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Curative and palliative surgery in patients with neuroendocrine tumors of the gastro-entero-pancreatic (GEP) tract

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Abstract

The incidence of neuroendocrine tumors (NET) increases with age. Lately, the diagnosis of NET was mainly caused by early detection of small NET (<1 cm) in the rectum and stomach, which are depicted by chance during routine and prophylactic endoscopy. Also in patients with large and metastatic pancreatic and intestinal tumors thorough pathologic investigation with use of different immunohistologic markers discovers more neuroendocrine tumors with low differentiation grade (G2-G3) and more neuroendocrine carcinomas (NEC), nowadays, than in former times. While gastric and rectal NET are discovered as small (<1 cm in diameter) and mainly highly differentiated tumors, demonstrating lymph node metastases in less than 10% of the patients, the majority of pancreatic and small bowel NET have already metastasized at the time of diagnosis. This is of clinical importance, since tumor stage and differentiation grade not only influence prognosis but also surgical procedure and may define whether a combination of surgery with systemic biologic therapy, chemotherapy or local cytoreductive procedures may be used. The indication for surgery and the preferred surgical procedure will have to consider personal risk factors of each patient (i.e. general health, additional illnesses, etc.) and tumor specific factors (i.e. tumor stage, grade of differentiation, functional activity, mass and variety of loco regional as well as distant metastases etc.). Together they define, whether radical curative or only palliative surgery can be applied. Altogether surgery is the only cure for locally advanced NET and helps to increase quality of life and overall survival in many patients with metastatic neuroendocrine tumors. The question of cure versus palliative therapy sometimes only can be answered with time, however. Many different aspects and various questions concerning the indication and extent of surgery and the best therapeutic procedure are still unanswered. Therefore, a close multidisciplinary cooperation of colleagues involved in biochemical and localization diagnostics and those active in various treatment areas is warranted to search for the optimal strategy in each individual patient. How far genetic screening impacts survival remains to be seen. Since surgeons do have a central role in the treatment of NET patients, they have to understand the need for integration into such an interdisciplinary team.

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References

  1. Boyar Cetinkaya R, Aagnes B, Thiis-Evensen E, et al. Trends in Incidence of Neuroendocrine Neoplasms in Norway: A Report of 16,075 Cases from 1993 through 2010. Neuroendocrinology. 2017;104(1):1–10.

    Article  CAS  Google Scholar 

  2. Zhou X, Xie H, Li J, et al. Factors associated with lymph node metastasis in radically esected rectal carcinoids: a systematic review and meta-analysis. J Gastrointest Surg. 2013;17:1689–97.

    Article  Google Scholar 

  3. Chi Y, Du F, Zhao H, et al. Characteristics and long-term prognosis of patients with rectal neuroendocrine tumors. World J Gastroenterol. 2014;20(43):16252–7.

    Article  CAS  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. Petersenn S, Koch CA. Neuroendocrine neoplasms - still a challenge despite major advances in clinical care with the development of specialized guidelines. Rev Endocr Metab Disord. 2017;18(4):373–8.

    Article  Google Scholar 

  6. Fitzgerald TL, Mosquera C, Lea CS, et al. Primary Site Predicts Grade for Gastroenteropancreatic Neuroendocrine Zumors. Am Surg. 2017;83(7):799–803.

    PubMed  Google Scholar 

  7. Martin JA, Warner RRP, Aronson A, et al. Lymph Node Metastases in the Prognosis of Gastroenteropancreatic Neuroendocrine Tumors. Pancreas. 2017;46(9):1214–8.

    Article  Google Scholar 

  8. Scherübl H, Streller B, Stabenow R, et al. Clinically detected gastroenteropancreatic neuroendocrine tumors are on the rise: epidemiological changes in Germany. World J Gastroenterol. 2013;19(47):9012–9.

    Article  Google Scholar 

  9. Begum N, Wellner U, Thorns C, et al. CUP Syndrome in Neuroendocrine Neoplasia: Analysis of Risk Factors and Impact of Surgical Intervention. World J Surg. 2015;39(6):1443–51.

    Article  Google Scholar 

  10. Fitzgerald TL, Dennis SO, Kachare SD, et al. Increasing incidence of duodenal neuroendocrine tumors: Incidental discovery of indolent disease? Surgery. 2015;158(2):466–71.

    Article  Google Scholar 

  11. Strosberg JR, Fine RL, Choi J, et al. First line chemotherapy with capecitabine and temozolomide in patients with metastastic pancreatic endocrine carcinoma. Cancer. 2011;117(2):268–75.

    Article  CAS  Google Scholar 

  12. Berardi R, Rinaldi A, Torniai M, et al. Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy-- A literature review. Crit Rev Oncol Hematol. 2016;98:264–74.

    Article  Google Scholar 

  13. Inzani F, Petrone G, Fadda G, et al. Cytohistology in NET: what is necessary today and what is the future? Rev Endocr Metab Disord. 2017;18(4):381–91.

    Article  Google Scholar 

  14. Ito T, Lee L, Jensen RT. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opin Pharmacother. 2016;17(16):2191–205.

    Article  CAS  Google Scholar 

  15. Landry CS, Brock G, Scoggins CR, et al. A proposed staging system for gastric carcinoid tumors based on an analysis of 1,543 patients. Ann Surg Oncol. 2009;16(1):51–60.

    Article  Google Scholar 

  16. Gladdy RA, Strong VE, Coit D, et al. Defining surgical indications for type I gastric carcinoid tumor. Ann Surg Oncol. 2009;16(11):3154–60.

    Article  Google Scholar 

  17. Xie JW, Sun YQ, Feng CY, et al. Evaluation of clinicopathological factors related to the prognosis of gastric neuroendocrine carcinoma. Eur J Surg Oncol. 2016;42(10):1464–70.

    Article  Google Scholar 

  18. Basuroy R, Srirajaskanthan R, Prachalias A, et al. Review article: the investigation and management of gastric neuroendocrine tumours. Aliment Pharmacol Ther. 2014;39(10):1071–84.

    Article  CAS  Google Scholar 

  19. Bartsch D, Waldmann J, Fendrich V, et al. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J Surg. 2012;99(9):1234–40.

    Article  CAS  Google Scholar 

  20. Fischer L, Mehrabi A, Büchler MW. Neuroendocrine tumors of the duodenum and pancreas. Surgical strategy. Chirurg. 2011;82(7):583–90.

    Article  CAS  Google Scholar 

  21. Kachare SD, Liner KR, Vohra NA, et al. A modified duodenal neuroendocrine tumor staging schema better defines the risk of lymph node metastasis and disease-free survival. Am Surg. 2014;80(8):821–6.

    PubMed  Google Scholar 

  22. 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.

    Article  Google Scholar 

  23. Partelli S, Bartsch DK, Capdevilla J, et al. ENETS Consensus Guidelines for Standard of Care in Neuroendocrine Tumours: Surgery for Small Intestinal and Pancreatic Neuroendocrine Tumours. Neuroendocrinology. 2017;105(3):255–65.

    Article  CAS  Google Scholar 

  24. Osera S, Oono Y, Ikematsu H, et al. Endoscopic submucosal resection with a ligation device for the treatment of duodenal neuroendocrine tumors. Surg Endosc. 2016;30(9):3928–32.

    Article  Google Scholar 

  25. Hata T, Motoi F, Ishida M, et al. Effect of Hospital Volume on Surgical Outcomes After Panceaticoduodenectomy: A Systematic Review and Meta-analysis. Ann Surg. 2016;263(4):664–72.

    Article  Google Scholar 

  26. 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(2):153–71.

    Article  CAS  Google Scholar 

  27. Mulvey CK, van Loon K, Bergsland EK, et al. Complicated Case Presentation: Management of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1. Pancreas. 2017;46(3):416–26.

    Article  Google Scholar 

  28. Genc CG, Jilesen AP, Partelli S, et al. A New Scoring System to Predict Recurrent Disease in Grade 1 and 2 Nonfunctional Pancreatic Neuroendocrine Tumors. Ann Surg. 2018;267(6):1148–54.

    Article  Google Scholar 

  29. Nell S, Verkooijen HM, Pieterman CRC, et al. Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group. Ann Surg. 2017;267(6):1155–60.

    Article  Google Scholar 

  30. Triponez F, Sadowski SM, Pattou F, et al. Long-term Follow-up of MEN1 Patients Who Do Not Have Initial Surgery for Small ≤2 cm Nonfunctioning Pancreatic Neuroendocrine Tumors, an AFCE and GTE Study: Association Francophone de Chirurgie Endocrinienne & Groupe d'Etude des Tumeurs Endocrines. Ann Surg. 2018;268(1):158–64.

    PubMed  Google Scholar 

  31. Krampitz GW, Norton JA, Poultsides GA, et al. Lymph nodes and survival in pancreatic neuroendocrine tumors. Arch Surg. 2012;147(9):820–7.

    Article  Google Scholar 

  32. Krauss T, Ferrara AM, Links TP, et al. Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2018;25(9):783–93.

    Article  Google Scholar 

  33. Glasker S, Neumann HPH, Koch CA, et al. Von Hippel Lindau Disease. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. www.endotext.org , South Dartmouth (MA): MDText.com, Inc.; 2000-. Last Update Sep 12, 2018.

  34. Nell S, Borel Rinkes IHM, Verkooijen HM, et al. Early and Late Complications After Surgery for MEN1-related Nonfunctioning Pancreatic Neuroendocrine Tumors. Ann Surg. 2018;267(2):352–6.

    Article  Google Scholar 

  35. Du ZY, Chen S, Han BS, et al. Middle segment pancreatectomy: a safe and organ-preserving option for benign and low-grade malignant lesions. World J Gastroenterol. 2013;19(9):1458–65.

    Article  CAS  Google Scholar 

  36. Sudo T, Murakami Y, Uemura K, et al. Middle pancreatectomy with pancreaticogastrostomy: a technique, operative outcomes, and long-term pancreatic function. J Surg Oncol. 2010;101(1):61–5.

    Article  Google Scholar 

  37. Andrén-Sandberg A, Ansorge C, Yadav TD. Are There Indications for Total Pancreatectomy in 2016? Dig Surg. 2016;33(4):329–34.

    Article  Google Scholar 

  38. Rosentraeger MJ, Garbrecht N, Anlauf M, et al. Syndromic versus non-syndromic neuroendocrine tumors of the duodenum: comparison of pathological features and biological behavior. Virchows Arch. 2016;468(3):277–87.

    Article  Google Scholar 

  39. Keutgen XM, Nilobul N, Kebebew E. Malignant-functioning neuroendocrine tumors of the pancreas: a survival analysis. Surgery. 2016;159(5):1382–9.

    Article  Google Scholar 

  40. Falconi M, Zerbi A, Crippa S, et al. Parenchyma-preserving resections for small onfunctioning pancreatic endocrine tumors. Ann Surg Oncol. 2010;17(6):1621–7.

    Article  Google Scholar 

  41. Akca A, Starke A, Goretzki PE, et al. Early postoperative glucose metabolism after insulinoma resection; abstract: CAEK 2018; LAS 2018.

  42. Rodriguez-Sanjuan JC, Gomez-Ruiz M, Trugeda-Carrera S, et al. Laparoscopic and robotic-assisted digestive surgery: present and future directions. World J Gastroenterol. 2016;22(6):1975–2004.

    Article  CAS  Google Scholar 

  43. Fendrich V, Waldmann J, Bartsch D, et al. Surgical management of pancreatic endocrine tumors. Nat Rev Clin Oncol. 2009;6(7):419–28.

    Article  Google Scholar 

  44. Mehrabi A, Fischer L, Hafezi M, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014;43(5):675–86.

    Article  Google Scholar 

  45. Thomaschewski M, Neeff H, Keck T, et al. Is there any role for minimally invasive surgery in NET? Rev Endocr Metab Disord. 2017;18(4):443–57.

    Article  CAS  Google Scholar 

  46. Norton JA, Fraker DL, Alexander HR, et al. Surgery increases survival in patients with gastrinoma. Ann Surg. 2006;244(3):410–9.

    PubMed  PubMed Central  Google Scholar 

  47. 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.14. Neuroendocrinology. 2016;103(2):172–85.

    Article  CAS  Google Scholar 

  48. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97(4):934–59.

    Article  Google Scholar 

  49. Grandhi MS, Lafaro KJ, Pawlik TM. Role of Locoregional and Systemic Approaches for the Treatment of Patients with Metastatic Neuroendocrine Tumors. J Gastrointest Surg. 2015;19(12):2273–82.

    Article  Google Scholar 

  50. Russolillo N, Vigano L, Razzore P, et al. Survival prognostic factors of gastro-enteric-pancreatic neuroendocrine tumors after primary tumor resection in a single tertiary center: comparison of gastro-enteric and pancreatic locations. Eur J Surg Oncol. 2015;41(6):751–7.

    Article  CAS  Google Scholar 

  51. Sposito C, Droz dit Busset M, Citterio D, et al. The place of liver transplantation in the treatment of hepatic metastases from neuroendocrine tumors: pros and cons. Rev Endocr Metab Disord. 2017;18(4):473–83.

    Article  CAS  Google Scholar 

  52. Jann H, Roll S, Couvelard A, et al. Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer. 2011;117(15):3332–41.

    Article  Google Scholar 

  53. Habbe N, Fendrich V, Heverhagen A, et al. Outcome of surgery for ileojejunal neuroendocrine tumors. Surg Today. 2013;43(10):1168–74.

    Article  Google Scholar 

  54. 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.

    Article  Google Scholar 

  55. Kim MK, Warner RR, Ward SC, et al. Prognostic significance of lymph node metastases in small intestinal neuroendocrine tumors. Neuroendocrinology. 2015;101(1):58–65.

    Article  CAS  Google Scholar 

  56. Schindl M, Kaczirek K, Passler C, et al. Treatment of small intestinal neuroendocrine umors: is an extended multimodal approach justified? World J Surg. 2002;26(8):976–84.

    Article  Google Scholar 

  57. Paquer A, Walter T, Hervieu V. Surgical management of small bowel neuroendocrine tumors: specific requirements and their impact on staging and prognosis. Ann Surg Oncol. 2015;3:S742–9.

    Article  Google Scholar 

  58. Singer J, Werner F, Koch CA, et al. Ectopic Cushing's syndrome caused by a well differentiated ACTH-secreting neuroendocrine carcinoma of the ileum. Exp Clin Endocrinol Diabetes. 2010;118(8):524–9.

    Article  CAS  Google Scholar 

  59. O'Shea T, Druce M. When should genetic testing be performed in patients with neuroendocrine tumors? Rev Endocr Metab Disord. 2017;18(4):499–515.

    Article  CAS  Google Scholar 

  60. Kaltsas G, Caplin M, Davies P, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology. 2017;105(3):245–54.

    Article  CAS  Google Scholar 

  61. Ramage JK, Ahmed A, Ardill J, et al. UK and Ireland Neuroendocrine Tumour Society. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61(1):6–32.

    Article  CAS  Google Scholar 

  62. Griniatsos J, Michail O. Appendiceal neuroendocrine tumors: Recent insights and clinical implications. World J Gastrointest Oncol. 2010;2(4):192–6.

    Article  Google Scholar 

  63. Boxberger N, Redlich A, Böger C, et al. Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer. 2013;60(1):65–70.

    Article  Google Scholar 

  64. Gustafsson BI, Siddique L, Chan A, et al. Uncommon cancers of the small intestine, appendix and colon: an analysis of SEER 1973-2004, and current diagnosis and therapy. Int J Oncol. 2008;33(6):1121–31.

    PubMed  Google Scholar 

  65. Kleiman DA, Finnerly B, Beninato T, et al. Features Associated With Metastases Among Well-Differentiated Neuroendocrine (Carcinoid) Tumors of the Appendix: The Significance of Small Vessel Invasion in Addition to Size. Dis Colon Rectum. 2015;58(12):1137–43.

    Article  Google Scholar 

  66. Rossi RE, Luong TV, Caplin ME, et al. Goblet cell appendiceal tumors—management dilemmas and long-term outcomes. Surg Oncol. 2015;24(1):47–53.

    Article  Google Scholar 

  67. Pahlavan PS, Kanthan R. Goblet cell carcinoid of the appendix. World J Surg Oncol. 2005;3:36.

    Article  Google Scholar 

  68. Lamarca A, Nonaka D, Lopez-Escola C, et al. Appendiceal Goblet Cell Carcinoids: Management Considerations from a Reference Peritoneal Tumour Service Centre and ENETS Centre of Excellence. Neuroendocrinology. 2016;103(5):500–17.

    Article  CAS  Google Scholar 

  69. Smith JD, Reidy DL, Goodman KA, et al. A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum. Ann Surg Oncol. 2014;21(9):2956–62.

    Article  Google Scholar 

  70. Shafqat H, Ali S, Salhab M, et al. Survival of patients with neuroendocrine carcinoma of the colon and rectum: a population-based analysis. Dis Colon Rectum. 2015;58(3):294–303.

    Article  Google Scholar 

  71. Sekiguchi M, Sekine S, Sakamoto T, et al. Excellent prognosis following endoscopic resection of patients with rectal neuroendocrine tumors despite the frequent presence of lymphovascular invasion. J Gastroenterol. 2015;50(12):1184–9.

    Article  Google Scholar 

  72. Shields CJ, Tiret E, Winter DC. Carcinoid tumors of the rectum: a multi-institutional international collaboration. Ann Surg. 2010;252(5):750–5.

    Article  Google Scholar 

  73. Brieau B, Lepere C, Walter T, et al. Radiochemotherapy Versus Surgery in Nonmetastatic Anorectal Neuroendocrine Carcinoma: A Multicenter Study by the Association des Gastro-Enterologues Oncologues. Medicine (Baltimore). 2015;94(42):e1864.

    Article  Google Scholar 

  74. Bacchetti S, Bertozzi S, Londero AP, et al. Surgical treatment and survival in patients with liver metastases from neuroendocrine tumors: a meta-analysis of observational studies. Int J Hepatol. 2013;2013:235040.

    Article  Google Scholar 

  75. Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15(1):e8–21.

    Article  Google Scholar 

  76. Lesurtel M, Nagorney DM, Mazzaferro V, et al. When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations. HPB (Oxford). 2015;17(1):17–22.

    Article  Google Scholar 

  77. Yuan CH, Wang J, Xiu DR, et al. Meta-analysis of Liver Resection Versus Nonsurgical Treatments for Pancreatic Neuroendocrine Tumors with Liver Metastases. Ann Surg Oncol. 2016;23(1):244–9.

    Article  Google Scholar 

  78. Du S, Wang Z, Sang X, et al. Surgical resection improves the outcome of the patients with neuroendocrine tumor liver metastases. Medicine (Baltimore). 2015;94(2):e388.

    Article  Google Scholar 

  79. Gaujoux S, Gonen M, Tang L, et al. Synchronous resection of primary and liver metastases for neuroendocrine tumors. Ann Surg Oncol. 2012;19(13):4270–7.

    Article  Google Scholar 

  80. Bacchetti S, Pasqual EM, Bertozzi S, et al. Curative versus palliative surgical resection of liver metastases in patients with neuroendocrine tumors: a meta-analysis of observational studies. Gland Surg. 2014;3(4):243–51.

    PubMed  PubMed Central  Google Scholar 

  81. Watzka FM, Fottner C, Miederer M, et al. Surgical therapy of neuroendocrine neoplasm with hepatic metastasis: patient selection and prognosis. Langenbeck's Arch Surg. 2015;400(3):349–58.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  83. Mandani A, Thomassen I, van Gestel YRBM, et al. Peritoneal metastases from gastroenteropancreatic neuroendocrine tumors: incidence, risk factors and prognosis. Ann Surg Oncol. 2017;24(8):2199–205.

    Article  Google Scholar 

  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(1):311–8.

    Article  Google Scholar 

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Goretzki, P.E., Mogl, M.T., Akca, A. et al. Curative and palliative surgery in patients with neuroendocrine tumors of the gastro-entero-pancreatic (GEP) tract. Rev Endocr Metab Disord 19, 169–178 (2018). https://doi.org/10.1007/s11154-018-9469-9

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