Indian Journal of Gastroenterology

, Volume 32, Issue 1, pp 3–17

Pancreatic neuroendocrine tumors

  • Shailesh V. Shrikhande
  • Bhawna Sirohi
  • Mahesh Goel
  • Savio G. Barreto


Pancreatic neuroendocrine tumors (pancreatic NETs) are rare, low- to intermediate-grade neoplasms thought to arise from the pancreatic islets. Recent advances in pathology and our understanding of the biological behavior of this group of tumors has resulted in changes in their nomenclature and how we treat them. This review puts into perspective our current understanding of pancreatic NETs in terms of their incidence, pathology, and management.


Chemoembolization Glucagon Insulin Somatostatin 


  1. 1.
    Yao J, Rindi G, Evans D. Pancreatic neuroendocrine tumors. In: DeVita V Jr, Lawrence T, Rosenberg S, editors. DeVita, Hellman, and Rosenberg's cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 1489–502.Google Scholar
  2. 2.
    Davies K, Conlon KC. Neuroendocrine tumors of the pancreas. Curr Gastroenterol Rep. 2009;11:119–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13–27.PubMedCrossRefGoogle Scholar
  4. 4.
    Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumors. Lancet Oncol. 2008;9:61–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Lam KY, Lo CY. Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature. Eur J Surg Oncol. 1997;23:36–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer. 2008;113:2655–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Amarapurkar DN, Juneja MP, Patel ND, Amarapurkar AD, Amarapurkar PD. A retrospective clinico-pathological analysis of neuroendocrine tumors of the gastrointestinal tract. Trop Gastroenterol. 2010;31:101–4.PubMedGoogle Scholar
  9. 9.
    Bhatia P, Srinivasan R, Rajwanshi A, et al. 5-year review and reappraisal of ultrasound-guided percutaneous transabdominal fine needle aspiration of pancreatic lesions. Acta Cytol. 2008;52:523–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Oberg K, Akerström G, Rindi G, Jelic S, ESMO Guidelines Working Group. Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v223–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Klöppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2011;18 Suppl 1:S1–S16.PubMedCrossRefGoogle Scholar
  12. 12.
    Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Rindi G, Arnold R, Bosman F, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman F, Carneiro F, Hruban R, Theise N (eds.) WHO Classification of Tumors of the Digestive System. Lyon: IARC Press; 2010. p. 13–4.Google Scholar
  14. 14.
    Sobin L, Gospodarowicz M, Wittekind C. UICC: TNM classification of malignant tumors. 7th ed. Oxford: Wiley-Blackwell; 2009.Google Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008;14:7798–803.PubMedCrossRefGoogle Scholar
  17. 17.
    Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011;29:3044–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Scarpa A, Mantovani W, Capelli P, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol. 2010;23:824–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Kloppel G, Rindi G, Perren A, Komminoth P, Klimstra DS. The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch. 2010;456:595–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Mallinson CN, Bloom SR, Warin AP, Salmon PR, Cox B. A glucagonoma syndrome. Lancet. 1974;2:1–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Remes-Troche JM, Garcia-de-Acevedo B, Zuniga-Varga J, Avila-Funes A, Orozco-Topete R. Necrolytic migratory erythema: a cutaneous clue to glucagonoma syndrome. J Eur Acad Dermatol Venereol. 2004;18:591–5.PubMedCrossRefGoogle Scholar
  22. 22.
    van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. 2004;151:531–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Nesi G, Marcucci T, Rubio CA, Brandi ML, Tonelli F. Somatostatinoma: clinico-pathological features of three cases and literature reviewed. J Gastroenterol Hepatol. 2008;23:521–6.PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958;25:374–80.PubMedCrossRefGoogle Scholar
  26. 26.
    Lawrence B, Gustafsson BI, Kidd M, Pavel M, Svejda B, Modlin IM. The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:111–34. viii.PubMedCrossRefGoogle Scholar
  27. 27.
    Nobels FR, Kwekkeboom DJ, Coopmans W, 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. 1997;82:2622–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Lindholm DP, Oberg K. Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors. Horm Metab Res. 2011;43:832–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Nehar D, Lombard-Bohas C, Olivieri S, et al. Interest of Chromogranin A for diagnosis and follow-up of endocrine tumors. Clin Endocrinol (Oxf). 2004;60:644–52.CrossRefGoogle Scholar
  30. 30.
    Ahmed A, Turner G, King B, et al. Midgut neuroendocrine tumors with liver metastases: results of the UKINETS study. Endocr Relat Cancer. 2009;16:885–94.PubMedCrossRefGoogle Scholar
  31. 31.
    Massironi S, Conte D, Sciola V, et al. Plasma chromogranin A response to octreotide test: prognostic value for clinical outcome in endocrine digestive tumors. Am J Gastroenterol. 2010;105:2072–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:4762–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76.PubMedCrossRefGoogle Scholar
  34. 34.
    Giusti M, Sidoti M, Augeri C, Rabitti C, Minuto F. Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man. Eur J Endocrinol. 2004;150:299–303.PubMedCrossRefGoogle Scholar
  35. 35.
    Binnick AN, Spencer SK, Dennison WL Jr, Horton ES. Glucagonoma syndrome. Report of two cases and literature review. Arch Dermatol. 1977;113:749–54.PubMedCrossRefGoogle Scholar
  36. 36.
    Shi W, Liao W, Mei X, Xiao Q, Zeng Y, Zhou Q. Necrolytic migratory erythema associated with glucagonoma syndrome. J Clin Oncol. 2010;28:e329–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Hayashi D, Tkacz JN, Hammond S, et al. Gastroenteropancreatic neuroendocrine tumors: multimodality imaging features with pathological correlation. Jpn J Radiol. 2011;29:85–91.PubMedCrossRefGoogle Scholar
  38. 38.
    Sheth S, Hruban RK, Fishman EK. Helical CT of islet cell tumors of the pancreas: typical and atypical manifestations. AJR Am J Roentgenol. 2002;179:725–30.PubMedGoogle Scholar
  39. 39.
    Phan GQ, Yeo CJ, Hruban RH, Lillemoe KD, Pitt HA, Cameron JL. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. 1998;2:472–82.PubMedCrossRefGoogle Scholar
  40. 40.
    Gouya H, Vignaux O, Augui J, et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol. 2003;181:987–92.PubMedGoogle Scholar
  41. 41.
    Ichikawa T, Peterson MS, Federle MP, et al. Islet cell tumor of the pancreas: biphasic CT versus MR imaging in tumor detection. Radiology. 2000;216:163–71.PubMedGoogle Scholar
  42. 42.
    Kraus BB, Ros PR. Insulinoma: diagnosis with fat-suppressed MR imaging. AJR Am J Roentgenol. 1994;162:69–70.PubMedGoogle Scholar
  43. 43.
    Owen NJ, Sohaib SA, Peppercorn PD, et al. MRI of pancreatic neuroendocrine tumors. Br J Radiol. 2001;74:968–73.PubMedGoogle Scholar
  44. 44.
    Bakir B, Salmaslioglu A, Poyanli A, Rozanes I, Acunas B. Diffusion weighted MR imaging of pancreatic islet cell tumors. Eur J Radiol. 2010;74:214–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Herwick S, Miller FH, Keppke AL. MRI of islet cell tumors of the pancreas. AJR Am J Roentgenol. 2006;187:W472–80.PubMedCrossRefGoogle Scholar
  46. 46.
    Ishikawa T, Itoh A, Kawashima H, et al. Usefulness of EUS combined with contrast-enhancement in the differential diagnosis of malignant versus benign and preoperative localization of pancreatic endocrine tumors. Gastrointest Endosc. 2010;71:951–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Pais SA, Al-Haddad M, Mohamadnejad M, et al. EUS for pancreatic neuroendocrine tumors: a single-center, 11-year experience. Gastrointest Endosc. 2010;71:1185–93.PubMedCrossRefGoogle Scholar
  48. 48.
    Figueiredo FA, Giovannini M, Monges G, et al. EUS-FNA predicts 5-year survival in pancreatic endocrine tumors. Gastrointest Endosc. 2009;70:907–14.PubMedCrossRefGoogle Scholar
  49. 49.
    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
  50. 50.
    Chatzipantelis P, Salla C, Konstantinou P, Karoumpalis I, Sakellariou S, Doumani I. Endoscopic ultrasound-guided fine-needle aspiration cytology of pancreatic neuroendocrine tumors: a study of 48 cases. Cancer. 2008;114:255–62.PubMedCrossRefGoogle Scholar
  51. 51.
    Malago R, D'Onofrio M, Zamboni GA, et al. Contrast-enhanced sonography of nonfunctioning pancreatic neuroendocrine tumors. AJR Am J Roentgenol. 2009;192:424–30.PubMedCrossRefGoogle Scholar
  52. 52.
    Oberg KE, Reubi JC, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010;139:742–53.PubMedCrossRefGoogle Scholar
  53. 53.
    Versari A, Camellini L, Carlinfante G, et al. Ga-68 DOTATOC PET, endoscopic ultrasonography, and multidetector CT in the diagnosis of duodenopancreatic neuroendocrine tumors: a single-centre retrospective study. Clin Nucl Med. 2010;35:321–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Kumar R, Sharma P, Garg P, et al. Role of Ga-DOTATOC PET-CT in the diagnosis and staging of pancreatic neuroendocrine tumors. Eur Radiol. 2011;21:2408–16.PubMedCrossRefGoogle Scholar
  55. 55.
    Yakemchuk VN, Jager PL, Chirakal R, Reid R, Major P, Gulenchyn KY. PET/CT using 18F-FDOPA provides improved staging of carcinoid tumor patients in a Canadian setting. Nucl Med Commun. 2012;33:322–30.PubMedCrossRefGoogle Scholar
  56. 56.
    Bilimoria KY, Talamonti MS, Tomlinson JS, et al. Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg. 2008;247:490–500.PubMedCrossRefGoogle Scholar
  57. 57.
    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;187:88–92. discussion −3.PubMedCrossRefGoogle Scholar
  58. 58.
    Musunuru S, Chen H, Rajpal S, et al. Metastatic neuroendocrine hepatic tumors: resection improves survival. Arch Surg. 2006;141:1000–4. discussion −5.PubMedCrossRefGoogle Scholar
  59. 59.
    Nomura N, Fujii T, Kanazumi N, et al. Nonfunctioning neuroendocrine pancreatic tumors: our experience and management. J Hepatobiliary Pancreat Surg. 2009;16:639–47.PubMedCrossRefGoogle Scholar
  60. 60.
    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;197:29–37.PubMedCrossRefGoogle Scholar
  61. 61.
    Schurr PG, Strate T, Rese K, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg. 2007;245:273–81.PubMedCrossRefGoogle Scholar
  62. 62.
    Touzios JG, Kiely JM, Pitt SC, et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg. 2005;241:776–83. discussion 83–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Barreto S, Chen J, Padbury R, Wilson T, Maddern G, Kanhere H. Pancreatic neuroendocrine tumors: The South Australian perspective. ANZ J Surg. 2010;80 Suppl 1:A46.Google Scholar
  64. 64.
    Zerbi A, Capitanio V, Boninsegna L, et al. Surgical treatment of pancreatic endocrine tumors in Italy: results of a prospective multicentre study of 262 cases. Langenbecks Arch Surg. 2011;396:313–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Hodul PJ, Strosberg JR, Kvols LK. Aggressive surgical resection in the management of pancreatic neuroendocrine tumors: when is it indicated? Cancer Control. 2008;15:314–21.PubMedGoogle Scholar
  66. 66.
    Sarmiento JM, Que FG, Grant CS, Thompson GB, Farnell MB, Nagorney DM. Concurrent resections of pancreatic islet cell cancers with synchronous hepatic metastases: outcomes of an aggressive approach. Surgery. 2002;132:976–82. discussion 82–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Hackert T, Hinz U, Fritz S, et al. Enucleation in pancreatic surgery: indications, technique, and outcome compared to standard pancreatic resections. Langenbecks Arch Surg. 2011;396:1197–203.PubMedCrossRefGoogle Scholar
  68. 68.
    Kimura W, Tezuka K, Hirai I. Surgical management of pancreatic neuroendocrine tumors. Surg Today. 2011;41:1332–43.PubMedCrossRefGoogle Scholar
  69. 69.
    Falconi M, Zerbi A, Crippa S, et al. Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol. 2010;17:1621–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Fernandez-Cruz L, Blanco L, Cosa R, Rendon H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors? World J Surg. 2008;32:904–17.PubMedCrossRefGoogle Scholar
  71. 71.
    Falconi M, Bartsch DF, Eriksson B, et al. ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System: Well-Differentiated Pancreatic Non-Functioning Tumors. Neuroendocrinology. 2012;95:120–34.PubMedCrossRefGoogle Scholar
  72. 72.
    Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. Ann Surg. 2001;234:495–505. discussion −6.PubMedCrossRefGoogle Scholar
  73. 73.
    Norton JA, Kivlen M, Li M, Schneider D, Chuter T, Jensen RT. Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Arch Surg. 2003;138:859–66.PubMedCrossRefGoogle Scholar
  74. 74.
    Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave G, Falconi M. Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology. 2011;93:223–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Bettini R, Mantovani W, Boninsegna L, et al. Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas. Dig Liver Dis. 2009;41:49–55.PubMedCrossRefGoogle Scholar
  76. 76.
    Nguyen SQ, Angel LP, Divino CM, Schluender S, Warner RR. Surgery in malignant pancreatic neuroendocrine tumors. J Surg Oncol. 2007;96:397–403.PubMedCrossRefGoogle Scholar
  77. 77.
    Solorzano CC, Lee JE, Pisters PW, et al. Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery. 2001;130:1078–85.PubMedCrossRefGoogle Scholar
  78. 78.
    Steinmuller T, Kianmanesh R, Falconi M, et al. Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2008;87:47–62.PubMedCrossRefGoogle Scholar
  79. 79.
    Jagannath P, Chhabra D, Shrikhande S, Shah R. Surgical treatment of liver metastases in neuroendocrine neoplasms. Int J Hepatol. 2012;2012:782672.PubMedGoogle Scholar
  80. 80.
    Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumors of gastroenteropancreatic origin. Endocr Relat Cancer. 2010;17:R75–90.PubMedCrossRefGoogle Scholar
  81. 81.
    Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980;303:1189–94.PubMedCrossRefGoogle Scholar
  82. 82.
    Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–23.PubMedCrossRefGoogle Scholar
  83. 83.
    Fjallskog ML, Janson ET, Falkmer UG, Vatn MH, Oberg KE, Eriksson BK. Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors. Neuroendocrinology. 2008;88:53–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol. 2001;12:1139–43.PubMedCrossRefGoogle Scholar
  85. 85.
    Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumors? Cancer Chemother Pharmacol. 2007;59:637–42.PubMedCrossRefGoogle Scholar
  86. 86.
    Cassier PA, Walter T, Eymard B, et al. Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience. Cancer. 2009;115:3392–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Kulke MH, Kim H, Clark JW, et al. A Phase II trial of gemcitabine for metastatic neuroendocrine tumors. Cancer. 2004;101:934–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268–75.PubMedCrossRefGoogle Scholar
  90. 90.
    Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumors. Aliment Pharmacol Ther. 2010;31:169–88.PubMedGoogle Scholar
  91. 91.
    Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–63.PubMedCrossRefGoogle Scholar
  92. 92.
    Kvols L, Wiedenmann B, Oberg K, et al. The SOM230 Carcinoid Study Group, 2006. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a phase II study. J Clin Oncol. 2006;24:198s.Google Scholar
  93. 93.
    Auernhammer CJ, Goke B. Therapeutic strategies for advanced neuroendocrine carcinomas of jejunum/ileum and pancreatic origin. Gut. 2011;60:1009–21.PubMedCrossRefGoogle Scholar
  94. 94.
    Harring TR, Nguyen NT, Goss JA, O'Mahony CA. Treatment of liver metastases in patients with neuroendocrine tumors: a comprehensive review. Int J Hepatol. 2011;2011:154541.PubMedGoogle Scholar
  95. 95.
    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;26:2124–30.PubMedCrossRefGoogle Scholar
  96. 96.
    Kwekkeboom D, Herder W, Kam B, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.PubMedCrossRefGoogle Scholar
  97. 97.
    Kwekkeboom D, Teunissen J, Bakker W, et al. Radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23:2754–62.PubMedCrossRefGoogle Scholar
  98. 98.
    Kam B, Teunissen J, Krenning E, et al. Lutetium-labelled peptides for therapy of neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2012;39 Suppl 1:S103–12.PubMedCrossRefGoogle Scholar
  99. 99.
    Dubey N, Varshney R, Shukla J, et al. Synthesis and evaluation of biodegradable PCL/PEG nanoparticles for neuroendocrine tumor targeted delivery of somatostatin analog. Drug Deliv. 2012;19:132–42.PubMedCrossRefGoogle Scholar
  100. 100.
    Hanson MW, Feldman JM, Blinder RA, Moore JO, Coleman RE. Carcinoid tumors: iodine-131 MIBG scintigraphy. Radiology. 1989;172:699–703.PubMedGoogle Scholar
  101. 101.
    Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci. 2001;321:306–20.PubMedCrossRefGoogle Scholar
  102. 102.
    Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955;142:709–23. discussion 24–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Metz DC. Diagnosis of the Zollinger-Ellison Syndrome. Clin Gastroenterol Hepatol. 2012;10:126–30.PubMedCrossRefGoogle Scholar
  104. 104.
    Gibril F, Reynolds JC, Chen CC, et al. Specificity of somatostatin receptor scintigraphy: a prospective study and effects of false-positive localizations on management in patients with gastrinomas. J Nucl Med. 1999;40:539–53.PubMedGoogle Scholar
  105. 105.
    Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–92.PubMedCrossRefGoogle Scholar
  106. 106.
    Wilcox CM, Seay T, Arcury JT, Mohnen J, Hirschowitz BI. Zollinger-Ellison syndrome: presentation, response to therapy, and outcome. Dig Liver Dis. 2011;43:439–43.PubMedCrossRefGoogle Scholar
  107. 107.
    Whipple A. The surgical therapy of hyperinsulinism. J Int Chir. 1938;3:237–76.Google Scholar
  108. 108.
    Whipple A, Franz V. Adenoma of islet cells with hyperinsulinism. Am Surg. 1935;101:1299–335.Google Scholar
  109. 109.
    Stefanini P, Carboni M, Patrassi N, Basoli A. Beta-islet cell tumors of the pancreas: results of a study on 1,067 cases. Surgery. 1974;75:597–609.PubMedGoogle Scholar
  110. 110.
    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;16:632–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Fidler JL, Fletcher JG, Reading CC, et al. Preoperative detection of pancreatic insulinomas on multiphasic helical CT. AJR Am J Roentgenol. 2003;181:775–80.PubMedGoogle Scholar
  112. 112.
    Varma V, Tariciotti L, Coldham C, Taniere P, Buckels JA, Bramhall SR. Preoperative localisation and surgical management of insulinoma: single centre experience. Dig Surg. 2011;28:63–73.PubMedCrossRefGoogle Scholar
  113. 113.
    Liu Y, Song Q, Jin HT, Lin XZ, Chen KM. The value of multidetector-row CT in the preoperative detection of pancreatic insulinomas. Radiol Med. 2009;114:1232–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int. 2010;9:234–41.PubMedGoogle Scholar
  115. 115.
    Angeli E, Vanzulli A, Castrucci M, et al. Value of abdominal sonography and MR imaging at 0.5 T in preoperative detection of pancreatic insulinoma: a comparison with dynamic CT and angiography. Abdom Imaging. 1997;22:295–303.PubMedCrossRefGoogle Scholar
  116. 116.
    Semelka RC, Cumming MJ, Shoenut JP, et al. Islet cell tumors: comparison of dynamic contrast-enhanced CT and MR imaging with dynamic gadolinium enhancement and fat suppression. Radiology. 1993;186:799–802.PubMedGoogle Scholar
  117. 117.
    Druce MR, Muthuppalaniappan VM, O'Leary B, et al. Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation. Eur J Endocrinol. 2010;162:971–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Sotoudehmanesh R, Hedayat A, Shirazian N, et al. Endoscopic ultrasonography (EUS) in the localization of insulinoma. Endocrine. 2007;31:238–41.PubMedCrossRefGoogle Scholar
  119. 119.
    Guettier JM, Kam A, Chang R, et al. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab. 2009;94:1074–80.PubMedCrossRefGoogle Scholar
  120. 120.
    Morganstein DL, Lewis DH, Jackson J, et al. The role of arterial stimulation and simultaneous venous sampling in addition to cross-sectional imaging for localisation of biochemically proven insulinoma. Eur Radiol. 2009;19:2467–73.PubMedCrossRefGoogle Scholar
  121. 121.
    Cohen M, Bower R, Fidler S, Johnsonbaugh R, Sode J. Inhibition of insulin release by diphenylhydantoin and diazoxide in a patient with benign insulinoma. Lancet. 1973;1:40–1.PubMedCrossRefGoogle Scholar
  122. 122.
    Wd H, Niederle B, Scoazec J, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84:183–8.CrossRefGoogle Scholar
  123. 123.
    Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg. 2006;93:264–75.PubMedCrossRefGoogle Scholar
  124. 124.
    Lo CY, Lo CM, Fan ST. Role of laparoscopic ultrasonography in intraoperative localization of pancreatic insulinoma. Surg Endosc. 2000;14:1131–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Mabrut JY, Fernandez-Cruz L, Azagra JS, et al. Laparoscopic pancreatic resection: results of a multicenter European study of 127 patients. Surgery. 2005;137:597–605.PubMedCrossRefGoogle Scholar
  126. 126.
    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;103:169–74.PubMedCrossRefGoogle Scholar
  127. 127.
    Liu H, Peng C, Zhang S, et al. Strategy for the surgical management of insulinomas: analysis of 52 cases. Dig Surg. 2007;24:463–70.PubMedCrossRefGoogle Scholar
  128. 128.
    Kress O, Wagner HJ, Wied M, Klose KJ, Arnold R, Alfke H. Transarterial chemoembolization of advanced liver metastases of neuroendocrine tumors–a retrospective single-center analysis. Digestion. 2003;68:94–101.PubMedCrossRefGoogle Scholar
  129. 129.
    Vogl TJ, Naguib NN, Zangos S, Eichler K, Hedayati A, Nour-Eldin NE. Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation. Eur J Radiol. 2009;72:517–28.PubMedCrossRefGoogle Scholar
  130. 130.
    Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer. 2005;104:1590–602.PubMedCrossRefGoogle Scholar
  131. 131.
    Kvols LK, Turaga KK, Strosberg J, Choi J. Role of interventional radiology in the treatment of patients with neuroendocrine metastases in the liver. J Natl Compr Canc Netw. 2009;7:765–72.PubMedGoogle Scholar
  132. 132.
    Madoff DC, Gupta S, Ahrar K, Murthy R, Yao JC. Update on the management of neuroendocrine hepatic metastases. J Vasc Interv Radiol. 2006;17:1235–49. quiz– 50.PubMedCrossRefGoogle Scholar
  133. 133.
    Nazario J, Gupta S. Transarterial liver-directed therapies of neuroendocrine hepatic metastases. Semin Oncol. 2010;37:118–26.PubMedCrossRefGoogle Scholar
  134. 134.
    Marrache F, Vullierme MP, Roy C, et al. Arterial phase enhancement and body mass index are predictors of response to chemoembolisation for liver metastases of endocrine tumors. Br J Cancer. 2007;96:49–55.PubMedCrossRefGoogle Scholar
  135. 135.
    Akyildiz HY, Mitchell J, Milas M, Siperstein A, Berber E. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery. 2010;148:1288–93. discussion–93.PubMedCrossRefGoogle Scholar
  136. 136.
    Berber E, Flesher N, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases. World J Surg. 2002;26:985–90.PubMedCrossRefGoogle Scholar
  137. 137.
    Berber E, Siperstein A. Laparoscopic radiofrequency thermal ablation of adrenal tumors: technical details. Surg Laparosc Endosc Percutan Tech. 2010;20:58–62.PubMedCrossRefGoogle Scholar
  138. 138.
    Berber E, Tsinberg M, Tellioglu G, Simpfendorfer CH, Siperstein AE. Resection versus laparoscopic radiofrequency thermal ablation of solitary colorectal liver metastasis. J Gastrointest Surg. 2008;12:1967–72.PubMedCrossRefGoogle Scholar
  139. 139.
    Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007;142:10–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Strosberg JR, Cheema A, Kvols LK. A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract. Cancer Control. 2011;18:127–37.PubMedGoogle Scholar
  141. 141.
    Kalinowski M, Dressler M, Konig A, et al. Selective internal radiotherapy with Yttrium-90 microspheres for hepatic metastatic neuroendocrine tumors: a prospective single center study. Digestion. 2009;79:137–42.PubMedCrossRefGoogle Scholar
  142. 142.
    Cao CQ, Yan TD, Bester L, Liauw W, Morris DL. Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases. Br J Surg. 2010;97:537–43.PubMedCrossRefGoogle Scholar
  143. 143.
    Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol. 2008;31:271–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg. 2008;247:1029–35.PubMedCrossRefGoogle Scholar
  145. 145.
    King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008;113:921–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Murthy R, Eng C, Krishnan S, et al. Hepatic yttrium-90 radioembolotherapy in metastatic colorectal cancer treated with cetuximab or bevacizumab. J Vasc Interv Radiol. 2007;18:1588–91.PubMedCrossRefGoogle Scholar
  147. 147.
    Crowder CD, Grabowski C, Inampudi S, Sielaff T, Sherman CA, Batts KP. Selective internal radiation therapy-induced extrahepatic injury: an emerging cause of iatrogenic organ damage. Am J Surg Pathol. 2009;33:963–75.PubMedCrossRefGoogle Scholar
  148. 148.
    Konda A, Savin MA, Cappell MS, Duffy MC. Radiation microsphere-induced GI ulcers after selective internal radiation therapy for hepatic tumors: an underrecognized clinical entity. Gastrointest Endosc. 2009;70:561–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Mascarenhas NB, Mulcahy MF, Lewandowski RJ, Salem R, Ryu RK. Hepatic abscess after yttrium-90 radioembolization for islet-cell tumor hepatic metastasis. Cardiovasc Intervent Radiol. 2010;33:650–3.PubMedCrossRefGoogle Scholar
  150. 150.
    Kennedy AS, McNeillie P, Dezarn WA, et al. Treatment parameters and outcome in 680 treatments of internal radiation with resin 90Y-microspheres for unresectable hepatic tumors. Int J Radiat Oncol Biol Phys. 2009;74:1494–500.PubMedCrossRefGoogle Scholar
  151. 151.
    Murthy R, Kamat P, Nunez R, et al. Yttrium-90 microsphere radioembolotherapy of hepatic metastatic neuroendocrine carcinomas after hepatic arterial embolization. J Vasc Interv Radiol. 2008;19:145–51.PubMedCrossRefGoogle Scholar
  152. 152.
    Saxena A, Chua TC, Bester L, Kokandi A, Morris DL. Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: a critical appraisal of 48 cases. Ann Surg. 2010;251:910–6.PubMedCrossRefGoogle Scholar
  153. 153.
    Detjen KM, Welzel M, Farwig K, et al. Molecular mechanism of interferon alfa-mediated growth inhibition in human neuroendocrine tumor cells. Gastroenterology. 2000;118:735–48.PubMedCrossRefGoogle Scholar
  154. 154.
    Hofland LJ, de Herder WW, Waaijers M, et al. Interferon-alpha-2a is a potent inhibitor of hormone secretion by cultured human pituitary adenomas. J Clin Endocrinol Metab. 1999;84:3336–43.PubMedCrossRefGoogle Scholar
  155. 155.
    Eriksson B, Kloppel G, Krenning E, et al. Consensus guidelines for the management of patients with digestive neuroendocrine tumors–well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology. 2008;87:8–19.PubMedCrossRefGoogle Scholar
  156. 156.
    Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas. 2010;39:753–66.PubMedCrossRefGoogle Scholar
  157. 157.
    Plockinger U, Wiedenmann B. Neuroendocrine tumors. Biotherapy. Best Pract Res Clin Endocrinol Metab. 2007;21:145–62.PubMedCrossRefGoogle Scholar
  158. 158.
    Verhoef S, van Diemen-Steenvoorde R, Akkersdijk WL, et al. Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur J Pediatr. 1999;158:284–7.PubMedCrossRefGoogle Scholar
  159. 159.
    Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16:525–37.PubMedCrossRefGoogle Scholar
  160. 160.
    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23.PubMedCrossRefGoogle Scholar
  161. 161.
    Pavel M, Hainsworth J, Baudin E, et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus+octreotide LAR vs placebo+octreotide lAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). Ann Oncol. 2010;21 suppl 8:viii4.Google Scholar
  162. 162.
    Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316–23.PubMedCrossRefGoogle Scholar
  163. 163.
    Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–10.PubMedCrossRefGoogle Scholar
  164. 164.
    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

Copyright information

© Indian Society of Gastroenterology 2012

Authors and Affiliations

  • Shailesh V. Shrikhande
    • 1
  • Bhawna Sirohi
    • 2
  • Mahesh Goel
    • 1
  • Savio G. Barreto
    • 1
  1. 1.Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial CentreMumbaiIndia
  2. 2.Medical and Hemato-Oncology, Artemis Health SciencesGurgaonIndia

Personalised recommendations