improves resectability but does not achieve cure. World J Surg. 2010;34(11):2648–61.PubMedCrossRefGoogle Scholar
  194. 194.
    Akatsu T, Aiura K, Shimazu M, et al. Successful pancreatectomy with En-bloc resection of the celiac artery and portal vein for pancreatic endocrine carcinoma. Hepato-Gastroenterology. 2007;54(76):1269–71.PubMedGoogle Scholar
  195. 195.
    Sakamoto E, Hasegawa H, Ogiso S, et al. Curative resection for a pancreatic endocrine carcinoma involving the portal vein. Hepato-Gastroenterology. 2004;51(60):1849–51.PubMedGoogle Scholar
  196. 196.
    Norton JA, Harris EJ, Chen Y, et al. Pancreatic endocrine tumors with major vascular abutment, involvement, or encasement and indication for resection. Arch Surg. 2011;146(6):724–32.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Gill GV, Rauf O, MacFarlane IA. Diazoxide treatment for insulinoma: a national UK survey. Postgrad Med J. 1997;73:640–1.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Goode PN, Farndon JR, Anderson J, et al. Diazoxide in the management of patients with insulinoma. World J Surg. 1986;10:586–92.PubMedCrossRefGoogle Scholar
  199. 199.
    Vezzosi D, Bennet A, Rochaix P, et al. Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies. Eur J Endocrinol. 2005;152:757–67.PubMedCrossRefGoogle Scholar
  200. 200.
    Jensen RT. Peptide therapy. Recent advances in the use of somatostatin and other peptide receptor agonists and antagonists. In: Lewis JH, Dubois A, editors. Current clinical topics in gastrointestinal pharmacology. Malden: Blackwell Science, Inc.; 1997. p. 144–223.Google Scholar
  201. 201.
    Lew EA, Pisegna JR, Starr JA, et al. Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Gastroenterology. 2000;118:696–704.PubMedCrossRefGoogle Scholar
  202. 202.
    Plöckinger U, Wiedenmann B. Neuroendocrine tumors. Biotherapy. Best Pract Res Clin Endocrinol Metab. 2007;21:145–62.PubMedCrossRefGoogle Scholar
  203. 203.
    Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15:966–73.PubMedCrossRefGoogle Scholar
  204. 204.
    Costa FP, Gumz B, Pasche B. Selecting patients for cytotoxic therapies in gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26:843–54.PubMedCrossRefGoogle Scholar
  205. 205.
    Öberg K, Knigge U, Kwekkeboom D, et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii124–30.PubMedGoogle Scholar
  206. 206.
    Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42:557–77.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.PubMedCrossRefGoogle Scholar
  209. 209.
    Yao J, Phan AT. Optimising therapeutic options for patients with advanced pancreatic neuroendocrine tumours. Eur Oncol Haematol. 2012;8:217–23.CrossRefGoogle Scholar
  210. 210.
    Yao JC, Pavel M, Phan AT, et al. Chromogranin a and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab. 2011;96:3741–9.PubMedCrossRefGoogle Scholar
  211. 211.
    Carstens PH, Cressman FK Jr. Malignant oncocytic carcinoid of the pancreas. Ultrastruct Pathol. 1989;13:69–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Alessandro Sanguinetti
    • 1
  • Andrea Polistena
    • 1
  • Louis Banka Johnson
    • 2
  • Nicola Avenia
    • 1
  1. 1.Unit of Endocrine Surgery, Department of Surgical SciencesSchool of Medicine University of Perugia, Azienda Ospedaliera “S. MariaTerniItaly
  2. 2.Department of Colorectal SurgeryUniversity Hospital of Malmoe-Lund, SUSLundSweden

Personalised recommendations