Tumor Biology

, Volume 35, Issue 11, pp 11057–11063 | Cite as

Neutrophil-to-lymphocyte ratio acts as a prognostic factor for patients with advanced hepatocellular carcinoma

  • Xing Li
  • Zhan-Hong Chen
  • Xiao-Kun Ma
  • Jie Chen
  • Dong-Hao Wu
  • Qu Lin
  • Min Dong
  • Li Wei
  • Tian-Tian Wang
  • Dan-Yun Ruan
  • Ze-Xiao Lin
  • Yan-Fang Xing
  • Yun Deng
  • Xiang-Yuan Wu
  • Jin-Yun Wen
Research Article

Abstract

Few studies investigated the prognosis of patients with advanced hepatocellular carcinoma (aHCC). This study was aimed to determine the prognostic value of differential blood cell counts including blood white cells, neutrophil, lymphocyte, neutrophil-lymphocyte ratio (NLR), and platelet in patients with aHCC. A total of 205 ethnic Chinese aHCC patients receiving non-systematic sorafenib were analyzed retrospectively. The prognostic value of differential blood cell counts and NLR for overall survival (OS) was determined by integration into Cancer of the Liver Italian Program (CLIP) score system using backward elimination model of multivariate Cox regression. As a result, NLR was confirmed to be an independent predictor for OS (p = 0.001) with the rest parameters presented negative results. Then, aHCC patients were dichotomized into two groups according to NLR values ≤2.43 or >2.43. Patients with low NLR presented lower CLIP score and higher 6-month survival rate (56.1 vs 25.9 %) compared with patients with high NLR level. Besides, low NLR level was associated with favorable prognostic factors such as lower α-fetoprotein, alkaline phosphatase, and total bilirubin, as well as decreased incidence of ascites, portal vein thrombosis, and metastasis. Besides, low NLR level was associated less white cells and neutrophil granulocytes, as well as more lymphocyte. In summary, the present study firstly indentified NLR as an independent prognostic factor in aHCC patients receiving no systematic sorafenib.

Keywords

Neutrophil-lymphocyte ratio Hepatocellular carcinoma Prognosis Blood cell counts Score system 

Notes

Conflict of interest

None

Financial support

This work was supported by grants from the National Natural Science Foundation of China (No. 81372374), the Combination Project of Production, Education and Research from Guangdong Province and Ministry of Education (No. 2012B091100460), and the Science and Technology Planning Project of Guangdong Province 2011B031800076 (to Q. Lin), 2011B031800014 (to M. Dong) and 2012B031800259 (to J. Wen)

References

  1. 1.
    Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63:844–55.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Li X, Dong M, Lin Q, Chen ZH, Ma XK, Xing YF, et al. Comparison of current staging systems for advanced hepatocellular carcinoma not amendable to locoregional therapy as inclusion criteria for clinical trials. Asia Pac J Clin Oncol. 2013;9:86–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Yau T, Yao TJ, Chan P, Ng K, Fan ST, Poon RT. A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to locoregional therapy: implication for patient selection in systemic therapy trials. Cancer. 2008;113:2742–51.CrossRefPubMedGoogle Scholar
  4. 4.
    Bugada D, Allegri M, Lavand'homme P, De Kock M, Fanelli G. Inflammation-based scores: a new method for patient-targeted strategies and improved perioperative outcome in cancer patients. Biomed Res Int. 2014;2014:142425.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339:286–91.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Llovet JM, Moitinho E, Sala M, Bataller R, Rodriguez-Iglesias P, Castells A, et al. Prevalence and prognostic value of hepatocellular carcinoma in cirrhotic patients presenting with spontaneous bacterial peritonitis. J Hepatol. 2000;33:423–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Nozoe T, Iguchi T, Adachi E, Matsukuma A, Ezaki T. Preoperative elevation of serum c-reactive protein as an independent prognostic indicator for gastric cancer. Surg Today. 2011;41:510–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Smith RA, Bosonnet L, Raraty M, Sutton R, Neoptolemos JP, Campbell F, et al. Preoperative platelet-lymphocyte ratio is an independent significant prognostic marker in resected pancreatic ductal adenocarcinoma. Am J Surg. 2009;197:466–72.CrossRefPubMedGoogle Scholar
  9. 9.
    Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S. Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via p2y2 receptor. Cancer Cell. 2013;24:130–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Grosse-Steffen T, Giese T, Giese N, Longerich T, Schirmacher P, Hansch GM, et al. Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase. Clin Dev Immunol. 2012;2012:720768.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schwaller J, Schneider P, Mhawech-Fauceglia P, McKee T, Myit S, Matthes T, et al. Neutrophil-derived april concentrated in tumor lesions by proteoglycans correlates with human b-cell lymphoma aggressiveness. Blood. 2007;109:331–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Xue TC, Zhang L, Xie XY, Ge NL, Li LX, Zhang BH, et al. Prognostic significance of the neutrophil-to-lymphocyte ratio in primary liver cancer: a meta-analysis. PLoS One. 2014;9:e96072.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Nakayama Y, Gotohda N, Shibasaki H, Nomura S, Kinoshita T, Hayashi R: Usefulness of the neutrophil/lymphocyte ratio measured preoperatively as a predictor of peritoneal metastasis in patients with advanced gastric cancer. Surg Today 2014. doi: 10.1007/s00595-014-0917-1
  14. 14.
    Wang DS, Luo HY, Qiu MZ, Wang ZQ, Zhang DS, Wang FH, et al. Comparison of the prognostic values of various inflammation based factors in patients with pancreatic cancer. Med Oncol. 2012;29:3092–100.CrossRefPubMedGoogle Scholar
  15. 15.
    Fu SJ, Shen SL, Li SQ, Hua YP, Hu WJ, Liang LJ, et al. Prognostic value of preoperative peripheral neutrophil-to-lymphocyte ratio in patients with HBV-associated hepatocellular carcinoma after radical hepatectomy. Med Oncol. 2013;30:721.CrossRefPubMedGoogle Scholar
  16. 16.
    Bertuzzo VR, Cescon M, Ravaioli M, Grazi GL, Ercolani G, Del Gaudio M, et al. Analysis of factors affecting recurrence of hepatocellular carcinoma after liver transplantation with a special focus on inflammation markers. Transplantation. 2011;91:1279–85.CrossRefPubMedGoogle Scholar
  17. 17.
    Dan J, Zhang Y, Peng Z, Huang J, Gao H, Xu L, et al. Postoperative neutrophil-to-lymphocyte ratio change predicts survival of patients with small hepatocellular carcinoma undergoing radiofrequency ablation. PLoS One. 2013;8:e58184.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wei K, Wang M, Zhang W, Mu H, Song TQ. Neutrophil-lymphocyte ratio as a predictor of outcomes for patients with hepatocellular carcinoma undergoing tae combined with sorafenib. Med Oncol. 2014;31:969.CrossRefPubMedGoogle Scholar
  19. 19.
    Gong Y, Koh DR. Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model. Cell Tissue Res. 2010;339:437–48.CrossRefPubMedGoogle Scholar
  20. 20.
    Kusumanto YH, Dam WA, Hospers GA, Meijer C, Mulder NH. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003;6:283–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Neagoe PE, Brkovic A, Hajjar F, Sirois MG. Expression and release of angiopoietin-1 from human neutrophils: intracellular mechanisms. Growth Factors. 2009;27:335–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Coussens LM, Tinkle CL, Hanahan D, Werb Z. Mmp-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell. 2000;103:481–90.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54:948–55.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhou SL, Dai Z, Zhou ZJ, Wang XY, Yang GH, Wang Z, et al. Overexpression of cxcl5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology. 2012;56:2242–54.CrossRefPubMedGoogle Scholar
  25. 25.
    Schwarz EC, Qu B, Hoth M. Calcium, cancer and killing: the role of calcium in killing cancer cells by cytotoxic t lymphocytes and natural killer cells. Biochim Biophys Acta. 1833;2013:1603–11.Google Scholar
  26. 26.
    Lee S, Margolin K. Tumor-infiltrating lymphocytes in melanoma. Curr Oncol Rep. 2012;14:468–74.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, et al. Foxp3+ regulatory t cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res. 2007;13:902–11.CrossRefPubMedGoogle Scholar
  28. 28.
    Pinato DJ, Stebbing J, Ishizuka M, Khan SA, Wasan HS, North BV, et al. A novel and validated prognostic index in hepatocellular carcinoma: the inflammation based index (ibi). J Hepatol. 2012;57:1013–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Motomura T, Shirabe K, Mano Y, Muto J, Toshima T, Umemoto Y, et al. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58:58–64.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Xing Li
    • 1
    • 2
  • Zhan-Hong Chen
    • 1
    • 2
  • Xiao-Kun Ma
    • 1
    • 2
  • Jie Chen
    • 1
    • 2
  • Dong-Hao Wu
    • 1
    • 2
  • Qu Lin
    • 1
    • 2
  • Min Dong
    • 1
    • 2
  • Li Wei
    • 1
    • 2
  • Tian-Tian Wang
    • 1
    • 2
  • Dan-Yun Ruan
    • 1
    • 2
  • Ze-Xiao Lin
    • 1
    • 2
  • Yan-Fang Xing
    • 2
    • 3
  • Yun Deng
    • 2
    • 4
  • Xiang-Yuan Wu
    • 1
    • 2
  • Jin-Yun Wen
    • 1
    • 2
  1. 1.Department of Medical OncologyThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Department of Medical OncologyShenzhen People’s HospitalShenzhenPeople’s Republic of China
  3. 3.Department of NephrologyThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouPeople’s Republic of China
  4. 4.Department of Radiation OncologyThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiPeople’s Republic of China

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