Advertisement

Journal of Gastrointestinal Surgery

, Volume 20, Issue 1, pp 180–188 | Cite as

Role of Staging in Patients with Small Intestinal Neuroendocrine Tumours

  • Ashley Kieran Clift
  • Omar Faiz
  • Adil Al-Nahhas
  • Andreas Bockisch
  • Marc Olaf Liedke
  • Erik Schloericke
  • Harpreet Wasan
  • John Martin
  • Paul Ziprin
  • Krishna Moorthy
  • Andrea Frilling
2015 SSAT Plenary Presentation

Abstract

Small bowel neuroendocrine tumours are the commonest malignancy arising in the small intestine and have substantially increased in incidence in recent decades. Patients with small bowel neuroendocrine tumours commonly develop lymph node and/or distant metastases. Here, we examine the role of staging in 84 surgically treated patients with small bowel neuroendocrine tumours, comparing diagnostic information yielded from morphological, functional and endoscopic modalities. Furthermore, we correlate pre-operative staging with intra-operative findings in a sub-cohort of 20 patients. The vast majority of patients had been histologically confirmed to have low-grade (Ki-67 <2 %) disease; however, lymph node and distant metastases were observed in 74 (88.1 %) and 51 (60.7 %) of patients at presentation, respectively. Liver metastases were evident in 48 (57.1 %) patients, with solely peritoneal and bone metastases observed in 2 (2.4 %) and 1 (1.2 %) patients, respectively. Forty patients (47.6 %) received multimodal treatment. In our sub-cohort analysis, pre-operative imaging understaged disease in 14/20 (70 %) when compared with intra-operative findings. In patients with multifocal primary tumours and miliary liver metastases, no imaging modality was able to detect entire disease spread. Overall, presently available imaging modalities heavily underestimate disease stage, with meticulous intra-operative abdominal examination being superior to any imaging technology. Multimodal treatment has an important role in prolonging survival.

Keywords

Small bowel Neuroendocrine tumours Staging Surgery 

Notes

References

  1. 1.
    Pan SY, Morrison H: Epidemiology of cancer of the small intestine. World J Gastrointest Oncol 2011;3:33–42.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM: The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:1–18, vii.PubMedCrossRefGoogle Scholar
  4. 4.
    Tsikitis VL, Wertheim BC, Guerrero MA: Trends of incidence and survival of gastrointestinal neuroendocrine tumors in the United States: a seer analysis. J Cancer 2012; 3:292–302.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Tsai H-J, Wu C-C, Tsai C-R, Lin S-F, Chen L-T, Chang JS: Second cancers in patients with neuroendocrine tumors. PLoS One 2013; 8:e86414.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Díaz-Pérez JA, Martínez Del Prado MP, Alonso Orduña V, Sevilla-Garcia I, Villabona-Artero C, Beguiristan-Gomez A, Llanos-Munoz M, Marazuela M, Alvarez-Escola C, Castellano D, Vilar E, Jiminez-Fonseca P, Teule A, Sastre-Valera J, Benavent-Vinuelas M, Monleon A, Salazar R.: Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010; 21:1794–803.PubMedCrossRefGoogle Scholar
  7. 7.
    Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AKC, Modlin IM: Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 2008; 113:2655–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Ellis L, Shale MJ, Coleman MP: Carcinoid tumors of the gastrointestinal tract: trends in incidence in England since 1971. Am J Gastroenterol 2010; 105:2563–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Guo Z, Li Q, Wilander E, Pontén J: Clonality analysis of multifocal carcinoid tumours of the small intestine by X-chromosome inactivation analysis. J Pathol 2000; 190:76–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Katona TM, Jones TD, Wang M, Abdul-Karim FW, Cummings OW, Cheng L: Molecular evidence for independent origin of multifocal neuroendocrine tumors of the enteropancreatic axis. Cancer Res 2006; 66:4936–42.PubMedCrossRefGoogle Scholar
  11. 11.
    Yantiss RK, Odze RD, Farraye FA, Rosenberg AE: Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases. Am J Surg Pathol 2003; 27:811–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Habal N, Sims C, Bilchik AJ: Gastrointestinal carcinoid tumors and second primary malignancies. J Surg Oncol 2000; 75:310–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Miller HC, Drymousis P, Flora R, Goldin R, Spalding D, Frilling A: Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease. World J Surg 2014; 38:1353–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Strosberg J, Gardner N, Kvols L: Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology 2009; 89:471–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Tomassetti P, Campana D, Piscitelli L, Casadei R, Nori F, Brocchi E, Santini D, Pezzilli R, Corinaldesi R: Endocrine tumors of the ileum: factors correlated with survival. Neuroendocrinology 2006; 83:380–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Ahmed A, Turner G, King B, Jones L, Culliford D, McCance D, Ardill J, Johnson BT, Poston G, Rees M, Buxton-Thomas M, Caplin M, Ramage JK: Midgut neuroendocrine tumours with liver metastases: results of the UKINETS study. Endocr Relat Cancer 2009; 16:885–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Norlén O, Stålberg P, Öberg K, Eriksson J, Hedberg J, Hessman O, Janson ET, Hellman P, Akerstrom G: Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 2012; 36:1419–31.PubMedCrossRefGoogle Scholar
  18. 18.
    Bader TR, Semelka RC, Chiu VC, Armao DM, Woosley JT: MRI of carcinoid tumors: spectrum of appearances in the gastrointestinal tract and liver. J Magn Reson Imaging 2001; 14:261–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Sundin A: Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol 2012; 26:803–18.PubMedCrossRefGoogle Scholar
  20. 20.
    Schreiter NF, Maurer M, Pape U-F, Hamm B, Brenner W, Froeling V: Detection of neuroendocrine tumours in the small intestines using contrast-enhanced multiphase Ga-68 DOTATOC PET/CT: the potential role of arterial hyperperfusion. Radiol Oncol 2014; 48:120–6.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Amzallag-Bellenger E, Oudjit A, Ruiz A, Cadiot G, Soyer PA, Hoeffel CC: Effectiveness of MR enterography for the assessment of small-bowel diseases beyond Crohn disease. Radiographics 2012; 32:1423–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Lee S-Y, Tomoyoshi S, Haga K, Sasaki H, Ogata C, Nomura O, Fukuo Y, Abe W, Osada T, Nagahara A, Ogihara T, Kamiyama H, Sakamoto K, Wantanabe S: Multiple carcinoid tumors of the small intestine preoperatively diagnosed by double-balloon endoscopy. Med Sci Monit 2012; 18:CS109–12.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Koornstra JJ, de Vries EGE, Porte RJ: Improvements in small bowel carcinoid diagnosis and staging: 18F-DOPA PET, capsule endoscopy and double balloon enteroscopy. Dig Liver Dis 2009; 41:e35–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Boudreaux JP, Wang Y-Z, Diebold AE, Frey DJ, Anthony L, Uhlhorn AP, Ryan P, Woltering EA: A single institution’s experience with surgical cytoreduction of stage IV, well-differentiated, small bowel neuroendocrine tumors. J Am Coll Surg 2014; 218:837–44.PubMedCrossRefGoogle Scholar
  25. 25.
    Wängberg B, Westberg G, Tylén U, Tisell L, Jansson S, Nilsson O, Johansson V, Schersten T, Ahlman H.: Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg 1996; 20:892–9; discussion 899.PubMedCrossRefGoogle Scholar
  26. 26.
    Bergestuen DS, Aabakken L, Holm K, Vatn M, Thiis-Evensen E: Small intestinal neuroendocrine tumors: prognostic factors and survival. Scand J Gastroenterol 2009; 44:1084–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B: TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007; 451:757–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Frilling A, Malago M, Martin H, Broelsch CE: Use of somatostatin receptor scintigraphy to image extrahepatic metastases of neuroendocrine tumors. Surgery 1998; 124:1000–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Frilling A, Sotiropoulos GC, Radtke A, Malago M, Bockisch A, Kuehl H, Broelsch CE: The impact of 68Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors. Ann Surg 2010; 252:850–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Mapelli P, Tam HH, Sharma R, Aboagye EO, Al-Nahhas A: Frequency and significance of physiological versus pathological uptake of 68Ga-DOTATATE in the pancreas: validation with morphological imaging. Nucl Med Commun 2014; 35:613–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Frilling A, Malago M, Weber F, Paul A, Nadalin S, Sotiropoulos GC, et al.: Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients. Liver Transpl 2006; 12:1089–96.PubMedCrossRefGoogle Scholar
  32. 32.
    Frilling A, Giele H, Vrakas G, Reddy S, Macedo R, Al-Nahhas A, Wasan H, Clift AK, Gondolesi GE, Vianna RM, Friend P, Vaidya A: Modified Liver-free Multivisceral Transplantation for a Metastatic Small Bowel Neuroendocrine Tumor: A Case Report. Transplant Proc 2015; 47:858–62.PubMedCrossRefGoogle Scholar
  33. 33.
    Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, Capella C, Caplin M, Coulevard A, Doglioni C, Delle Fave G, Fischer L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijger RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B: TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 2012; 104:764–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Müller-Nordhorn J, Koch M, Rocken C, Rindi G, Ruszniewski P, Wiedenmann B, Pape UF: Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 2011; 117:3332–41.PubMedCrossRefGoogle Scholar
  35. 35.
    Gonzalez RS, Liu EH, Alvarez JR, Ayers GD, Washington MK, Shi C: Should mesenteric tumor deposits be included in staging of well-differentiated small intestine neuroendocrine tumors? Mod Pathol 2014; 27:1288–95.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Chambers AJ, Pasieka JL, Dixon E, Rorstad O: Role of imaging in the preoperative staging of small bowel neuroendocrine tumors. J Am Coll Surg 2010; 211:620–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Søreide O, Berstad T, Bakka A, Schrumpf E, Hanssen LE, Engh V, Bergan A, Flatmark A: Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery 1992; 111:48–54.PubMedGoogle Scholar
  38. 38.
    Ruf J, Heuck F, Schiefer J, Denecke T, Elgeti F, Pascher A, Pavel M, Stelter L, Kropf S, Wiedenmann B, Amthauer H: Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors. Neuroendocrinology 2010; 91:101–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Ambrosini V, Campana D, Bodei L, Nanni C, Castellucci P, Allegri V, Nanni C, Malvi D, Tonveronachi E, Fasano L, Fabbri M, Fanti S: 68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors. J Nucl Med 2010; 51:669–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Schraml C, Schwenzer NF, Sperling O, Aschoff P, Lichy MP, Müller M, Brendle C, Werner MK, Claussen CD, Pfannenberg C: Staging of neuroendocrine tumours: comparison of [68Ga]DOTATOC multiphase PET/CT and whole-body MRI. Cancer Imaging 2013; 13:63–72.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A: 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res 2010; 16:978–85.PubMedCrossRefGoogle Scholar
  42. 42.
    Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, Kwekkeboom D, Lau WY, Klersky C, Vilgrain V, Davidson B, Siegler M, Caplin M, Solcia E, Schilsky R; Working Group on Neuroendocrine Liver Metastases: Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 2014; 15:e8–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Hörsch D, Kulkarni HR, Baum RP: THERANOSTICS—clinical aimshots in surgical warfare against well-differentiated neuroendocrine neoplasms. Ann Transl Med 2014; 2:1. doi:  10.3978/j.issn.2305-5839.2013.07.03 PubMedPubMedCentralGoogle Scholar
  44. 44.
    Elias D, Lefevre JH, Duvillard P, Goéré D, Dromain C, Dumont F, Baudin E: Hepatic metastases from neuroendocrine tumors with a “thin slice” pathological examination: they are many more than you think… Ann Surg 2010; 251:307–10.PubMedCrossRefGoogle Scholar
  45. 45.
    Imperiale A, Averous G, Chilinseva-Natorov N, Hubelé F, Triki E, Bellocq J-P, Namer IJ, Brigand C: Unknown multifocal ileal carcinoid revealed by (18)F-FDOPA PET/CT. J Clin Endocrinol Metab 2014; 99:1510–1.PubMedCrossRefGoogle Scholar
  46. 46.
    Le Roux C, Lombard-Bohas C, Delmas C, Dominguez-Tinajero S, Ruszniewski P, Samalin E, Raoul JL, Renard P, Baudin E, Robaskiewicz M, Mitry E, Cadiot G, Groupe d’etude des Tumeurs Endocrines (GTE): Relapse factors for ileal neuroendocrine tumours after curative surgery: a retrospective French multicentre study. Dig Liver Dis 2011; 43:828–33.PubMedCrossRefGoogle Scholar
  47. 47.
    Figueiredo MN, Maggiori L, Gaujoux S, Couvelard A, Guedj N, Ruszniewski P, Panis Y: Surgery for small-bowel neuroendocrine tumors: is there any benefit of the laparoscopic approach? Surg Endosc 2014; 28:1720–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Modlin IM, Champaneria MC, Chan AKC, Kidd M: A three-decade analysis of 3,911 small intestinal neuroendocrine tumors: the rapid pace of no progress. Am J Gastroenterol 2007; 102:1464–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Lepage C, Ciccolallo L, De Angelis R, Bouvier AM, Faivre J, Gatta G: European disparities in malignant digestive endocrine tumours survival. Int J Cancer 2010; 126:2928–34.PubMedGoogle Scholar
  50. 50.
    Boudreaux JP, Putty B, Frey DJ, Woltering E, Anthony L, Daly I, Ramcharan T, Lopera J, Castaneda W: Surgical treatment of advanced-stage carcinoid tumors: lessons learned. Ann Surg 2005; 241:839–45; discussion 845–6.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Schindl M, Kaczirek K, Passler C, Kaserer K, Prager G, Scheuba C, Raderer M, Niederle B: Treatment of small intestinal neuroendocrine tumors: is an extended multimodal approach justified? World J Surg 2002; 26:976–84.PubMedCrossRefGoogle Scholar
  52. 52.
    Rinke A, Müller H-H, Schade-Brittinger C, Klose K-J, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R, PROMID Study Group: 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; 27:4656–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P, CLARINET Investigators: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371:224–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Sabet A, Dautzenberg K, Haslerud T, Aouf A, Sabet A, Simon B, Mayer K, Biersack HJ, Ezziddin S: Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging 2015; DOI:  10.1007/s00259-015-3041-6 Google Scholar
  55. 55.
    Modlin IM, Drozdov I, Kidd M: The identification of gut neuroendocrine tumor disease by multiple synchronous transcript analysis in blood. PLoS One 2013; 8:e63364.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Bodei L, Kidd M, Modlin IM, Prasad V, Severi S, Ambrosini V, Kwekkeboom DJ, Krenning EP, Baum RP, Paganelli G, Drozdov I:: Gene transcript analysis blood values correlate with (68)Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status. Eur J Nucl Med Mol Imaging 2015; DOI:  10.1007/s00259-015-3075-9 Google Scholar
  57. 57.
    Modlin IM, Drozdov I, Bodei L, Kidd M: Blood transcript analysis and metastatic recurrent small bowel carcinoid management. BMC Cancer 2014; 14:564.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2015

Authors and Affiliations

  • Ashley Kieran Clift
    • 1
  • Omar Faiz
    • 2
  • Adil Al-Nahhas
    • 3
  • Andreas Bockisch
    • 4
  • Marc Olaf Liedke
    • 5
  • Erik Schloericke
    • 5
  • Harpreet Wasan
    • 1
  • John Martin
    • 6
  • Paul Ziprin
    • 1
  • Krishna Moorthy
    • 1
  • Andrea Frilling
    • 1
  1. 1.Department of Surgery and CancerImperial College LondonLondonUK
  2. 2.Department of SurgerySt. Mark’s HospitalLondonUK
  3. 3.Department of Nuclear MedicineImperial College LondonLondonUK
  4. 4.Department of Nuclear MedicineUniversity Hospital EssenEssenGermany
  5. 5.Department of SurgeryWestkuesten Klinikum HeideHeideGermany
  6. 6.Department of GastroenterologyImperial College LondonLondonUK

Personalised recommendations