Skip to main content
SpringerLink
Log in

Carcinoid Tumors: Past, Present, and Future

  • Review Article
  • Published:
Indian Journal of Surgical Oncology Aims and scope Submit manuscript

Abstract

Carcinoid tumors are being seen with increasing frequency by surgeons and have become the most common type of tumors of the small bowel. These tumors produce a variety of hormones, which leads to many unique characteristics in terms of symptoms and presentation. Our knowledge of the natural history and treatment of these tumors continues to evolve, and this article will summarize these advances.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lubarsch O (1888) Ueber dem primaren Krebs des Ileum nebst Bemerkungen uber das gleichzeitige Vorkommen von Krebs und Tuberculose. Virchows Arch Pathol Anat 111:280–317

    Article  Google Scholar 

  2. Ransom WB (1890) A case of primary carcinoma of the ileum. Lancet 2:1020–1023

    Article  Google Scholar 

  3. Oberndorfer S (1907) Karzinoide tumoren des dunndarms. Frankf Z Pathol 1:426–432

    Google Scholar 

  4. Oberndorfer S (1929) Karzinoide. In: Handbook of Pathological Anatomy. Verlag von Julius Springer, Berlin, Germany

  5. Masson P (1928) Carcinoids (argentaffin-cell tumors) and nerve hyperplasia of the appendicular mucosa. Am J Path 4:181–211

    CAS  PubMed  Google Scholar 

  6. Lembeck F (1953) 5-hydroxytryptamine in a carcinoid tumour. Nature 172:910–911

    Article  CAS  Google Scholar 

  7. Thorson A, Biorck G, Bjorkman G, Waldenstrom J (1954) Malignant carcinoid of the small intestine with metastases to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis. Am Heart J 47(47):795–817

    Article  CAS  Google Scholar 

  8. Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH (1961) Life history of the carcinoid tumor of the small intestine. Cancer 14:901–912. https://doi.org/10.1002/1097-0142(196109/10)14:5<901::aid-cncr2820140502>3.0.co;2-q

    Article  CAS  PubMed  Google Scholar 

  9. Moertel CG (1987) Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5(10):1502–1522

    Article  CAS  Google Scholar 

  10. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T, Yao JC (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 3(10):1335–1342. https://doi.org/10.1001/jamaoncol.2017.0589

    Article  PubMed  PubMed Central  Google Scholar 

  11. Howe JR, Karnell LH, Menck HR, Scott-Conner C (1999) The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel: review of the National Cancer Data Base, 1985-1995. Cancer 86(12):2693–2706

    Article  CAS  Google Scholar 

  12. Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS (2009) Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg 249(1):63–71. https://doi.org/10.1097/SLA.0b013e31818e4641

    Article  PubMed  Google Scholar 

  13. Creutzfeldt W (1996) Carcinoid tumors: development of our knowledge. World J Surg 20(2):126–131. https://doi.org/10.1007/s002689900020

    Article  CAS  PubMed  Google Scholar 

  14. Sjoerdsma A (1959) Serotonin. N Engl J Med 261(5):231–237 concl. https://doi.org/10.1056/NEJM195907302610505

    Article  CAS  PubMed  Google Scholar 

  15. Kaehler HJ, Heilmeyer L (1961) Clinical aspects and pathophysiology of carcinoid and carcinoid syndrome with special reference to the pharmacology of 5-hydroxytryptamine. Ergeb Inn Med Kinderheilkd 16:292–559

    CAS  PubMed  Google Scholar 

  16. Sherman SK, Maxwell JE, O’Dorisio MS, O’Dorisio TM, Howe JR (2014) Pancreastatin predicts survival in neuroendocrine tumors. Ann Surg Oncol 21(9):2971–2980. https://doi.org/10.1245/s10434-014-3728-0

    Article  PubMed  PubMed Central  Google Scholar 

  17. Maxwell JE, O’Dorisio TM, Howe JR (2016) Biochemical diagnosis and preoperative imaging of gastroenteropancreatic neuroendocrine tumors. Surg Oncol Clin N Am 25(1):171–194. https://doi.org/10.1016/j.soc.2015.08.008

    Article  PubMed  Google Scholar 

  18. Scott AT, Howe JR (2018) Management of small bowel neuroendocrine tumors. J Oncol Pract 14(8):471–482. https://doi.org/10.1200/JOP.18.00135

    Article  PubMed  PubMed Central  Google Scholar 

  19. Maxwell JE, Howe JR (2015) Imaging in neuroendocrine tumors: an update for the clinician. Int J Endocr Oncol 2(2):159–168. https://doi.org/10.2217/ije.14.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Keck KJ, Maxwell JE, Menda Y, Bellizzi A, Dillon J, O’Dorisio TM, Howe JR (2017) Identification of primary tumors in patients presenting with metastatic gastroenteropancreatic neuroendocrine tumors. Surgery 161(1):272–279. https://doi.org/10.1016/j.surg.2016.05.055

    Article  PubMed  Google Scholar 

  21. Maxwell JE, Sherman SK, Menda Y, Wang D, O’Dorisio TM, Howe JR (2014) Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors. J Surg Res 190(2):548–553. https://doi.org/10.1016/j.jss.2014.05.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sadowski SM, Neychev V, Millo C, Shih J, Nilubol N, Herscovitch P, Pacak K, Marx SJ, Kebebew E (2016) Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J Clin Oncol 34(6):588–596. https://doi.org/10.1200/JCO.2015.64.0987

    Article  CAS  PubMed  Google Scholar 

  23. Hope TA, Bergsland EK, Bozkurt MF, Graham M, Heaney AP, Herrmann K, Howe JR, Kulke MH, Kunz PL, Mailman J, May L, Metz DC, Millo C, O’Dorisio S, Reidy-Lagunes DL, Soulen MC, Strosberg JR (2018) Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors. J Nucl Med 59(1):66–74. https://doi.org/10.2967/jnumed.117.202275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bellizzi AM (2013) Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry. Adv Anat Pathol 20(5):285–314. https://doi.org/10.1097/PAP.0b013e3182a2dc67

    Article  CAS  PubMed  Google Scholar 

  25. Maxwell JE, Sherman SK, Stashek KM, O’Dorisio TM, Bellizzi AM, Howe JR (2014) A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors. Surgery 156(6):1359–1365; discussion 1365-1356. https://doi.org/10.1016/j.surg.2014.08.008

    Article  PubMed  PubMed Central  Google Scholar 

  26. Keck KJ, Choi A, Maxwell JE, Li G, O’Dorisio TM, Breheny P, Bellizzi AM, Howe JR (2017) Increased grade in neuroendocrine tumor metastases negatively impacts survival. Ann Surg Oncol 24(8):2206–2212. https://doi.org/10.1245/s10434-017-5899-y

    Article  PubMed  PubMed Central  Google Scholar 

  27. Howe JR (2017) Small bowel resection and lymphadenectomy for jejunoileal neuroendocrine tumors. In: Howe JR (ed) Endocrine and neuroendocrine surgery. Springer, Berlin, pp 301–316. https://doi.org/10.1007/978-3-662-54067-1

    Chapter  Google Scholar 

  28. Keck KJ, Maxwell JE, Utria AF, Bellizzi AM, Dillon JS, O’Dorisio TM, Howe JR (2018) The distal predilection of small bowel neuroendocrine tumors. Ann Surg Oncol 25(11):3207–3213. https://doi.org/10.1245/s10434-018-6676-2

    Article  PubMed  PubMed Central  Google Scholar 

  29. Howe JR, Cardona K, Fraker DL, Kebebew E, Untch BR, Wang YZ, Law CH, Liu EH, Kim MK, Menda Y, Morse BG, Bergsland EK, Strosberg JR, Nakakura EK, Pommier RF (2017) The surgical management of small bowel neuroendocrine tumors: consensus guidelines of the North American Neuroendocrine Tumor Society. Pancreas 46(6):715–731. https://doi.org/10.1097/MPA.0000000000000846

    Article  PubMed  PubMed Central  Google Scholar 

  30. Elias D, David A, Sourrouille I, Honore C, Goere D, Dumont F, Stoclin A, Baudin E (2014) Neuroendocrine carcinomas: optimal surgery of peritoneal metastases (and associated intra-abdominal metastases). Surgery 155(1):5–12. https://doi.org/10.1016/j.surg.2013.05.030

    Article  PubMed  Google Scholar 

  31. Maxwell JE, Sherman SK, O’Dorisio TM, Bellizzi AM, Howe JR (2016) Liver-directed surgery of neuroendocrine metastases: what is the optimal strategy? Surgery 159(1):320–333. https://doi.org/10.1016/j.surg.2015.05.040

    Article  PubMed  Google Scholar 

  32. Foster JH, Berman MM (1977) Solid liver tumors. Major Probl Clin Surg 22:1–342

    CAS  PubMed  Google Scholar 

  33. Foster JH, Lundy J (1981) Liver metastases. Curr Probl Surg 18(3):157–202

    Article  CAS  Google Scholar 

  34. McEntee GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS (1990) Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 108(6):1091–1096

    CAS  PubMed  Google Scholar 

  35. Graff-Baker AN, Sauer DA, Pommier SJ, Pommier RF (2014) Expanded criteria for carcinoid liver debulking: maintaining survival and increasing the number of eligible patients. Surgery 156(6):1369–1376; discussion 1376-1367. https://doi.org/10.1016/j.surg.2014.08.009

    Article  PubMed  Google Scholar 

  36. Scott AT, Breheny PJ, Keck KJ, Bellizzi AM, Dillon JS, O’Dorisio TM, Howe JR (2019) Effective cytoreduction can be achieved in patients with numerous neuroendocrine tumor liver metastases (NETLMs). Surgery 165(1):166–175. https://doi.org/10.1016/j.surg.2018.04.070

    Article  PubMed  Google Scholar 

  37. Mayo SC, de Jong MC, Pulitano C, Clary BM, Reddy SK, Gamblin TC, Celinksi SA, Kooby DA, Staley CA, Stokes JB, Chu CK, Ferrero A, Schulick RD, Choti MA, Mentha G, Strub J, Bauer TW, Adams RB, Aldrighetti L, Capussotti L, Pawlik TM (2010) Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 17(12):3129–3136. https://doi.org/10.1245/s10434-010-1154-5

    Article  PubMed  Google Scholar 

  38. Elias D, Lefevre JH, Duvillard P, Goere D, Dromain C, Dumont F, Baudin E (2010) Hepatic metastases from neuroendocrine tumors with a “thin slice” pathological examination: they are many more than you think. Ann Surg 251(2):307–310. https://doi.org/10.1097/SLA.0b013e3181bdf8cf

    Article  PubMed  Google Scholar 

  39. Norlen O, Hessman O, Stalberg P, Akerstrom G, Hellman P (2010) Prophylactic cholecystectomy in midgut carcinoid patients. World J Surg 34(6):1361–1367. https://doi.org/10.1007/s00268-010-0428-1

    Article  PubMed  Google Scholar 

  40. Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R, Group PS (2009) 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 27(28):4656–4663. https://doi.org/10.1200/JCO.2009.22.8510

    Article  CAS  PubMed  Google Scholar 

  41. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P, Investigators C (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371(3):224–233. https://doi.org/10.1056/NEJMoa1316158

    Article  CAS  PubMed  Google Scholar 

  42. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Delle Fave G, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME, Rad001 in Advanced Neuroendocrine Tumours FTSG (2016) 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. Lancet 387(10022):968–977. https://doi.org/10.1016/S0140-6736(15)00817-X

    Article  CAS  PubMed  Google Scholar 

  43. Strosberg J (2016) NETTER-1 phase III: progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate. J Clin Oncol 34(4S):194

    Article  Google Scholar 

  44. El Lakis M, Gianakou A, Nockel P, Wiseman D, Tirosh A, Quezado MA, Patel D, Nilubol N, Pacak K, Sadowski SM, Kebebew E (2019) Radioguided surgery with gallium 68 dotatate for patients with neuroendocrine tumors. JAMA Surg 154(1):40–45. https://doi.org/10.1001/jamasurg.2018.3475

    Article  PubMed  Google Scholar 

  45. Howe JR (2019) Radioguided surgery with gallium for neuroendocrine tumors. JAMA Surg 154(1):45–46. https://doi.org/10.1001/jamasurg.2018.3480

    Article  PubMed  Google Scholar 

  46. Kulke MH, Freed E, Chiang DY, Philips J, Zahrieh D, Glickman JN, Shivdasani RA (2008) High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes Cancer 47(7):591–603. https://doi.org/10.1002/gcc.20561

    Article  CAS  PubMed  Google Scholar 

  47. Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, Zhang L, Thorland EC, Minn KT, Tentu R, Eckloff BW, Wieben ED, Wu Y, Cunningham JM, Nagorney DM, Gilbert JA, Ames MM, Beutler AS (2013) The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest 123(6):2502–2508. https://doi.org/10.1172/JCI67963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Francis JM, Kiezun A, Ramos AH, Serra S, Pedamallu CS, Qian ZR, Banck MS, Kanwar R, Kulkarni AA, Karpathakis A, Manzo V, Contractor T, Philips J, Nickerson E, Pho N, Hooshmand SM, Brais LK, Lawrence MS, Pugh T, McKenna A, Sivachenko A, Cibulskis K, Carter SL, Ojesina AI, Freeman S, Jones RT, Voet D, Saksena G, Auclair D, Onofrio R, Shefler E, Sougnez C, Grimsby J, Green L, Lennon N, Meyer T, Caplin M, Chung DC, Beutler AS, Ogino S, Thirlwell C, Shivdasani R, Asa SL, Harris CR, Getz G, Kulke M, Meyerson M (2013) Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet 45(12):1483–1486. https://doi.org/10.1038/ng.2821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Crona J, Gustavsson T, Norlen O, Edfeldt K, Akerstrom T, Westin G, Hellman P, Bjorklund P, Stalberg P (2015) Somatic mutations and genetic heterogeneity at the CDKN1B locus in small intestinal neuroendocrine tumors. Ann Surg Oncol 22(Suppl 3):S1428–S1435. https://doi.org/10.1245/s10434-014-4351-9

    Article  PubMed  Google Scholar 

  50. Maxwell JE, Sherman SK, Li G, Choi AB, Bellizzi AM, O’Dorisio TM, Howe JR (2015) Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors. Cancer Genet 208(11):564–570. https://doi.org/10.1016/j.cancergen.2015.08.003

    Article  CAS  Google Scholar 

  51. Sei Y, Zhao X, Forbes J, Szymczak S, Li Q, Trivedi A, Voellinger M, Joy G, Feng J, Whatley M, Jones MS, Harper UL, Marx SJ, Venkatesan AM, Chandrasekharappa SC, Raffeld M, Quezado MM, Louie A, Chen CC, Lim RM, Agarwala R, Schaffer AA, Hughes MS, Bailey-Wilson JE, Wank SA (2015) A hereditary form of small intestinal carcinoid associated with a germline mutation in inositol polyphosphate multikinase. Gastroenterology 149(1):67–78. https://doi.org/10.1053/j.gastro.2015.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Huang VJ, Erlander MG, Brachtel EF, Dry SM (2014) A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors. Mod Pathol 27(1):44–54. https://doi.org/10.1038/modpathol.2013.105

    Article  CAS  PubMed  Google Scholar 

  53. Sherman SK, Maxwell JE, Carr JC, Wang D, Bellizzi AM, Sue O’Dorisio M, O’Dorisio TM, Howe JR (2014) Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors. Clin Exp Metastasis 31(8):935–944. https://doi.org/10.1007/s10585-014-9681-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H (2015) The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am J Gastroenterol 110(8):1223–1232. https://doi.org/10.1038/ajg.2015.160

    Article  CAS  PubMed  Google Scholar 

  55. Keck KJ, Breheny P, Braun TA, Darbro B, Li G, Dillon JS, Bellizzi AM, O’Dorisio TM, Howe JR (2018) Changes in gene expression in small bowel neuroendocrine tumors associated with progression to metastases. Surgery 163(1):232–239. https://doi.org/10.1016/j.surg.2017.07.031

    Article  PubMed  Google Scholar 

  56. Ear PH, Li G, Wu M, Abusada E, Bellizzi AM, Howe JR (2019) Establishment and characterization of small bowel neuroendocrine tumor spheroids. J Vis Exp 152. https://doi.org/10.3791/60303

Download references

Acknowledgments

Thanks to the Society of Surgical Oncology for their relationship with the IASO.

Funding

Thanks to the NIH Iowa SPORE grant P50CA174521-01 for sponsoring our research.

Author information

Authors and Affiliations

  1. University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    James R. Howe

Authors
  1. James R. Howe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James R. Howe.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Howe, J.R. Carcinoid Tumors: Past, Present, and Future. Indian J Surg Oncol 11, 182–187 (2020). https://doi.org/10.1007/s13193-020-01079-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13193-020-01079-6

Keywords

Search

Navigation