Journal of Gastrointestinal Surgery

, Volume 21, Issue 11, pp 1821–1830 | Cite as

Early Recurrence of Neuroendocrine Liver Metastasis After Curative Hepatectomy: Risk Factors, Prognosis, and Treatment

  • Xu-Feng Zhang
  • Eliza W. Beal
  • Jeffery Chakedis
  • Yi Lv
  • Fabio Bagante
  • Luca Aldrighetti
  • George A. Poultsides
  • Todd W. Bauer
  • Ryan C. Fields
  • Shishir Kumar Maithel
  • Hugo P. Marques
  • Matthew Weiss
  • Timothy M. PawlikEmail author
Original Article



Early tumor recurrence after curative resection typically indicates a poor prognosis. The objective of the current study was to investigate the risk factors, treatment, and prognosis of early recurrence of neuroendocrine tumor (NET) liver metastasis (NELM) after hepatic resection.


A total of 481 patients who underwent curative-intent resection for NELM were identified from a multi-institutional database. Data on clinicopathological characteristics, intraoperative details, and outcomes were documented. The optimal cutoff value to differentiate early and late recurrence was determined to be 3 years based on linear regression.


With a median follow-up of 60 months, 223 (46.4%) patients developed a recurrence, including 158 (70.9%) early and 65 (29.1%) late recurrences. On multivariable analysis, pancreatic NET, primary tumor lymph node metastasis, and a microscopic positive surgical margin were independent risk factors for early intrahepatic recurrence. While recurrence patterns and treatments were comparable among patients with early and late recurrences, early recurrence was associated with worse disease-specific survival than late recurrences (10-year NELM-specific survival, 44.5 vs 75.8%, p < 0.001). Among the 34 (21.5%) patients who underwent curative treatment for early recurrence, post-recurrence disease-specific survival was better than non-curatively treated patients (10-year NELM-specific survival, 54.2 vs 26.3%, p = 0.028), yet similar to patients with late recurrences treated with curative intent (10-year NELM-specific survival, 54.2 vs 37.4%, p = 0.519).


Early recurrence after surgery for NELM was associated with the pancreatic type, primary lymph node metastasis, and extrahepatic disease. Re-treatment with curative intent prolonged survival after recurrence, and therefore, operative intervention even for early recurrences of NELM should be considered.


Neuroendocrine liver metastasis Recurrence Hepatectomy Early Late 



X.-F. Z. was supported in part by the China Scholarship Council.

Author Contributions

Study design, XF Zhang, TM Pawlik; data collection and interpretation, EW Beal, J Chakedis, F Bagante, L Aldrighetti, GA Poultsides, TW Bauer, RC Fields, SK Maithel, HP Marques, M Weiss; Data analysis, XF Zhang, Y Lv, EW Beal, Chakedis, F Bagante; Drafting, XF Zhang, EW Beal; revision of the draft: EW Beal, TM Pawlik.

Compliance with Ethical Standards

The Institutional Review Boards of each participating institution approved the study.


  1. 1.
    Yao JC, Hassan M, Phan A, 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;26:3063–3072.CrossRefPubMedGoogle Scholar
  2. 2.
    Frilling A, Clift AK. Therapeutic strategies for neuroendocrine liver metastases. Cancer. 2015;121:1172–1186.CrossRefPubMedGoogle Scholar
  3. 3.
    Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:e8–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Rindi G, D'Adda T, Froio E, Fellegara G, Bordi C. Prognostic factors in gastrointestinal endocrine tumors. Endocr Pathol. 2007;18:145–149.CrossRefPubMedGoogle Scholar
  5. 5.
    Farley HA, Pommier RF. Treatment of Neuroendocrine Liver Metastases. Surg Oncol Clin N Am. 2016;25:217–225.CrossRefPubMedGoogle Scholar
  6. 6.
    Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010;17:3129–3136.CrossRefPubMedGoogle Scholar
  7. 7.
    Spolverato G, Bagante F, Aldrighetti L, et al. Management and outcomes of patients with recurrent neuroendocrine liver metastasis after curative surgery: An international multi-institutional analysis. J Surg Oncol. 2017.Google Scholar
  8. 8.
    Mayo SC, Herman JM, Cosgrove D, et al. Emerging approaches in the management of patients with neuroendocrine liver metastasis: role of liver-directed and systemic therapies. J Am Coll Surg. 2013;216:123–134.CrossRefPubMedGoogle Scholar
  9. 9.
    Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg. 2003;197:29–37.CrossRefPubMedGoogle Scholar
  10. 10.
    Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer. 2000;89:500–507.CrossRefPubMedGoogle Scholar
  11. 11.
    Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–207.CrossRefPubMedGoogle Scholar
  12. 12.
    Portolani N, Coniglio A, Ghidoni S, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243:229–235.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cucchetti A, Piscaglia F, Caturelli E, et al. Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population. Ann Surg Oncol. 2009;16:413–422.CrossRefPubMedGoogle Scholar
  14. 14.
    Vigano L, Capussotti L, Lapointe R, et al. Early recurrence after liver resection for colorectal metastases: risk factors, prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients. Ann Surg Oncol. 2014;21:1276–1286.CrossRefPubMedGoogle Scholar
  15. 15.
    Malik HZ, Gomez D, Wong V, et al. Predictors of early disease recurrence following hepatic resection for colorectal cancer metastasis. Eur J Surg Oncol. 2007;33:1003–1009.CrossRefPubMedGoogle Scholar
  16. 16.
    Imai K, Allard MA, Benitez CC, et al. Early Recurrence After Hepatectomy for Colorectal Liver Metastases: What Optimal Definition and What Predictive Factors? Oncologist. 2016;21:887–894.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Terminology Committee of the IHPBA. Terminology of liver anatomy and resections. HPB (Oxford). 2000;2:333–339.CrossRefGoogle Scholar
  18. 18.
    Graff-Baker AN, Sauer DA, Pommier SJ, Pommier RF. Expanded criteria for carcinoid liver debulking: Maintaining survival and increasing the number of eligible patients. Surgery. 2014;156:1369–1376; discussion 1376-1367.CrossRefPubMedGoogle Scholar
  19. 19.
    Gurusamy KS, Ramamoorthy R, Sharma D, Davidson BR. Liver resection versus other treatments for neuroendocrine tumours in patients with resectable liver metastases. Cochrane Database Syst Rev. 2009:CD007060.Google Scholar
  20. 20.
    Gurusamy KS, Pamecha V, Sharma D, Davidson BR. Palliative cytoreductive surgery versus other palliative treatments in patients with unresectable liver metastases from gastro-entero-pancreatic neuroendocrine tumours. Cochrane Database Syst Rev. 2009:CD007118.Google Scholar
  21. 21.
    Spolverato G, Vitale A, Ejaz A, et al. Net health benefit of hepatic resection versus intraarterial therapies for neuroendocrine liver metastases: A Markov decision model. Surgery. 2015;158:339–348.CrossRefPubMedGoogle Scholar
  22. 22.
    Shah SA, Greig PD, Gallinger S, et al. Factors associated with early recurrence after resection for hepatocellular carcinoma and outcomes. J Am Coll Surg. 2006;202:275–283.CrossRefPubMedGoogle Scholar
  23. 23.
    Lu X, Zhao H, Yang H, et al. A prospective clinical study on early recurrence of hepatocellular carcinoma after hepatectomy. J Surg Oncol. 2009;100:488–493.CrossRefPubMedGoogle Scholar
  24. 24.
    Yamauchi K, Kokuryo T, Yokoyama Y, Uehara K, Yamaguchi J, Nagino M. Prediction of Early Recurrence After Curative Resection of Colorectal Liver Metastasis and Subsequent S-1 Chemotherapy. Anticancer Res. 2016;36:2175–2179.PubMedGoogle Scholar
  25. 25.
    Bhogal RH, Hodson J, Bramhall SR, et al. Predictors of early recurrence after resection of colorectal liver metastases. World J Surg Oncol. 2015;13:135.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Takahashi S, Konishi M, Nakagohri T, Gotohda N, Saito N, Kinoshita T. Short time to recurrence after hepatic resection correlates with poor prognosis in colorectal hepatic metastasis. Jpn J Clin Oncol. 2006;36:368–375.CrossRefPubMedGoogle Scholar
  27. 27.
    Kaibori M, Iwamoto Y, Ishizaki M, et al. Predictors and outcome of early recurrence after resection of hepatic metastases from colorectal cancer. Langenbecks Arch Surg. 2012;397:373–381.CrossRefPubMedGoogle Scholar
  28. 28.
    Marble K, Banerjee S, Greenwald L. Colorectal carcinoma in young patients. J Surg Oncol. 1992;51:179–182.CrossRefPubMedGoogle Scholar
  29. 29.
    Cusack JC, Giacco GG, Cleary K, et al. Survival factors in 186 patients younger than 40 years old with colorectal adenocarcinoma. J Am Coll Surg. 1996;183:105–112.PubMedGoogle Scholar
  30. 30.
    Bagante F, Spolverato G, Merath K, et al. Neuroendocrine liver metastasis: The chance to be cured after liver surgery. J Surg Oncol. 2017.Google Scholar
  31. 31.
    Cho CS, Labow DM, Tang L, et al. Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms. Cancer. 2008;113:126–134.CrossRefPubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2017

Authors and Affiliations

  • Xu-Feng Zhang
    • 1
    • 2
  • Eliza W. Beal
    • 2
  • Jeffery Chakedis
    • 2
  • Yi Lv
    • 1
  • Fabio Bagante
    • 3
  • Luca Aldrighetti
    • 4
  • George A. Poultsides
    • 5
  • Todd W. Bauer
    • 6
  • Ryan C. Fields
    • 7
  • Shishir Kumar Maithel
    • 8
  • Hugo P. Marques
    • 9
  • Matthew Weiss
    • 3
  • Timothy M. Pawlik
    • 2
    Email author
  1. 1.Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and EngineeringThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  2. 2.Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer ResearchThe Ohio State University Wexner Medical CenterColumbusUSA
  3. 3.Department of SurgeryJohns Hopkins HospitalBaltimoreUSA
  4. 4.Department of Surgery, Scientific Institute San RaffaeleVita-Salute San Raffaele UniversityMilanItaly
  5. 5.Department of SurgeryStanford UniversityStanfordUSA
  6. 6.Department of SurgeryUniversity of VirginiaCharlottesvilleUSA
  7. 7.Department of SurgeryWashington University, School of MedicineSt LouisUSA
  8. 8.Department of SurgeryEmory UniversityAtlantaGeorgia
  9. 9.Department of SurgeryCurry Cabral HospitalLisbonPortugal

Personalised recommendations