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The Landmark Series: Management of Small Bowel Neuroendocrine Tumors


Surgical resection is the foundation for treatment of small bowel neuroendocrine tumors (SBNETs). Guidelines for surgical management of SBNETs rely on retrospective data, which suggest that primary tumor resection and cytoreduction improve symptoms, prevent future complications, and lengthen survival. In advanced NETs, improvement in progression-free survival has been reported in large, randomized, controlled trials of various medical treatments, including somatostatin analogues, targeted therapy, and peptide receptor radionuclide therapy. This review discusses important studies influencing the management of SBNETs and the limitations of current evidence regarding surgical interventions for SBNETs.

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  1. 1.

    Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH. Life history of the carcinoid tumor of the small intestine. Cancer. 1961;14:901–12.

    CAS  PubMed  Google Scholar 

  2. 2.

    Kuiper DH, Gracie Jr. WA, Pollard HM. Twenty years of gastrointestinal carcinoids. Cancer. 1970;25(6):1424–30.

    CAS  PubMed  Google Scholar 

  3. 3.

    Berge T, Linell F. Carcinoid tumours: frequency in a defined population during a 12-year-period. Acta Pathol Microbiol Scand A Pathol. 1976;84(4):322–30.

    CAS  Google Scholar 

  4. 4.

    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(6):1086–93.

    CAS  PubMed  Google Scholar 

  5. 5.

    Wang SC, Parekh JR, Zuraek MB, et al. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg. 2010;145(3):276–80.

    PubMed  Google Scholar 

  6. 6.

    Keck KJ, Maxwell JE, Utria AF, et al. The distal predilection of small bowel neuroendocrine tumors. Ann Surg Oncol. 2018;25(11):3207–13.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg. 2009;249(1):63–71.

    PubMed  Google Scholar 

  8. 8.

    Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–42.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Niederle B, Pape UF, Costa F, et al. ENETS Consensus Guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology. 2016;103(2):125–38.

    CAS  PubMed  Google Scholar 

  10. 10.

    Howe JR, Cardona K, Fraker DL, et al. The surgical management of small bowel neuroendocrine tumors: consensus guidelines of the North American Neuroendocrine Tumor Society. Pancreas. 2017;46(6):715–31.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    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.

    PubMed  Google Scholar 

  12. 12.

    Givi B, Pommier SJ, Thompson AK, Diggs BS, Pommier RF. Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival. Surgery. 2006;140(6):891–7. (discussion 897–8).

    PubMed  Google Scholar 

  13. 13.

    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.

    PubMed  Google Scholar 

  14. 14.

    Tierney JF, Chivukula SV, Wang X, et al. Resection of primary tumor may prolong survival in metastatic gastroenteropancreatic neuroendocrine tumors. Surgery. 2019;165(3):644–51.

    PubMed  Google Scholar 

  15. 15.

    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(4):645–51. (discussion 651–3).

    PubMed  Google Scholar 

  16. 16.

    Makridis C, Rastad J, Oberg K, Akerström G. Progression of metastases and symptom improvement from laparotomy in midgut carcinoid tumors. World J Surg. 1996;20(7):900–6. (discussion 907).

    CAS  PubMed  Google Scholar 

  17. 17.

    Rajaretnam NS, Meyer-Rochow GY. Commonwealth neuroendocrine tumor research collaborative (CommNETs) surgical section. Surgical management of primary small bowel NET presenting acutely with obstruction or perforation. World J Surg. 2021;45(1):203–7.

    Google Scholar 

  18. 18.

    Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg. 2000;190(4):432–45.

    CAS  PubMed  Google Scholar 

  19. 19.

    Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. Priorities for Improving the Management of Gastroenteropancreatic Neuroendocrine Tumors. JNCI J Natl Cancer Inst. 2008;100(18):1282–9.

    PubMed  Google Scholar 

  20. 20.

    Singh S, Law C. Multidisciplinary reference centers: the care of neuroendocrine tumors. J Oncol Pract. 2010;6(6):e11–6.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Søreide O, Berstad T, Bakka A, et al. Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery. 1992;111(1):48–54.

    PubMed  Google Scholar 

  22. 22.

    Ahmed A, Turner G, King B, et al. Midgut neuroendocrine tumours with liver metastases: results of the UKINETS study. Endocr Relat Cancer. 2009;16(3):885–94.

    CAS  PubMed  Google Scholar 

  23. 23.

    Capurso G, Rinzivillo M, Bettini R, Boninsegna L, Delle Fave G, Falconi M. Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases. Br J Surg. 2012;99(11):1480–6.

    CAS  PubMed  Google Scholar 

  24. 24.

    Daskalakis K, Karakatsanis A, Hessman O, et al. Association of a prophylactic surgical approach to stage IV small intestinal neuroendocrine tumors with survival. JAMA Oncol. 2018;4(2):183–9.

    PubMed  Google Scholar 

  25. 25.

    Norlén O, Stålberg P, Öberg K, et al. Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg. 2012;36(6):1419–31.

    PubMed  Google Scholar 

  26. 26.

    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(7):1695–700.

    PubMed  Google Scholar 

  27. 27.

    Watzka FM, Fottner C, Miederer M, et al. Surgical treatment of NEN of small bowel: a retrospective analysis. World J Surg. 2016;40(3):749–58.

    CAS  PubMed  Google Scholar 

  28. 28.

    Keck KJ, Choi A, Maxwell JE, et al. Increased grade in neuroendocrine tumor metastases negatively impacts survival. Ann Surg Oncol. 2017;24(8):2206–12.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Hellman P, Lundström 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(8):991–7.

    PubMed  Google Scholar 

  30. 30.

    Öhrvall U, Eriksson B, Juhlin C, et al. Method for dissection of mesenteric metastases in mid-gut carcinoid tumors. World J Surg. 2000;24(11):1402–8.

    PubMed  Google Scholar 

  31. 31.

    Howe JR. Small bowel resection and lymphadenectomy for jejunoileal neuroendocrine tumors. In: Howe JR, editor. Endocrine and neuroendocrine surgery. Berlin: Springer; 2017. pp. 301–315.

    Google Scholar 

  32. 32.

    Tran CG, Sherman SK, Howe JR. Small bowel neuroendocrine tumors. Curr Probl Surg. 2020;57(12):100823.

    Google Scholar 

  33. 33.

    McCulloch P, Niita ME, Kazi H, Gama-Rodrigues JJ. Gastrectomy with extended lymphadenectomy for primary treatment of gastric cancer. Br J Surg. 2005;92(1):5–13.

    CAS  PubMed  Google Scholar 

  34. 34.

    Farnell MB, Aranha GV, Nimura Y, Michelassi F. The role of extended lymphadenectomy for adenocarcinoma of the head of the pancreas: strength of the evidence. J Gastrointest Surg. 2008;12(4):651–6.

    PubMed  Google Scholar 

  35. 35.

    Massimino KP, Han E, Pommier SJ, Pommier RF. Laparoscopic surgical exploration is an effective strategy for locating occult primary neuroendocrine tumors. Am J Surg. 2012;203(5):628–31.

    PubMed  Google Scholar 

  36. 36.

    Reissman P, Shmailov S, Grozinsky-Glasberg S, Gross DJ. Laparoscopic resection of primary midgut carcinoid tumors. Surg Endosc. 2013;27(10):3678–82.

    PubMed  Google Scholar 

  37. 37.

    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(5):1720–6.

    PubMed  Google Scholar 

  38. 38.

    Kasai Y, Mahuron K, Hirose K, et al. A novel stratification of mesenteric mass involvement as a predictor of challenging mesenteric lymph node dissection by minimally invasive approach for ileal neuroendocrine tumors. J Surg Oncol. 2020;122(2):204–11.

    CAS  PubMed  Google Scholar 

  39. 39.

    Touzios JG, Kiely JM, Pitt SC, et al. Neuroendocrine hepatic metastases: Does aggressive management improve survival? Ann Surg. 2005;241(5):776–83. (discussion 783–5).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Maxwell JE, Sherman SK, O’Dorisio TM, Bellizzi AM, Howe JR. Liver-directed surgery of neuroendocrine metastases: What is the optimal strategy? Surgery. 2016;159(1):320–33.

    PubMed  Google Scholar 

  41. 41.

    Jacobson R, Sherman SK, Dahdaleh F, Turaga KK. Peritoneal metastases in colorectal cancer. Ann Surg Oncol. 2018;25(8):2145–51.

    PubMed  Google Scholar 

  42. 42.

    Chicago Consensus Working Group. The Chicago consensus on peritoneal surface malignancies: management of appendiceal neoplasms. Ann Surg Oncol. 2020;27(6):1753–60.

  43. 43.

    Chicago Consensus Working Group. The Chicago consensus on peritoneal surface malignancies: management of peritoneal mesothelioma. Cancer. 2020;126(11):2547–52.

  44. 44.

    Elias D, David A, Sourrouille I, et al. Neuroendocrine carcinomas: optimal surgery of peritoneal metastases (and associated intra-abdominal metastases). Surgery. 2014;155(1):5–12.

    PubMed  Google Scholar 

  45. 45.

    Chicago Consensus Working Group. The Chicago consensus on peritoneal surface malignancies: management of neuroendocrine tumors. Ann Surg Oncol. 2020;27(6):1788–92.

  46. 46.

    Nelson DR, Stachura ME, Dunlap DB. Ileal carcinoid tumor complicated by retroperitoneal fibrosis and a prolactinoma. Am J Med Sci. 1988;296(2):129–33.

    CAS  PubMed  Google Scholar 

  47. 47.

    Sakai D, Murakami M, Kawazoe K, Tsutsumi Y. Ileal carcinoid tumor complicating carcinoid heart disease and secondary retroperitoneal fibrosis. Pathol Int. 2000;50(5):404–11.

    CAS  PubMed  Google Scholar 

  48. 48.

    Moertel CG. Treatment of the carcinoid tumor and the malignant carcinoid syndrome. J Clin Oncol. 1983;1(11):727–40.

    CAS  PubMed  Google Scholar 

  49. 49.

    Norheim I, Oberg K, Theodorsson-Norheim E, et al. Malignant carcinoid tumors An analysis of 103 patients with regard to tumor localization, hormone production, and survival. Ann Surg. 1987;206(2):115–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    McEntee GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery. 1990;108(6):1091–6.

    CAS  PubMed  Google Scholar 

  51. 51.

    Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg. 1995;169(1):36–42. (discussion 42–3).

    CAS  PubMed  Google Scholar 

  52. 52.

    Scott AT, Breheny PJ, Keck KJ, et al. Effective cytoreduction can be achieved in patients with numerous neuroendocrine tumor liver metastases (NETLMs). Surgery. 2019;165(1):166–75.

    PubMed  Google Scholar 

  53. 53.

    Gangi A, Howe JR. The landmark series: neuroendocrine tumor liver metastases. Ann Surg Oncol. 2020;27(9):3270–80.

    PubMed  Google Scholar 

  54. 54.

    Kvols LK, Moertel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986;315(11):663–6.

    CAS  PubMed  Google Scholar 

  55. 55.

    Reubi JC, Hacki WH, Lamberts SW. Hormone-producing gastrointestinal tumors contain a high density of somatostatin receptors. J Clin Endocrinol Metab. 1987;65(6):1127–34.

    CAS  PubMed  Google Scholar 

  56. 56.

    Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res. 1990;50(18):5969–77.

    CAS  PubMed  Google Scholar 

  57. 57.

    Sherman SK, Howe JR. Translational research in endocrine surgery. Surg Oncol Clin N Am. 2013;22(4):857–84.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    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(28):4656–63.

    CAS  PubMed  Google Scholar 

  59. 59.

    Rinke A, Wittenberg M, 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 (PROMID): results of long-term survival. Neuroendocrinology. 2017;104(1):26–32.

    CAS  PubMed  Google Scholar 

  60. 60.

    Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33.

    PubMed  Google Scholar 

  61. 61.

    Wolin EM. The expanding role of somatostatin analogs in the management of neuroendocrine tumors. Gastrointest Cancer Res GCR. 2012;5(5):161–8.

    PubMed  Google Scholar 

  62. 62.

    Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95(2):157–76.

    CAS  PubMed  Google Scholar 

  63. 63.

    Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46(6):707–14.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Maxwell JE, Sherman SK, Howe JR. Translational diagnostics and therapeutics in pancreatic neuroendocrine tumors. Clin Cancer Res. 2016;22(20):5022–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Hennrich U, Kopka K. Lutathera(®): the First FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals (Basel). 2019;12(3):114.

    CAS  PubMed Central  Google Scholar 

  67. 67.

    Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology. 2017;105(3):295–309.

    CAS  PubMed  Google Scholar 

  68. 68.

    Hope TA, Bodei L, Chan JA, et al. NANETS/SNMMI consensus statement on patient selection and appropriate use of (177)Lu-DOTATATE Peptide Receptor Radionuclide Therapy. J Nucl Med. 2020;61(2):222–7.

    CAS  PubMed  Google Scholar 

  69. 69.

    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005–12.

    CAS  PubMed  Google Scholar 

  71. 71.

    Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. The Lancet. 2016;387(10022):968–77.

    CAS  PubMed  Google Scholar 

  72. 72.

    Buzzoni R, Carnaghi C, Strosberg J, et al. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4. Onco Targets Ther. 2017;10:5013–30.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Singh S, Carnaghi C, Buzzoni R, et al. Everolimus in neuroendocrine tumors of the gastrointestinal tract and unknown primary. Neuroendocrinology. 2018;106(3):211–20.

    CAS  PubMed  Google Scholar 

  74. 74.

    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(18):3063–72.

    PubMed  Google Scholar 

  75. 75.

    Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology. 2009;89(4):471–6.

    CAS  PubMed  Google Scholar 

  76. 76.

    van der Horst-Schrivers AN, Post WJ, Kema IP, et al. Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours. Eur J Cancer. 2007;43(18):2651–7.

    PubMed  Google Scholar 

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This work was supported by NIH Grants T32 CA148062 (CGT), T32 CA078586 (SKS), and Specialized Programs of Research Excellence Grant P50 CA174521-01 (JRH).

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Correspondence to James R. Howe MD.

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This work was supported by NIH Grants T32 CA148062 (CGT), T32 CA078586 (SKS), and Specialized Programs of Research Excellence Grant P50 CA174521-01 (JRH).

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Tran, C.G., Sherman, S.K. & Howe, J.R. The Landmark Series: Management of Small Bowel Neuroendocrine Tumors. Ann Surg Oncol 28, 2741–2751 (2021).

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