Reviews in Endocrine and Metabolic Disorders

, Volume 18, Issue 4, pp 473–483 | Cite as

The place of liver transplantation in the treatment of hepatic metastases from neuroendocrine tumors: Pros and cons

  • Carlo Sposito
  • Michele Droz dit Busset
  • Davide Citterio
  • Marco Bongini
  • Vincenzo Mazzaferro


Liver metastases occur in nearly half of NET patients (MNETs) and heavily affect prognosis, with 5-yr. OS around 19–38%. Although it is difficult to show outcome differences for available treatments, due to the long course of disease, surgery for MNETs remains the most effective option in terms of survival and symptom control. Since MNETs frequently present as an oligo-metastatic, liver-limited disease, unresectable in 80% of cases, liver transplantation (LT) has emerged as a potential curative treatment. Nevertheless, experience with LT for MNETs is limited and burdened by highly heterogeneous outcomes and significant recurrence rate, mostly explained by the variability of selection criteria. Several prognostic factors have been identified: extended surgery on primary tumor associated to LT, elderly patients, pancreatic primary (pNET), extensive liver involvement, poorly differentiated tumors, high Ki67 levels and short wait time to LT. A proper patients’ selection based on these data (Milan NET criteria) allows a significant survival advantage over non-transplant strategies, with excellent outcomes in recent series (69–97.2% 5-yr. OS) as opposed to patients undergoing non-surgical treatments (34–50.9%). Evidence indicates LT as the best option for selected patients with MNETs. The use of organs for MNETs is therefore justified.


Cancer/malignancy/neoplasia Neuroendocrine tumors Metastatic disease Liver disease: malignant Liver transplantation Liver metastases Recipient selection 


Compliance with ethical standards

No conflicts of interest are declared by the Authors with respect to the material and methodology presented in the manuscript.


  1. 1.
    Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, 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. Scholar
  2. 2.
    Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumours: The current incidence and staging based on the WHO and European neuroendocrine tumour society classification: An analysis based on prospectively collected parameters. Endocr Relat Cancer. 2010;17(4):909–18. Scholar
  3. 3.
    Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40(1):1–18, vii. Scholar
  4. 4.
    Frilling A, Clift AK. Therapeutic strategies for neuroendocrine liver metastases. Cancer. 2015;121(8):1172–86. Scholar
  5. 5.
    Riihimaki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer. 2016;139(12):2679–86. Scholar
  6. 6.
    Riihimaki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J, et al. Metastatic sites and survival in lung cancer. Lung Cancer. 2014;86(1):78–84. Scholar
  7. 7.
    Elias D, Lefevre JH, Duvillard P, Goere D, Dromain C, Dumont F, et al. Hepatic metastases from neuroendocrine tumors with a "thin slice" pathological examination: They are many more than you think. Ann Surg. 2010;251(2):307–10. Scholar
  8. 8.
    Pavel M, O'Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, 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. Neuroendocrinology. 2016;103(2):172–85. Scholar
  9. 9.
    Mayo SC, de Jong MC, Bloomston M, Pulitano C, Clary BM, Reddy SK, et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: A multicenter international analysis. Ann Surg Oncol. 2011;18(13):3657–65. Scholar
  10. 10.
    Musunuru S, Chen H, Rajpal S, Stephani N, McDermott JC, Holen K, et al. Metastatic neuroendocrine hepatic tumors: Resection improves survival. Arch Surg. 2006;141(10):1000–4. Scholar
  11. 11.
    Touzios JG, Kiely JM, Pitt SC, Rilling WS, Quebbeman EJ, Wilson SD, et al. Neuroendocrine hepatic metastases: Does aggressive management improve survival? Ann Surg. 2005;241(5):776–83. Scholar
  12. 12.
    Yao KA, Talamonti MS, Nemcek A, Angelos P, Chrisman H, Skarda J, et al. Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery. 2001;130(4):677–82. Scholar
  13. 13.
    Watzka FM, Fottner C, Miederer M, Schad A, Weber MM, Otto G, et al. Surgical therapy of neuroendocrine neoplasm with hepatic metastasis: Patient selection and prognosis. Langenbeck's Arch Surg. 2015;400(3):349–58. Scholar
  14. 14.
    Karabulut K, Akyildiz HY, Lance C, Aucejo F, McLennan G, Agcaoglu O, et al. Multimodality treatment of neuroendocrine liver metastases. Surgery. 2011 Aug;150(2):316–25. Scholar
  15. 15.
    Osborne DA, Zervos EE, Strosberg J, Boe BA, Malafa M, Rosemurgy AS, et al. Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors. Ann Surg Oncol. 2006;13(4):572–81. Scholar
  16. 16.
    Landry CS, Scoggins CR, McMasters KM, Martin RC. Management of hepatic metastasis of gastrointestinal carcinoid tumors. J Surg Oncol. 2008;97(3):253–8. Scholar
  17. 17.
    Gupta S, Johnson MM, Murthy R, Ahrar K, Wallace MJ, Madoff DC, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: Variables affecting response rates and survival. Cancer. 2005;104(8):1590–602. Scholar
  18. 18.
    Bloomston M, Al-Saif O, Klemanski D, Pinzone JJ, Martin EW, Palmer B, et al. Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: Lessons learned. J Gastrointest Surg. 2007;11(3):264–71. Scholar
  19. 19.
    Marrache F, Vullierme MP, Roy C, El AY, Couvelard A, O'Toole D, et al. Arterial phase enhancement and body mass index are predictors of response to chemoembolisation for liver metastases of endocrine tumours. Br J Cancer. 2007;96(1):49–55. Scholar
  20. 20.
    Pitt SC, Knuth J, Keily JM, McDermott JC, Weber SM, Chen H, et al. Hepatic neuroendocrine metastases: Chemo- or bland embolization? J Gastrointest Surg. 2008;12(11):1951–60. Scholar
  21. 21.
    Whitney R, Valek V, Fages JF, Garcia A, Narayanan G, Tatum C, et al. Transarterial chemoembolization and selective internal radiation for the treatment of patients with metastatic neuroendocrine tumors: A comparison of efficacy and cost. Oncologist. 2011;16(5):594–601. Scholar
  22. 22.
    Dong XD, Carr BI. Hepatic artery chemoembolization for the treatment of liver metastases from neuroendocrine tumors: A long-term follow-up in 123 patients. Med Oncol. 2011;28(Suppl 1):S286–90.CrossRefPubMedGoogle Scholar
  23. 23.
    Hur S, Chung JW, Kim HC, DY O, Lee SH, Bang YJ, et al. Survival outcomes and prognostic factors of transcatheter arterial chemoembolization for hepatic neuroendocrine metastases. J Vasc Interv Radiol. 2013;24(7):947–56. Scholar
  24. 24.
    Sofocleous CT, Petre EN, Gonen M, Reidy-Lagunes D, Ip IK, Alago W, et al. Factors affecting periprocedural morbidity and mortality and long-term patient survival after arterial embolization of hepatic neuroendocrine metastases. J Vasc Interv Radiol. 2014;25(1):22–30. Scholar
  25. 25.
    Kennedy AS, Dezarn WA, McNeillie P, Coldwell D, Nutting C, Carter D, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: Early results in 148 patients. Am J Clin Oncol. 2008;31(3):271–9. Scholar
  26. 26.
    Rhee TK, Lewandowski RJ, Liu DM, Mulcahy MF, Takahashi G, Hansen PD, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: Preliminary results from a multi-institutional experience. Ann Surg. 2008;247(6):1029–35. Scholar
  27. 27.
    Saxena A, Chua TC, Bester L, Kokandi A, Morris DL. Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: A critical appraisal of 48 cases. Ann Surg. 2010;251(5):910–6. Scholar
  28. 28.
    Rinke A, Wittenberg M, Schade-Brittinger C, et al. 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 (PROMID): Results. Neuroendocrinology. 2017;104(1):26–32.
  29. 29.
    Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33.
  30. 30.
    Martin-Richard M, Massuti B, Pineda E, Alonso V, Marmol M, Castellano D, et al. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: A Spanish, multicentre, open-label, single arm phase II study. BMC Cancer. 2013;13(1):427. Scholar
  31. 31.
    Jann H, Denecke T, Koch M, Pape UF, Wiedenmann B, Pavel M. Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. Neuroendocrinology. 2013;98(2):137–43. Scholar
  32. 32.
    Faggiano A, Carratu AC, Guadagno E, Tafuto S, Tatangelo F, Riccardi F, et al. Somatostatin analogues according to Ki67 index in neuroendocrine tumours: An observational retrospective-prospective analysis from real life. Oncotarget. 2016;7(5):5538–47. Scholar
  33. 33.
    Panzuto F, Rinzivillo M, Fazio N, de Braud F, Luppi G, Zatelli MC, et al. Real-world study of everolimus in advanced progressive neuroendocrine tumors. Oncologist. 2014;19(9):966–74. Scholar
  34. 34.
    Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. 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. 2016;387(10022):968–77. Scholar
  35. 35.
    Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29(17):2416–23. Scholar
  36. 36.
    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13. Scholar
  37. 37.
    Bushnell DL Jr, O'Dorisio TM, O'Dorisio MS, Menda Y, Hicks RJ, Van CE, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28(10):1652–9. Scholar
  38. 38.
    Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: Toxicity, efficacy, and survival. J Clin Oncol 2008;26(13):2124–2130, DOI:
  39. 39.
    Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for Midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35. Scholar
  40. 40.
    Soga J, Yakuwa Y, Osaka M. Carcinoid syndrome: A statistical evaluation of 748 reported cases. J Exp Clin Cancer Res. 1999;18(2):133–41.PubMedGoogle Scholar
  41. 41.
    Ruutiainen AT, Soulen MC, Tuite CM, Clark TW, Mondschein JI, Stavropoulos SW, et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol. 2007;18(7):847–55. Scholar
  42. 42.
    King J, Quinn R, Glenn DM, Janssen J, Tong D, Liaw W, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008;113(5):921–9. Scholar
  43. 43.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van CE, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364(6):514–523.Google Scholar
  44. 44.
    Gedaly R, Daily MF, Davenport D, McHugh PP, Koch A, Angulo P, et al. Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: An analysis of the UNOS database. Arch Surg. 2011;146(8):953–8. Scholar
  45. 45.
    Mazzaferro V, Sposito C, Coppa J, Miceli R, Bhoori S, Bongini M, et al. The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors. Am J Transplant. 2016;16(10):2892–902. Scholar
  46. 46.
    Sher LS, Levi DM, Wecsler JS, Lo M, Petrovic LM, Groshen S, et al. Liver transplantation for metastatic neuroendocrine tumors: Outcomes and prognostic variables. J Surg Oncol. 2015;112(2):125–32. Scholar
  47. 47.
    Grat M, Remiszewski P, Smoter P, Wronka KM, Grat K, Lewandowski Z, et al. Outcomes following liver transplantation for metastatic neuroendocrine tumors. Transplant Proc. 2014;46(8):2766–9. Scholar
  48. 48.
    Le Treut YP, Gregoire E, Klempnauer J, Belghiti J, Jouve E, Lerut J, et al. Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: A 213-case European liver transplant registry study. Ann Surg. 2013;257(5):807–15. Scholar
  49. 49.
    Nguyen NT, Harring TR, Goss JA, O'Mahony CA. Neuroendocrine liver metastases and Orthotopic liver transplantation: The US experience. Int J Hepatol. 2011;2011:742890. Scholar
  50. 50.
    Mathe Z, Tagkalos E, Paul A, Molmenti EP, Kobori L, Fouzas I, et al. Liver transplantation for hepatic metastases of neuroendocrine pancreatic tumors: A survival-based analysis. Transplantation. 2011;91(5):575–82. Scholar
  51. 51.
    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 Jul;12(7):1089–96. Scholar
  52. 52.
    Le Treut YP, Gregoire E, Belghiti J, Boillot O, Soubrane O, Mantion G, et al. Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: An 85-case French multicentric report. Am J Transplant. 2008;8(6):1205–13. Scholar
  53. 53.
    Olausson M, Friman S, Herlenius G, Cahlin C, Nilsson O, Jansson S, et al. Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl. 2007;13(3):327–33. Scholar
  54. 54.
    van Vilsteren FG, Baskin-Bey ES, Nagorney DM, Sanderson SO, Kremers WK, Rosen CB, et al. Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival. Liver Transpl. 2006;12(3):448–56. Scholar
  55. 55.
    Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, et al. Liver transplantation for neuroendocrine tumors. J Gastrointest Surg. 2004;8(2):208–12. Scholar
  56. 56.
    Cahlin C, Friman S, Ahlman H, Backman L, Mjornstedt L, Lindner P, et al. Liver transplantation for metastatic neuroendocrine tumor disease. Transplant Proc. 2003;35(2):809–10. Scholar
  57. 57.
    Rosenau J, Bahr MJ, WR v, Mengel M, Schmidt HH, Nashan B, et al. Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors. Transplantation. 2002;73(3):386–94. Scholar
  58. 58.
    Gregoire E, Le Treut YP. Liver transplantation for primary or secondary endocrine tumors. Transpl Int. 2010;23(7):704–11. Scholar
  59. 59.
    Frilling A, Li J, Malamutmann E, Schmid KW, Bockisch A, Broelsch CE. Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease. Br J Surg. 2009;96(2):175–84. Scholar
  60. 60.
    Leboulleux S, Dromain C, Vataire AL, Malka D, Auperin A, Lumbroso J, et al. Prediction and diagnosis of bone metastases in well-differentiated gastro-entero-pancreatic endocrine cancer: A prospective comparison of whole body magnetic resonance imaging and somatostatin receptor scintigraphy. J Clin Endocrinol Metab. 2008;93(8):3021–8. Scholar
  61. 61.
    Dromain C, De Baere T, Lumbroso J, Caillet H, Laplanche A, Boige V, et al. Detection of liver metastases from endocrine tumors: A prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol. 2005;23(1):70–8. Scholar
  62. 62.
    Scigliano S, Lebtahi R, Maire F, Stievenart JL, Kianmanesh R, Sauvanet A, et al. Clinical and imaging follow-up after exhaustive liver resection of endocrine metastases: A 15-year monocentric experience. Endocr Relat Cancer. 2009;16(3):977–90. Scholar
  63. 63.
    Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: How to select patients for liver transplantation? J Hepatol. 2007;47(4):460–6. Scholar
  64. 64.
    Lang H, Oldhafer KJ, Weimann A, Schlitt HJ, Scheumann GF, Flemming P, et al. Liver transplantation for metastatic neuroendocrine tumors. Ann Surg. 1997;225(4):347–54. Scholar
  65. 65.
    Grossman EJ, Millis JM. Liver transplantation for non-hepatocellular carcinoma malignancy: Indications, limitations, and analysis of the current literature. Liver Transpl. 2010;16(8):930–42. Scholar
  66. 66.
    Coppa J, Pulvirenti A, Schiavo M, Romito R, Collini P, Di BM, et al. Resection versus transplantation for liver metastases from neuroendocrine tumors. Transplant Proc. 2001;33(1–2):1537–9. Scholar
  67. 67.
    Fan ST, Le Treut YP, Mazzaferro V, Burroughs AK, Olausson M, Breitenstein S, et al. Liver transplantation for neuroendocrine tumour liver metastases. HPB (Oxford). 2015;17(1):23–8. Scholar
  68. 68.
    Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: An analysis of 103 patients. Transplantation. 1998;66(10):1307–12. Scholar
  69. 69.
    Burra P, Rodriguez-Castro KI. Neoplastic disease after liver transplantation: Focus on de novo neoplasms. World J Gastroenterol. 2015;21(29):8753–68. Scholar
  70. 70.
    Pavel M, Baudin E, Couvelard A, Krenning E, Oberg K, Steinmuller T, et al. 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(2):157–76. Scholar
  71. 71.
  72. 72.
    Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, 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):753–66. Scholar
  73. 73.
    Cillo U, Burra P, Mazzaferro V, Belli L, Pinna AD, Spada M, et al. A multistep, consensus-based approach to organ allocation in liver transplantation: Toward a "blended principle model". Am J Transplant. 2015;15(10):2552–61. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Carlo Sposito
    • 1
  • Michele Droz dit Busset
    • 1
  • Davide Citterio
    • 1
  • Marco Bongini
    • 1
  • Vincenzo Mazzaferro
    • 1
    • 2
  1. 1.Gastrointestinal Surgery and Liver TransplantationFondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute)MilanItaly
  2. 2.University of MilanMilanItaly

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