MODERN APPROACHES AND RECENT ADVANCES IN NEUROENDOCRINE TUMORS

Modern Approaches and Recent Advances in Neuroendocrine Tumors-kapak

GENERAL CHARACTERISTICS AND MANAGEMENT OF NEUROENDOCRINE TUMORS OF JEJENUM AND ILEUM

Alp Ömer Cantürk

Sakarya University Training and Research Hospital, Department of General Surgery, Sakarya, Türkiye

Cantürk AÖ. General Characteristics and Management of Neuroendocrine Tumors of Jejenum and Ileum. In: Gönüllü E, Karaman K, editors. Modern Approaches and Recent Advances in Neuroendocrine Tumors. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.133-143.

ABSTRACT

This chapter details the general characteristics and management of neuroendocrine tumors (NETs) of the jejunum and ileum of the small intestine. NETs are a heterogeneous group of tumors that arise from cells with endocrine and neural properties. NETs located in this region, called the midgut, are the most common malignancy of the small intestine and are diagnosed especially at an advanced age (average 60-65 years). They usually have a slow course and often metastasize at the time of diagnosis. Jejuno-ileal NETs originate from enterochromaffin cells and often secrete various hormones, especially serotonin. In metastatic cases, this condition may present with typical symptoms, such as carcinoid syndrome (flushing, diarrhea, and bronchospasm). Pathologically, well-differentiated NETs have a low mutation burden, and genetic alterations such as loss of chromosome 18 and CDKN1B mutations can be observed. Histologic grading (G1, G2, G3) is based on the Ki-67 index and mitotic activity; well-differentiated G1-G2 NETs are usually indolent, whereas G3 or poorly differentiated tumors are more aggressive. The clinical findings may range from silent progression to nonspecific abdominal pain, obstruction, or carcinoid syndrome. Imaging modalities (three-phase CT, MRI, Ga-68 DOTATATE PET/CT), endoscopy, and biochemical markers (chromogranin A and 5-HIAA in the blood) play a critical role in diagnosis. Surgical resection is the mainstay treatment. In localized cases, block removal of the primary tumor and lymph nodes may be curative. In metastatic patients, somatostatin analogs, peptide receptor radionuclide therapy (PRRT), and targeted agents (everolimus, etc.) are used for symptom control and to delay disease progression. In patients with liver metastasis, debulking or ablative procedures may provide vital benefits. If carcinoid syndrome is present, symptom management (serotonin inhibition, diet) is important. In general, midgut NETs are characterized by long survival times. In stage I-II cases, the 5-year survival can reach 80-90%. Some cases can be kept under control for many years, even with liver metastasis. In addition to the signs and symptoms, regular follow-up with CT/MR or DOTATATE PET is essential. Owing to the nature of the disease, long-term follow-up protocols are recommended, as recurrence may be observed even in later years. This chapter summarizes the current diagnostic and therapeutic approaches to midgut NETs by evaluating their surgical and medical applications using a holistic approach.

Keywords: Neuroendocrine tumors; Jejunal neoplasms; Ileal neoplasms; Malignant carcinoid Syndrome surgery; Receptors, somatostatin Chromogranins; Kromograninler

Referanslar

  1. Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol. 2020;12(8):791-807. [Crossref]  [PubMed]  [PMC]
  2. 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(6):753-766. [Crossref]  [PubMed]
  3. Kupietzky A, Dover R, Mazeh H. Surgical aspects of small intestinal neuroendocrine tumors. World J Gastrointest Surg. 2023;15(4):566-577. [Crossref]  [PubMed]  [PMC]
  4. Moertel CG. Karnofsky memorial lecture. An odyssey in the land of small tumors. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1987;5(10):1502-22. [Crossref]  [PubMed]
  5. Dasari A, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA oncology. 2017;3(10):1335-1342. [Crossref]  [PubMed]  [PMC]
  6. 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;249:63-71. [Crossref]  [PubMed]
  7. Das S, Dasari A. Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences? Curr Oncol Rep. 2021;23:43. [Crossref]  [PubMed]  [PMC]
  8. Rindi G, Bordi C, Rappel S, La Rosa S, Stolte M, Solcia E. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior. World J Surg. 1996;20:168-172. [Crossref]  [PubMed]
  9. Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glaz er M, Kramer MR. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest. 2001;119:1647-1651. [Crossref]  [PubMed]
  10. Anlauf M, Sipos B, Boeck I, Baldus SE, Heikaus S, Krausch M, et al. Neuroendocrine neoplasms of the distal jejunum and ileum Pathologe. 2014;35:283-93; quiz 294. [Crossref]  [PubMed]
  11. Eriksson B, Klöppel G, Krenning E, Ahlman H, Plöckinger U, Wiedenmann B, Arnold R, et al. Frascati Consensus Conference participants. Consensus guidelines for the management of patients with digestive neuroendocrine tumors--well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology. 2008;87:8-19. [Crossref]  [PubMed]
  12. Francis JM, Kiezun A, Ramos AH, Serra S, Pedamallu CS, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet. 2013;45(12):1483-6. [Crossref]  [PubMed]  [PMC]
  13. Kim JY, Hong SM, Ro JY. Recent updates on grading and classification of neuroendocrine tumors. Ann Diagn Pathol. 2017;29:11-16. [Crossref]  [PubMed]
  14. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-188. [Crossref]  [PubMed]  [PMC]
  15. Popa O, Taban SM, Pantea S, Plopeanu AD, Barna RA, Cornianu M, et al. The new WHO classification of gastrointestinal neuroendocrine tumors and immunohistochemical expression of somatostatin receptor 2 and 5. Exp Ther Med. 2021;22:1179. [Crossref]  [PubMed]  [PMC]
  16. Choe J, Kim KW, Kim HJ, Kim DW, Kim KP, Hong SM, Ryu JS, et al. What Is New in the 2017 World Health Organization Classification and 8th American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Neoplasms? Korean J Radiol. 2019;20:5-17. [Crossref]  [PubMed]  [PMC]
  17. Howe JR, Cardona K, Fraker DL, Kebebew E, Untch BR, Wang YZ, Law CH, et al. The Surgical Management of Small Bowel Neuroendocrine Tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society. Pancreas. 2017;46:715-731. [Crossref]  [PubMed]  [PMC]
  18. Bendelow J, Apps E, Jones LE, Poston GJ. Carcinoid syndrome. Eur J Surg Oncol. 2008;34:289-296. [Crossref]  [PubMed]
  19. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med. 1999;340:858-868. [Crossref]  [PubMed]
  20. Strosberg JR, Halfdanarson TR, Bellizzi AM, Chan JA, Dillon JS, Heaney AP, Kunz PL, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. Pancreas. 2017;46(6):707-714. [Crossref]  [PubMed]  [PMC]
  21. Hofland J, Kaltsas G, de Herder WW. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocr Rev. 2020;41:371-403. [Crossref]  [PubMed]  [PMC]
  22. Keck KJ, Maxwell JE, Menda Y, Bellizzi A, Dillon J, O'Dorisio TM, Howe JR. Identification of primary tumors in patients presenting with metastatic gastroenteropancreatic neuroendocrine tumors. Surgery. 2017;161:272-279. [Crossref]  [PubMed]  [PMC]
  23. Watzka FM, Fottner C, Miederer M, Weber MM, Schad A, Lang H, Musholt TJ. Surgical Treatment of NEN of Small Bowel: A Retrospective Analysis. World J Surg. 2016;40:749-758. [Crossref]  [PubMed]
  24. Wang YZ, Joseph S, Lindholm E, Lyons J, Boudreaux JP, Woltering EA. Lymphatic mapping helps to define resection margins for midgut carcinoids. Surgery. 2009;146:993-997. [Crossref]  [PubMed]
  25. Tsilimigras DI, Ntanasis-Stathopoulos I, Kostakis ID, Moris D, Schizas D, Cloyd JM, Pawlik TM. Is Resection of Primary Midgut Neuroendocrine Tumors in Patients with Unresectable Metastatic Liver Disease Justified? J Gastrointest Surg. 2019;23:1044-1054. [Crossref]  [PubMed]
  26. Kianmanesh R, O'Toole D, Sauvanet A, Ruszniewski P, Belghiti J. [Surgical treatment of gastric, enteric pancreatic endocrine tumors. Part 2. treatment of hepatic metastases] J Chir (Paris) 2005;142:208-219. [Crossref]
  27. Glazer ES, Tseng JF, Al-Refaie W, Solorzano CC, Liu P, Willborn KA, Abdalla EK, Vauthey JN, Curley SA. Longterm survival after surgical management of neuroendocrine hepatic metastases. HPB (Oxford) 2010;12:427-433. [Crossref]  [PubMed]  [PMC]
  28. Almond LM, Hodson J, Ford SJ, Gourevitch D, Roberts KJ, Shah T, Isaac J, Desai A. Role of palliative resection of the primary tumour in advanced pancreatic and small intestinal neuroendocrine tumours: A systematic review and meta-analysis. Eur J Surg Oncol. 2017;43:1808-1815. [Crossref]  [PubMed]
  29. Faiss S, Pape UF, Böhmig M, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003;21:2689-2696. [Crossref]  [PubMed]
  30. Arnold R, Rinke A, Klose KJ, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3:761-771. [Crossref]  [PubMed]
  31. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376:125-135. [Crossref]  [PubMed]  [PMC]
  32. Pavel M, Baudin E, Couvelard A, Krenning E, Öberg K, Steinmüller T, et al. Barcelona Consensus Conference participants. 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;95:157-176. [Crossref]  [PubMed]
  33. Daskalakis K, Karakatsanis A, Hessman O, Stuart HC, Welin S, Tiensuu Janson E, Öberg K, Hellman P, Norlén O, Stålberg P. Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival. JAMA Oncol. 2018;4:183-189. [Crossref]  [PubMed]  [PMC]
  34. Landry CS, Lin HY, Phan A, Charnsangavej C, Abdalla EK, Aloia T, Nicolas Vauthey J, Katz MH, Yao JC, Fleming JB. 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. [Crossref]  [PubMed]  [PMC]
  35. Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3-Octreotide PET in neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48:508-518. [Crossref]  [PubMed]