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Appendiceal Neuroendocrine Neoplasms: an Update for 2023

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Abstract

Purpose of Review

To summarize the literature from the last 5 years on treatment of appendiceal neuroendocrine neoplasms (aNEN). Furthermore, to evaluate the prognostic significance of lymph node metastases, indications for adjuvant treatment, and challenges of the current follow-up regimen.

Recent Findings

Simple appendectomy is sufficient in tumors < 1 cm while extended surgery is indicated in tumors > 2 cm. In a multicenter study of aNENs measuring 1–2 cm, extended surgery offered no significant prognostic advantage and is now limited to incomplete tumor resection or high-grade G2 or G3 aNEN. Follow-up remains debatable, as the use of imaging and biomarkers lacks validation.

Summary

While surgical procedure is well established in aNEN tumors < 1 cm and > 2 cm, the need for extended surgery in aNEN tumors 1–2 cm is questionable. Future studies should address the prognostic impact of lymph node metastases and the optimal design and duration of follow-up.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Kaltsas G, Walter T, Knigge U, Toumpanakis C, Santos AP, Begum N, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for appendiceal neuroendocrine tumours (aNET). J Neuroendocrinol. 2023;35(10):e13332. https://doi.org/10.1111/jne.13332.

  2. Pape U-F, Niederle B, Costa F, Gross D, Kelestimur F, Kianmanesh R, et al. ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology. 2016;103(2):144–52.

    Article  CAS  PubMed  Google Scholar 

  3. • Holmager P, Willemoe GL, Nielsen K, Grøndahl V, Klose M, Andreassen M, et al. Neuroendocrine neoplasms of the appendix: characterization of 335 patients referred to the Copenhagen NET Center of Excellence. Eur J Surg Oncol. 2021;47(6):1357–63. This is a large European study on aNEN and describes the importance of EC-cell aNEN compared to L-cell aNEN.

    Article  PubMed  Google Scholar 

  4. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, 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  PubMed  PubMed Central  Google Scholar 

  5. Toumpanakis C, Fazio N, Tiensuu Janson E, Hörsch D, Pascher A, Reed N, et al. Unmet needs in appendiceal neuroendocrine neoplasms. Neuroendocrinology. 2019;108(1):37–44.

    Article  CAS  PubMed  Google Scholar 

  6. Rault-Petit B, Do Cao C, Guyétant S, Guimbaud R, Rohmer V, Julié C, et al. Current management and predictive factors of lymph node metastasis of appendix neuroendocrine tumors. Ann Surg [Internet]. 2019 Jul;270(1):165–71. Available from: http://journals.lww.com/00000658-201907000-00026.

  7. Pawa N, Clift AK, Osmani H, Drymousis P, Cichocki A, Flora R, et al. Surgical management of patients with neuroendocrine neoplasms of the appendix: appendectomy or more. Neuroendocrinology. 2018;106(3):242–51.

    Article  CAS  PubMed  Google Scholar 

  8. • Brighi N, La Rosa S, Rossi G, Grillo F, Pusceddu S, Rinzivillo M, et al. Morphological factors related to nodal metastases in neuroendocrine tumors of the appendix: a multicentric retrospective study. Ann Surg. 2020;271(3):527–33. This study reports that only size > 2 cm is associated with presence of lymph node metastases.

    Article  PubMed  Google Scholar 

  9. • Alabraba E, Pritchard DM, Griffin R, Diaz-Nieto R, Banks M, Cuthbertson DJ, et al. The impact of lymph node metastases and right hemicolectomy on outcomes in appendiceal neuroendocrine tumours (aNETs). Eur J Surg Oncol. 2021;47(6):1332–8. This study finds that none of the well-known risk factors is associated with presence of lymph node metastases.

    Article  PubMed  Google Scholar 

  10. Steffen T, Ebinger SM, Warschkow R, Lüthi C, Schmied BM, Clerici T. Long-term survival is not impaired after the complete resection of neuroendocrine tumors of the appendix. World J Surg. 2015;39(11):2670–6.

    Article  PubMed  Google Scholar 

  11. Ricci C, Ingaldi C, Alberici L, Brighi N, Santini D, Mosconi C, et al. Histopathological diagnosis of appendiceal neuroendocrine neoplasms: when to perform a right hemicolectomy? A systematic review and meta-analysis. Endocrine. 2019;66(3):460–6.

    Article  CAS  PubMed  Google Scholar 

  12. Moertel CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid tumor of the appendix: treatment and prognosis. N Engl J Med. 1987;317(27):1699–701.

    Article  CAS  PubMed  Google Scholar 

  13. Mullen JT, Savarese DMF. Carcinoid tumors of the appendix: a population-based study. J Surg Oncol. 2011;104(1):41–4.

    Article  PubMed  Google Scholar 

  14. Grozinsky-Glasberg S, Alexandraki KI, Barak D, Doviner V, Reissman P, Kaltsas GA, et al. Current size criteria for the management of neuroendocrine tumors of the appendix: are they valid? Clinical experience and review of the literature. Neuroendocrinology. 2013;98(1):31–7.

    Article  CAS  PubMed  Google Scholar 

  15. Nussbaum DP, Speicher PJ, Gulack BC, Keenan JE, Ganapathi AM, Englum BR, et al. Management of 1- to 2-cm carcinoid tumors of the appendix: using the National Cancer Data Base to address controversies in general surgery. J Am Coll Surg. 2015;220(5):894–903.

    Article  PubMed  Google Scholar 

  16. Galanopoulos M, McFadyen R, Drami I, Naik R, Evans N, Luong TV, et al. Challenging the current risk factors of appendiceal neuroendocrine neoplasms: can they accurately predict local lymph nodal invasion? Results from a large case series. Neuroendocrinology. 2019;109(2):179–86.

    Article  CAS  PubMed  Google Scholar 

  17. Niederle B, Pape U-F, Costa F, Gross D, Kelestimur F, Knigge U, et al. ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology. 2016;103(2):125–38.

    Article  CAS  PubMed  Google Scholar 

  18. Mosquera C, Fitzgerald TL, Vora H, Grzybowski M. Novel nomogram combining depth of invasion and size can accurately predict the risk for regional nodal metastases for appendiceal neuroendocrine tumors (A-NET). J Surg Oncol. 2017;116(6):651–7.

    Article  PubMed  Google Scholar 

  19. Alexandraki KI, Kaltsas G, Grozinsky-Glasberg S, Oleinikov K, Kos-Kudła B, Kogut A, et al. The effect of prophylactic surgery in survival and HRQoL in appendiceal NEN. Endocrine. 2020;70(1):178–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Palmer K, Weerasuriya S, Chandrakumaran K, Rous B, White BE, Paisey S, et al. Goblet cell adenocarcinoma of the appendix: a systematic review and incidence and survival of 1,225 cases from an English cancer registry. Front Oncol. 2022;12:915028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Korse CM, Taal BG, van Velthuysen M-LF, Visser O. Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer. 2013;49(8):1975–83.

    Article  PubMed  Google Scholar 

  22. van Velthuysen M-LF, Couvelard A, Rindi G, Fazio N, Hörsch D, Nieveen van Dijkum EJ, et al. ENETS standardized (synoptic) reporting for neuroendocrine tumour pathology. J Neuroendocrinol. 2022;34(3):e13100.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Moertel CG, Dockerty MB, Judd ES. Carcinoid tumors of the vermiform appendix. Cancer. 1968;21(2):270–8.

    Article  CAS  PubMed  Google Scholar 

  24. Shibahara Y, Krzyzanowska M, Vajpeyi R. Appendiceal well-differentiated neuroendocrine tumors: a single-center experience and new insights into the effective use of immunohistochemistry. Int J Surg Pathol. 2023;31(3):252–9.

    Article  CAS  PubMed  Google Scholar 

  25. Alexandraki KI, Griniatsos J, Bramis KI, Ballian N, Dimitriou N, Giannakakis T, et al. Clinical value of right hemicolectomy for appendiceal carcinoids using pathologic criteria. J Endocrinol Invest. 2011;34(4):255–9.

    Article  CAS  PubMed  Google Scholar 

  26. Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61(1):6–32.

    Article  CAS  PubMed  Google Scholar 

  27. Storan D, Swan N, Swan K, Thuillier R, Skehan S, Gallagher T, et al. Clinical features and outcomes of appendiceal neuroendocrine tumours: 10 year audit from the Irish NET Centre of Excellence. J Neuroendocrinol. 2023;35(10):e13329. https://doi.org/10.1111/jne.13329.

  28. Daskalakis K, Alexandraki K, Kassi E, Tsoli M, Angelousi A, Ragkousi A, et al. The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms: a systematic review and meta-analysis of adult and paediatric patients. Endocrine. 2020;67(1):20–34.

    Article  CAS  PubMed  Google Scholar 

  29. •• Nesti C, Bräutigam K, Benavent M, Bernal L, Boharoon H, Botling J, et al. Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1–2 cm in size: a retrospective, Europe-wide, pooled cohort study. Lancet Oncol. 2023;24(2):187–94. This is a large study of aNEN size 1–2 cm. It is the first study to demonstrate that presence of lymph node metastases is not associated with a poorer prognosis. Furthermore, it demonstrates that none of the previous pathological biomarkers is not associated with a poorer prognosis in aNEN size 1–2 cm.

    Article  PubMed  Google Scholar 

  30. Li M-X, Lopez-Aguiar AG, Poultsides G, Rocha F, Weber S, Fields R, et al. Surgical treatment of neuroendocrine tumors of the terminal ileum or cecum: ileocecectomy versus right hemicolectomy. J Gastrointest Surg Off J Soc Surg Aliment Tract. 2022;26(6):1266–74.

    Article  Google Scholar 

  31. Dam G, Gronbaek H, Sorbye H, ThiisEvensen E, Paulsson B, Sundin A, et al. Prospective study of Chromogranin A as a predictor of progression in patients with pancreatic, small-intestinal, and unknown primary neuroendocrine tumors. Neuroendocrinology. 2020;110(3–4):217–24.

    Article  CAS  PubMed  Google Scholar 

  32. Chan DL, Hoang J, Roach PJ, Arena J, Bailey DL, Nevell D, et al. Routine early 68Ga-DOTATATE positron emission tomography has low yield after resection of appendiceal neuroendocrine neoplasms. Pancreas. 2020;49(7):891–6.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Pernille Holmager, Seppo W. Langer, Andreas Kjaer, Lene Ringholm, Rajendra Singh Garbyal, Carsten Palnæs Hansen, Mikkel Andreassen & Ulrich Knigge

  2. Department of Endocrinology and Metabolism, Copenhagen University Hospital - Rigshospitalet, Ole Maaløes Vej 24, 2200, Copenhagen, Denmark

    Pernille Holmager, Lene Ringholm, Mikkel Andreassen & Ulrich Knigge

  3. Department of Oncology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Seppo W. Langer

  4. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Seppo W. Langer, Lene Ringholm & Mikkel Andreassen

  5. Department of Clinical Physiology, Nuclear Medicine and PET & Cluster for Molecular Imaging, Copenhagen University Hospital - Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

    Andreas Kjaer

  6. Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Rajendra Singh Garbyal

  7. Department of Surgery and Transplantation, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Carsten Palnæs Hansen & Ulrich Knigge

Authors
  1. Pernille Holmager
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  2. Seppo W. Langer
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  8. Ulrich Knigge
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Contributions

The study was conceptualized by PH, MA, UK. Finding literature: PH and UK. Methodology: PH, MA, LR, RSG, SWL, CPH, UK, AK. Project administration: PH, UK. Resources: UK, AK. Supervision: MA, LR, RSG, CPH, AK, SWL, UK. Visualization: PH, LR, RSG, MA, SWL, AK, CPH, UK. Writing - original draft: PH, UK. Writing - review & editing: PH, LR, RSG, MA, SWL, AK, CPH, UK.

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Correspondence to Pernille Holmager.

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Holmager, P., Langer, S.W., Kjaer, A. et al. Appendiceal Neuroendocrine Neoplasms: an Update for 2023. Curr Oncol Rep 26, 114–120 (2024). https://doi.org/10.1007/s11912-023-01484-4

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