Prognostic role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with midgut neuroendocrine tumors undergoing resective surgery

  • Anna Pozza
  • Bruno Pauletti
  • Marco ScarpaEmail author
  • Cesare Ruffolo
  • Nicolò Bassi
  • Marco Massani
Original Article



Several studies demonstrated the prognostic value of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and platelet-to-white blood cells ratio (PWR) in different types of tumors. However, there is no information about a possible role of NLR, PLR and PWR as predictor of presence of metastasis or multifocal disease in patients undergoing surgery with curative intent for midgut NET. The aim of our study was to test the role of preoperative NLR, PLR and PWR as predictors of patients undergoing surgery with curative intent for midgut NET.


We retrospectively enrolled seven foregut, 35 midgut and six hindgut NET patients with gastrointestinal neuroendocrine tumors operated in our Units from January 2005 to June 2016. Details about preoperative laboratory data, surgical operation, histology and follow-up were retrieved. Non-parametric statistics, ROC curve analysis and survival analysis were used.


NLR was significantly higher in patients with distant metastasis (p = 0.04). The ROC curve analysis indicated that a threshold value of NLR of 2.6 predicted the presence of peritoneal metastasis with a specificity of 100% and a sensitivity of 71% and an overall accuracy of AUC = 0.81 (95%CI: 0.59–0.94), p = 0.05. PLR and PWR was not be associated to metastasis but tended to be associated to multifocal disease.


In patients with midgut NET, an impaired adaptive immune response, as suggested by a high NLR ratio, was associated to the presence of distant metastasis and in particular of peritoneal metastasis. This information may be helpful when planning the treatment of a patient with a midgut NET.


Midgut neuroendocrine tumors Neutrophil-lymphocyte ratio Platelet-lymphocyte ratio 


Author contributions

Anna Pozza: study conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, critical revision of manuscript

Bruno Pauletti: acquisition of data, analysis and interpretation of data, drafting of manuscript, critical revision of manuscript

Marco Scarpa: study conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, critical revision of manuscript

Cesare Ruffolo: acquisition of data, drafting of manuscript, critical revision of manuscript

Nicolò Bassi: drafting of manuscript, critical revision of manuscript

Marco Massani: study conception and design, drafting of manuscript, critical revision of manuscript

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Ramage JK, Davies AH, Ardill J et al (2005) Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 54(Suppl 4):iv1–iv16. PMC 1867801 Freely accessibleGoogle Scholar
  2. 2.
    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors. Accessed 27 June 2016
  3. 3.
    Öberg K, Castellano D (2011) Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 30:3–7. CrossRefGoogle Scholar
  4. 4.
    Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (2010) The pathologic classification of neuroendocrine tumors. Pancreas. 39(6):707–712. CrossRefGoogle Scholar
  5. 5.
    Griniatsos J, Michail O (2010) Appendiceal neuroendocrine tumors: recent insights and clinical implications. World J Gastrointest Oncol 2(4):192–196. PMC 2999180Freely accessibleCrossRefGoogle Scholar
  6. 6.
    Ni S, Sheng W, Du X (2010) Pathologic research update of colorectal neuroendocrine tumors. World J Gastroenterol 16(14):1713–1719. PMC 2852818 Freely accessibleCrossRefGoogle Scholar
  7. 7.
    Konishi T, Watanabe T, Nagawa H, Oya M, Ueno M, Kuroyanagi H, Fujimoto Y, Akiyoshi T, Yamaguchi T, Muto T (2010) Treatment of colorectal carcinoids: a new paradigm. World J Gastrointest Surg 2(5):153–156. PMC 2999232Freely accessibleCrossRefGoogle Scholar
  8. 8.
    Figueiredo MN, Maggiori L, Gaujoux S, Couvelard A, Guedj N, Ruszniewski P, Panis Y (2014) Surgery for small-bowel neuroendocrine tumors: is there any benefit of the laparoscopic approach? Surg Endosc 28(5):1720–1726. CrossRefGoogle Scholar
  9. 9.
    Ethun CG, Postlewait LM, Baptiste GG, McInnis MR, Cardona K, Russell MC, Kooby DA, Staley CA, Maithel SK (2016) Small bowel neuroendocrine tumors: a critical analysis of diagnostic work-up and operative approach. J Surg Oncol 114(6):671–676. CrossRefGoogle Scholar
  10. 10.
    Clift AK, Faiz O, Al-Nahhas A, Bockisch A, Liedke MO, Schloericke E, Wasan H, Martin J, Ziprin P, Moorthy K, Frilling A (2016) Role of staging in patients with small intestinal neuroendocrine tumours. J Gastrointest Surg 20(1):180–188; discussion 188. CrossRefGoogle Scholar
  11. 11.
    Kao SC, Pavlakis N, Harvie R, Vardy JL, Boyer MJ, van Zandwijk N et al (2010) High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res 16:5805–5813CrossRefGoogle Scholar
  12. 12.
    Raungkaewmanee S, Tangjitgamol S, Manusirivithaya S, Srijaipracharoen S, Thavaramara T (2013) Platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer. J Gynecol Oncol 23:265–273CrossRefGoogle Scholar
  13. 13.
    Szkandera J, Gerger A, Liegl-Atzwanger B, Absenger G, Stotz M, Friesenbichler J, Trajanoski S, Stojakovic T, Eberhard K, Leithner A, Pichler M (2014) The lymphocyte/monocyte ratio predicts poor clinical outcome and improves the predictive accuracy in patients with soft tissue sarcomas. Int J Cancer 135:362–370CrossRefGoogle Scholar
  14. 14.
    Absenger G, Szkandera J, Pichler M, Stotz M, Arminger F, Weissmueller M, Schaberl-Moser R, Samonigg H, Stojakovic T, Gerger A (2013) A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer 109:395–400CrossRefGoogle Scholar
  15. 15.
    Kubo H, Murayama Y, Arita T, Kuriu Y, Nakanishi M, Otsuji E (2016) The prognostic value of preoperative neutrophil-to-lymphocyte ratio in colorectal cancer. World J Surg 40(11):2796–2802CrossRefGoogle Scholar
  16. 16.
    Ferrucci PF, Gandini S, Battaglia A, Alfieri S, Di Giacomo AM, Giannarelli D, Antonini Cappellini GC, De Galitiis F, Marchetti P, Amato G, Lazzeri A, Pala L, Cocorocchio E, Martinoli C (2015) Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer 112:1904–1910. CrossRefGoogle Scholar
  17. 17.
    Salman T, Kazaz SN, Varol U, Oflazoglu U, Unek IT, Kucukzeybek Y, Alacacioglu A, Atag E, Semiz HS, Cengiz H, Oztop I, Tarhan MO (2016) Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for patients with neuroendocrine tumors: an Izmir Oncology Group study. Chemotherapy. 61(6):281–286. CrossRefGoogle Scholar
  18. 18.
    Park MI (2013) Endoscopic treatment for early foregut neuroendocrine tumors. Clin Endosc 46(5):450–455CrossRefGoogle Scholar
  19. 19.
    Edge SB, Byrd DR, Compton CC (eds) (2010) AJCC cancer staging handbook, 7th edn. Springer, New YorkGoogle Scholar
  20. 20.
    Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, DC MM, Clarke SJ (2013) The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol 88(1):218–230. CrossRefGoogle Scholar
  21. 21.
    Yodying H, Matsuda A, Miyashita M, Matsumoto S, Sakurazawa N, Yamada M, Uchida E (2016) Prognostic significance of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in oncologic outcomes of esophageal cancer: a systematic review and meta-analysis. Ann Surg Oncol 23:646–654CrossRefGoogle Scholar
  22. 22.
    Ha H, Nam AR, Bang JH, Park JE, Kim TY, Lee KH, Han SW, Im SA, Kim TY, Bang YJ, Oh DY (2016) Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. Oncotarget 7(47):76604–76612. CrossRefGoogle Scholar
  23. 23.
    Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K (2011) Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer. 117(20):4617–4622. CrossRefGoogle Scholar
  24. 24.
    Schwarzberg AB, Stover EH, Sengupta T, Michelini A, Vincitore M, Baden LR, Kulke MH (2007) Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide. Cancer Investig 25(4):249–255CrossRefGoogle Scholar
  25. 25.
    McMillan DC, Canna K, McArdle CS (2003) Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg 90:215–219CrossRefGoogle Scholar
  26. 26.
    Nozoe T, Mori E, Takahashi I, Ezaki T (2008) Preoperative elevation of serum C-reactive protein as an independent prognostic indicator of colorectal carcinoma. Surg Today 38:597–602CrossRefGoogle Scholar
  27. 27.
    Sengupta S, Lohse CM, Cheville JC, Leibovich BC, Thompson RH, Webster WS, Frank I, Zincke H, Blute ML, Kwon ED (2006) The preoperative erythrocyte sedimentation rate is an independent prognostic factor in renal cell carcinoma. Cancer 106:304–312CrossRefGoogle Scholar
  28. 28.
    Choi ES, Kim HS, Han I (2014) Elevated preoperative systemic inflammatory markers predict poor outcome in localized soft tissue sarcoma. Ann Surg Oncol 21:778–85. 12CrossRefGoogle Scholar
  29. 29.
    Teramukai S, Kitano T, Kishida Y, Kawahara M, Kubota K, Komuta K, Minato K, Mio T, Fujita Y, Yonei T, Nakano K, Tsuboi M, Shibata K, Furuse K, Fukushima M (2009) Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer 45:1950–1958CrossRefGoogle Scholar
  30. 30.
    Chua W, Charles KA, Baracos VE, Clarke SJ (2011) Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer 104:1288–1295CrossRefGoogle Scholar
  31. 31.
    Smith RA, Bosonnet L, Raraty M, Sutton R, Neoptolemos JP, Campbell F, Ghaneh P (2009) Preoperative platelet-lymphocyte ratio is an independent significant prognostic marker in resected pancreatic ductal adenocarcinoma. Am J Surg 197:466–472CrossRefGoogle Scholar
  32. 32.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998CrossRefGoogle Scholar
  33. 33.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313(5795):1960–1964CrossRefGoogle Scholar
  34. 34.
    Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666CrossRefGoogle Scholar
  35. 35.
    Gangi A, Siegel E, Barmparas G, Lo S, Jamil LH, Hendifar A, Nissen NN, Wolin EM, Amersi F (2018) Multifocality in small bowel neuroendocrine tumors. J Gastrointest Surg 22(2):303–309. CrossRefGoogle Scholar
  36. 36.
    Numbere N, Huber AR, Shi C, Cates JMM, Gonzalez RS (2019) Should Ki67 immunohistochemistry be performed on all lesions in multifocal small intestinal neuroendocrine tumours? Histopathology. 74(3):424–429. CrossRefGoogle Scholar
  37. 37.
    Mitsuya K, Nakasu Y, Kurakane T, Hayashi N, Harada H, Nozaki K (2016) Elevated preoperative neutrophil-to-lymphocyte ratio as a predictor of worse survival after resection in patients with brain metastasis. J Neurosurg 2:1–5Google Scholar
  38. 38.
    Romano C, Morgillo F, Mosca L, Diadema MR, Lieto E, Procaccini E, De Vita F, Ciardiello F (2016) Neutrophil to lymphocyte ratio (NLR) for prediction of distant metastasis-free survival (DMFS) in early breast cancer: a propensity score-matched analysis. ESMO Open 1(2):e000038CrossRefGoogle Scholar
  39. 39.
    Dalpiaz O, Luef T, Seles M, Stotz M, Stojakovic T, Pummer K, Zigeuner R, Hutterer GC, Pichler M (2016) Critical evaluation of the potential prognostic value of the pretreatment-derived neutrophil-lymphocyte ratio under consideration of C-reactive protein levels in clear cell renal cell carcinoma. Br J Cancer:1.
  40. 40.
    Wu M, Guo J, Guo L, Zuo Q (2016) The C-reactive protein/albumin ratio predicts overall survival of patients with advanced pancreatic cancer. Tumour Biol 37(9):12525–12533CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of SurgeryAzienda ULSS2 Marca TrevigianaTrevisoItaly
  2. 2.General Surgery UnitAzienda Ospedaliera di PadovaPaduaItaly

Personalised recommendations