The small intestine and pancreas are among the most frequent abdominal sites of origin of neuroendocrine tumours. Distinctive features of these forms are represented by the relatively low incidence and the wide heterogeneity in biological behaviour. In this light, it is difficult to standardize indications for surgery and the most appropriate approach. It would be helpful for surgeons managing patients with these tumours to have guidelines for surgical treatment of small intestinal neuroendocrine tumours and pancreatic neuroendocrine tumours. The proposed guidelines represent a consensus of the working group of the European Neuroendocrine Tumor Society (ENETS).

Keywords:
Neuroendocrine tumours, Surgery, Guidelines
1.
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;26:3063-3072.
2.
Niederle B, Pape UF, Costa F, et al: ENETS Consensus Guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology 2016;103:125-138.
3.
Lardiere-Deguelte S, de Mestier L, Appere F, et al: Toward a preoperative classification of lymph node metastases in patients with small intestinal neuroendocrine tumors in the era of intestinal-sparing surgery. Neuroendocrinology 2016;103:552-559.
4.
Clift AK, Faiz O, Al-Nahhas A, et al: Role of staging in patients with small intestinal neuroendocrine tumours. J Gastrointest Surg 2016;20:180-188;discussion 188.
5.
Dahdaleh FS, Lorenzen A, Rajput M, et al: The value of preoperative imaging in small bowel neuroendocrine tumors. Ann Surg Oncol 2013;20:1912-1917.
6.
Moryoussef F, de Mestier L, Belkebir M, et al: Impact on management of liver and whole-body diffusion-weighted magnetic resonance imaging sequences for neuroendocrine tumors: a pilot study. Neuroendocrinology 2017;104:264-272.
7.
Chambers AJ, Pasieka JL, Dixon E, Rorstad O: The palliative benefit of aggressive surgical intervention for both hepatic and mesenteric metastases from neuroendocrine tumors. Surgery 2008;144:645-651;discussion 651-653.
8.
Prommegger R, Ensinger C, Steiner P, et al: Neuroendocrine tumors and second primary malignancy - a relationship with clinical impact? Anticancer Res 2004;24:1049-1051.
9.
Habbe N, Fendrich V, Heverhagen A, et al: Outcome of surgery for ileojejunal neuroendocrine tumors. Surg Today 2013;43:1168-1174.
10.
Yantiss RK, Odze RD, Farraye FA, Rosenberg AE: Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases. Am J Surg Pathol 2003;27:811-817.
11.
Burke AP, Thomas RM, Elsayed AM, Sobin LH: Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer 1997;79:1086-1093.
12.
Pasquer A, Walter T, Hervieu V, et al: Surgical management of small bowel neuroendocrine tumors: specific requirements and their impact on staging and prognosis. Ann Surg Oncol 2015;22(suppl 3):S742-S749.
13.
van Tuyl SA, van Noorden JT, Timmer R, et al: Detection of small-bowel neuroendocrine tumors by video capsule endoscopy. Gastrointest Endosc 2006;64:66-72.
14.
Ross A, Mehdizadeh S, Tokar J, et al: Double balloon enteroscopy detects small bowel mass lesions missed by capsule endoscopy. Dig Dis Sci 2008;53:2140-2143.
15.
Bellutti M, Fry LC, Schmitt J, et al: Detection of neuroendocrine tumors of the small bowel by double balloon enteroscopy. Dig Dis Sci 2009;54:1050-1058.
16.
Falconi M, Eriksson B, Kaltsas G, et al: ENETS Consensus Guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016;103:153-171.
17.
Heeger K, Falconi M, Partelli S, et al: Increased rate of clinically relevant pancreatic fistula after deep enucleation of small pancreatic tumors. Langenbecks Arch Surg 2014;399:315-321.
18.
Brient C, Regenet N, Sulpice L, et al: Risk factors for postoperative pancreatic fistulization subsequent to enucleation. J Gastrointest Surg 2012;16:1883-1887.
19.
Foti G, Boninsegna L, Falconi M, Mucelli RP: Preoperative assessment of nonfunctioning pancreatic endocrine tumours: role of MDCT and MRI. Radiol Med 2013;118:1082-1101.
20.
de Mestier L, Lardiere-Deguelte S, Brixi H, et al: Updating the surgical management of peritoneal carcinomatosis in patients with neuroendocrine tumors. Neuroendocrinology 2015;101:105-111.
21.
Modlin IM, Shapiro MD, Kidd M: Carcinoid tumors and fibrosis: an association with no explanation. Am J Gastroenterol 2004;99:2466-2478.
22.
Gonzalez RS, Liu EH, Alvarez JR, et al: Should mesenteric tumor deposits be included in staging of well-differentiated small intestine neuroendocrine tumors? Mod Pathol 2014;27:1288-1295.
23.
Ohrvall U, Eriksson B, Juhlin C, et al: Method for dissection of mesenteric metastases in mid-gut carcinoid tumors. World J Surg 2000;24:1402-1408.
24.
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.
25.
Sobin LH: UICC: TNM Classification of Malignant Tumours. Oxford, Wiley-Blackwell, 2009.
26.
Katz MH, Marsh R, Herman JM, et al: Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. Ann Surg Oncol 2013;20:2787-2795.
27.
Hughes MS, Azoury SC, Assadipour Y, et al: Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs). Surgery 2016;159:350-356.
28.
Walsh JC, Schaeffer DF, Kirsch R, et al: Ileal “carcinoid” tumors-small size belies deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size. Hum Pathol 2016;56:123-127.
29.
Kuo EJ, Salem RR: Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol 2013;20:2815-2821.
30.
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;142:347-354.
31.
Bettini R, Partelli S, Boninsegna L, et al: Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011;150:75-82.
32.
Crippa S, Partelli S, Zamboni G, et al: Incidental diagnosis as prognostic factor in different tumor stages of nonfunctioning pancreatic endocrine tumors. Surgery 2014;155:145-153.
33.
Regenet N, Carrere N, Boulanger G, et al: Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: a French multicenter study. Surgery 2016;159:901-907.
34.
Partelli S, Cirocchi R, Crippa S, et al: Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms. Br J Surg 2017;104:34-41.
35.
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;243:265-272.
36.
Triponez F, Goudet P, Dosseh D, et al: Is surgery beneficial for MEN1 patients with small (≤2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg 2006;30:654-662;discussion 663-654.
37.
Partelli S, Tamburrino D, Lopez C, et al: Active surveillance versus surgery of nonfunctioning pancreatic neuroendocrine neoplasms ≤2 cm in MEN1 patients. Neuroendocrinology 2016;103:779-786.
38.
Nanno Y, Matsumoto I, Zen Y, et al: Pancreatic duct involvement in well-differentiated neuroendocrine tumors is an independent poor prognostic factor. Ann Surg Oncol 2017;24:1127-1133.
39.
Crippa S, Bassi C, Warshaw AL, et al: Middle pancreatectomy: indications, short- and long-term operative outcomes. Ann Surg 2007;246:69-76.
40.
Goudard Y, Gaujoux S, Dokmak S, et al: Reappraisal of central pancreatectomy a 12-year single-center experience. JAMA Surg 2014;149:356-363.
41.
Jilesen AP, van Eijck CH, Busch OR, et al: Postoperative outcomes of enucleation and standard resections in patients with a pancreatic neuroendocrine tumor. World J Surg 2016;40:715-728.
42.
Falconi M, Zerbi A, Crippa S, et al: Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. Ann Surg Oncol 2010;17:1621-1627.
43.
Jilesen AP, van Eijck CH, Busch OR, et al: Postoperative outcomes of enucleation and standard resections in patients with a pancreatic neuroendocrine tumor. World J Surg 2016;40:715-728.
44.
Chua TC, Yang TX, Gill AJ, Samra JS: Systematic review and meta-analysis of enucleation versus standardized resection for small pancreatic lesions. Ann Surg Oncol 2016;23:592-599.
45.
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;147:261-266.
46.
Bartsch DK, Albers M, Knoop R, et al: Enucleation and limited pancreatic resection provide long-term cure for insulinoma in multiple endocrine neoplasia type 1. Neuroendocrinology 2013;98:290-298.
47.
Le Roux C, Lombard-Bohas C, Delmas C, et al: Relapse factors for ileal neuroendocrine tumours after curative surgery: a retrospective French multicentre study. Dig Liver Dis 2011;43:828-833.
48.
Norlen O, Stalberg P, Oberg K, et al: Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 2012;36:1419-1431.
49.
Kim MK, Warner RR, Ward SC, et al: Prognostic significance of lymph node metastases in small intestinal neuroendocrine tumors. Neuroendocrinology 2015;101:58-65.
50.
Watzka FM, Fottner C, Miederer M, et al: Surgical treatment of NEN of small bowel: a retrospective analysis. World J Surg 2016;40:749-758.
51.
Landry CS, Lin HY, Phan A, et al: Resection of at-risk mesenteric lymph nodes is associated with improved survival in patients with small bowel neuroendocrine tumors. World J Surg 2013;37:1695-1700.
52.
Dahdaleh FS, Calva-Cerqueira D, Carr JC, et al: Comparison of clinicopathologic factors in 122 patients with resected pancreatic and ileal neuroendocrine tumors from a single institution. Ann Surg Oncol 2012;19:966-972.
53.
Conrad C, Kutlu OC, Dasari A, et al: Prognostic value of lymph node status and extent of lymphadenectomy in pancreatic neuroendocrine tumors confined to and extending beyond the pancreas. J Gastrointest Surg 2016;20:1966-1974.
54.
Curran T, Pockaj BA, Gray RJ, et al: Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection. J Gastrointest Surg 2015;19:152-160;discussion 160.
55.
Hashim YM, Trinkaus KM, Linehan DC, et al: Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg 2014;259:197-203.
56.
Krampitz GW, Norton JA, Poultsides GA, et al: Lymph nodes and survival in pancreatic neuroendocrine tumors. Arch Surg 2012;147:820-827.
57.
Partelli S, Gaujoux S, Boninsegna L, et al: Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg 2013;148:932-939.
58.
Wong J, Fulp WJ, Strosberg JR, et al: Predictors of lymph node metastases and impact on survival in resected pancreatic neuroendocrine tumors: a single-center experience. Am J Surg 2014;208:775-780.
59.
Slidell MB, Chang DC, Cameron JL, et al: Impact of total lymph node count and lymph node ratio on staging and survival after pancreatectomy for pancreatic adenocarcinoma: a large, population-based analysis. Ann Surg Oncol 2008;15:165-174.
60.
Pawlik TM, Gleisner AL, Cameron JL, et al: Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery 2007;141:610-618.
61.
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;41:840-844.
62.
Makridis C, Rastad J, Oberg K, Akerstrom G: Progression of metastases and symptom improvement from laparotomy in midgut carcinoid tumors. World J Surg 1996;20:900-906;discussion 907.
63.
Hellman P, Lundstrom T, Ohrvall U, et al: Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg 2002;26:991-997.
64.
Thiels CA, Bergquist JR, Laan DV, et al: Outcomes of pancreaticoduodenectomy for pancreatic neuroendocrine tumors: are combined procedures justified? J Gastrointest Surg 2016;20:891-898.
65.
Haugvik SP, Labori KJ, Waage A, et al: Pancreatic surgery with vascular reconstruction in patients with locally advanced pancreatic neuroendocrine tumors. J Gastrointest Surg 2013;17:1224-1232.
66.
Panzeri F, Marchegiani G, Malleo G, et al: Distal pancreatectomy associated with multivisceral resection: results from a single centre experience. Langenbecks Arch Surg 2016, Epub ahead of print.
67.
Kleine M, Schrem H, Vondran FW, et al: Extended surgery for advanced pancreatic endocrine tumours. Br J Surg 2012;99:88-94.
68.
Schurr PG, Strate T, Rese K, et al: Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg 2007;245:273-281.
69.
Teh SH, Deveney C, Sheppard BC: Aggressive pancreatic resection for primary pancreatic neuroendocrine tumor: is it justifiable? Am J Surg 2007;193:610-613;discussion 613.
70.
Pavel M, O'Toole D, Costa F, et al: ENETS Consensus Guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016;103:172-185.
71.
Frilling A, Modlin IM, Kidd M, et al: Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 2014;15:e8-e21.
72.
Cho CS, Labow DM, Tang L, et al: Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms. Cancer 2008;113:126-134.
73.
Partelli S, Inama M, Rinke A, et al: Long-term outcomes of surgical management of pancreatic neuroendocrine tumors with synchronous liver metastases. Neuroendocrinology 2015;102:68-76.
74.
Saxena A, Chua TC, Sarkar A, et al: Progression and survival results after radical hepatic metastasectomy of indolent advanced neuroendocrine neoplasms (NENs) supports an aggressive surgical approach. Surgery 2011;149:209-220.
75.
Frilling A, Li J, Malamutmann E, et al: Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease. Br J Surg 2009;96:175-184.
76.
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;247:659-665.
77.
Kianmanesh R, Farges O, Abdalla EK, et al: Right portal vein ligation: a new planned two-step all-surgical approach for complete resection of primary gastrointestinal tumors with multiple bilateral liver metastases. J Am Coll Surg 2003;197:164-170.
78.
Capurso G, Rinzivillo M, Bettini R, et al: Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases. Br J Surg 2012;99:1480-1486.
79.
Norlen O, Stalberg P, Zedenius J, Hellman P: Outcome after resection and radiofrequency ablation of liver metastases from small intestinal neuroendocrine tumours. Br J Surg 2013;100:1505-1514.
80.
Schindl M, Kaczirek K, Passler C, et al: Treatment of small intestinal neuroendocrine tumors: is an extended multimodal approach justified? World J Surg 2002;26:976-984.
81.
Capurso G, Bettini R, Rinzivillo M, et al: Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology 2011;93:223-229.
82.
Bertani E, Fazio N, Radice D, et al: Assessing the role of primary tumour resection in patients with synchronous unresectable liver metastases from pancreatic neuroendocrine tumour of the body and tail. A propensity score survival evaluation. Eur J Surg Oncol 2017;43:372-379.
83.
Bertani E, Fazio N, Radice D, et al: Resection of the primary tumor followed by peptide receptor radionuclide therapy as upfront strategy for the treatment of G1-G2 pancreatic neuroendocrine tumors with unresectable liver metastases. Ann Surg Oncol 2016;23(Suppl 5):981-989.
84.
Keutgen XM, Nilubol N, Glanville J, et al: Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors. Surgery 2016;159:311-318.
85.
Huttner FJ, Schneider L, Tarantino I, et al: Palliative resection of the primary tumor in 442 metastasized neuroendocrine tumors of the pancreas: a population-based, propensity score-matched survival analysis. Langenbecks Arch Surg 2015;400:715-723.
86.
Mazzaferro V, Sposito C, Coppa J, et al: The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors. Am J Transplant 2016, Epub ahead of print.
87.
Frilling A, Malago M, Weber F, et al: Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients. Liver Transpl 2006;12:1089-1096.
88.
Olausson M, Friman S, Herlenius G, et al: Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl 2007;13:327-333.
89.
Le Treut YP, Gregoire E, Klempnauer J, et al: Liver transplantation for neuroendocrine tumors in Europe - results and trends in patient selection: a 213-case European liver transplant registry study. Ann Surg 2013;257:807-815.
90.
de Wilde RF, Besselink MG, van der Tweel I, et al: Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg 2012;99:404-410.
91.
Fendrich V, Merz MK, Waldmann J, et al: Neuroendocrine pancreatic tumors are risk factors for pancreatic fistula after pancreatic surgery. Dig Surg 2011;28:263-269.
92.
Jilesen AP, van Eijck CH, in't Hof KH, et al: Postoperative complications, in-hospital mortality and 5-year survival after surgical resection for patients with a pancreatic neuroendocrine tumor: a systematic review. World J Surg 2016;40:729-748.
93.
Zerbi A, Capitanio V, Boninsegna L, et al: Surgical treatment of pancreatic endocrine tumours in Italy: results of a prospective multicentre study of 262 cases. Langenbecks Arch Surg 2011;396:313-321.
94.
Fischer L, Bergmann F, Schimmack S, et al: Outcome of surgery for pancreatic neuroendocrine neoplasms. Br J Surg 2014;101:1405-1412.
95.
Jilesen AP, van Eijck CH, in't Hof KH, et al: Postoperative complications, in-hospital mortality and 5-year survival after surgical resection for patients with a pancreatic neuroendocrine tumor: a systematic review. World J Surg 2016;40:729-748.
96.
Figueiredo MN, Maggiori L, Gaujoux S, et al: Surgery for small-bowel neuroendocrine tumors: is there any benefit of the laparoscopic approach? Surg Endosc 2014;28:1720-1726.
97.
Kandil E, Noureldine SI, Koffron A, et al: Outcomes of laparoscopic and open resection for neuroendocrine liver metastases. Surgery 2012;152:1225-1231.
98.
Drymousis P, Raptis DA, Spalding D, et al: Laparoscopic versus open pancreas resection for pancreatic neuroendocrine tumours: a systematic review and meta-analysis. HPB (Oxford) 2014;16:397-406.
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2017
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