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Annals of Surgical Oncology

, Volume 24, Issue 12, pp 3706–3714 | Cite as

Utility of Serum Inflammatory Markers for Predicting Microvascular Invasion and Survival for Patients with Hepatocellular Carcinoma

  • Jian Zheng
  • Ken Seier
  • Mithat Gonen
  • Vinod P. Balachandran
  • T. Peter Kingham
  • Michael I. D’Angelica
  • Peter J. Allen
  • William R. Jarnagin
  • Ronald P. DeMatteo
Hepatobiliary Tumors
  • 456 Downloads

Abstract

Background

Preoperative serum inflammatory markers have been correlated with outcome after resection of hepatocellular carcinoma (HCC), but studies have had conflicting results. This study aimed to evaluate the association of six inflammatory markers with recurrence-free survival (RFS), overall survival (OS), and microvascular invasion (MVI), a well-known prognostic factor.

Methods

This study investigated 370 patients who underwent resection of HCC from 1992 to 2016, retrospectively evaluating their inflammatory indices and individual components including their neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index (APRI), and aspartate aminotransferase-to-neutrophil ratio index (ANRI). Uni- and multivariate analyses were performed to evaluate these markers for RFS, OS, and MVI.

Results

The median RFS was 23 months, and the median OS was 60 months. Factors independently associated with worse RFS were higher PLR and alpha-fetoprotein level, male gender, and the presence of MVI as well as multiple nodules. Factors independently associated with worse OS were higher PLR and international normalized ratio, male gender, older age, presence of MVI and multiple nodules, larger tumor, presence of cirrhosis, and absence of steatosis. The study identified MVI in 47% of the patients. Lower level of albumin, higher level of alpha-fetoprotein, and larger tumor on preoperative imaging were independently associated with MVI.

Conclusions

This largest Western series to evaluate the utility of preoperative inflammatory markers in patients with HCC found that only PLR was associated with RFS and OS and that albumin was associated with MVI.

Notes

Disclosure

There are no conflicts of interest.

Funding

This work was supported in part by Cancer Center Support Grant NIH/NCI P30 CA008748.

References

  1. 1.
    Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.CrossRefPubMedGoogle Scholar
  2. 2.
    Cho CS, Gonen M, Shia J, Kattan MW, Klimstra DS, Jarnagin WR et al. A novel prognostic nomogram is more accurate than conventional staging systems for predicting survival after resection of hepatocellular carcinoma. J Am Coll Surg. 2008;206:281–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Shim JH, Jun MJ, Han S, Lee YJ, Lee SG, Kim KM et al. Prognostic nomograms for prediction of recurrence and survival after curative liver resection for hepatocellular carcinoma. Ann Surg. 2015;261:939–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014;146:1691–700 e1693.Google Scholar
  5. 5.
    Ang SF, Ng ES, Li H, Ong YH, Choo SP, Ngeow J, et al. The Singapore Liver Cancer Recurrence (SLICER) Score for relapse prediction in patients with surgically resected hepatocellular carcinoma. PLoS ONE. 2015;10:e0118658.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mano Y, Shirabe K, Yamashita Y, Harimoto N, Tsujita E, Takeishi K, et al. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 2013;258:301–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Lu SD, Wang YY, Peng NF, Peng YC, Zhong JH, Qin HG, et al. Preoperative ratio of neutrophils to lymphocytes predicts postresection survival in selected patients with early or intermediate stage hepatocellular carcinoma. Medicine. 2016;95:e2722.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Shen J, He L, Li C, Wen T, Chen W, Lu C, et al. Prognostic nomograms for patients with resectable hepatocelluar carcinoma incorporating systemic inflammation and tumor characteristics. Oncotarget. 2016;7:80783–93.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ma W, Zhang P, Qi J, Gu L, Zang M, Yao H, et al. Prognostic value of platelet-to-lymphocyte ratio in hepatocellular carcinoma: a meta-analysis. Sci Rep. 2016;6:35378.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wu SJ, Lin YX, Ye H, Li FY, Xiong XZ, Cheng NS. (2016) Lymphocyte-to-monocyte ratio and prognostic nutritional index predict survival outcomes of hepatitis B virus-associated hepatocellular carcinoma patients after curative hepatectomy. J Surg Oncol. 114:202–216.CrossRefPubMedGoogle Scholar
  12. 12.
    Chan AW, Chan SL, Wong GL, Wong VW, Chong CC, Lai PB, et al. Prognostic nutritional index (PNI) predicts tumor recurrence of very-early-/early-stage hepatocellular carcinoma after surgical resection. Ann Surg Oncol. 2015;22:4138–48.CrossRefPubMedGoogle Scholar
  13. 13.
    Shen SL, Fu SJ, Chen B, Kuang M, Li SQ, Hua YP, et al. Preoperative aspartate aminotransferase-to-platelet ratio is an independent prognostic factor for hepatitis B-induced hepatocellular carcinoma after hepatic resection. Ann Surg Oncol. 2014;21:3802–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Ji F, Liang Y, Fu SJ, Guo ZY, Shu M, Shen SL, et al. A novel and accurate predictor of survival for patients with hepatocellular carcinoma after surgical resection: the neutrophil-to-lymphocyte ratio (NLR) combined with the aspartate aminotransferase/platelet-count ratio index (APRI). BMC Cancer. 2016;16:137.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ji F, Fu S, Guo Z, Pang H, Chen D, Wang X, et al. Prognostic significance of preoperative aspartate aminotransferase-to-neutrophil ratio index in patients with hepatocellular carcinoma after hepatic resection. Oncotarget. 2016;7:72276–89.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Sullivan KM, Groeschl RT, Turaga KK, Tsai S, Christians KK, White SB, et al. Neutrophil-to-lymphocyte ratio as a predictor of outcomes for patients with hepatocellular carcinoma: a Western perspective. J Surg Oncol. 2014;109:95–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Parisi I, Tsochatzis E, Wijewantha H, Rodríguez‐Perálvarez M, Luca LD, Manousou P, et al. Inflammation-based scores do not predict post-transplant recurrence of hepatocellular carcinoma in patients within Milan criteria. Liver Transplant. 2014;20:1327–35.CrossRefGoogle Scholar
  18. 18.
    Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Fushiya N, et al. Comparison of the prognostic value of inflammation-based prognostic scores in patients with hepatocellular carcinoma. Br J Cancer. 2012;107:988–93.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cha C, Fong Y, Jarnagin WR, Blumgart LH, DeMatteo RP. Predictors and patterns of recurrence after resection of hepatocellular carcinoma. J Am Coll Surg. 2003;197:753–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early- and late-phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Hirokawa F, Hayashi M, Asakuma M, Shimizu T, Inoue Y, Uchiyama K. Risk factors and patterns of early recurrence after curative hepatectomy for hepatocellular carcinoma. Surg Oncol. 2016;25:24–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Rodriguez-Peralvarez M, Luong TV, Andreana L, Meyer T, Dhillon AP, Burroughs AK. A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol. 2013;20:325–39.CrossRefPubMedGoogle Scholar
  23. 23.
    Zheng J, Kuk D, Gonen M, Balachandran VP, Kingham TP, Allen PJ, et al. Actual 10-year survivors after resection of hepatocellular carcinoma. Ann Surg Oncol. 2017;24:1358–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical patterns of hepatocellular carcinoma (hcc) in nonalcoholic fatty liver disease (NAFLD): a multicenter prospective study. Hepatology. 2015;63:827–38.CrossRefGoogle Scholar
  25. 25.
    Hastie T, Tibshirani R, Friedman JH. The elements of statistical learning: data mining, inference, and prediction. 2nd ed. New York: Springer; 2009.CrossRefGoogle Scholar
  26. 26.
    Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.CrossRefPubMedGoogle Scholar
  27. 27.
    Rothschild MA, Oratz M, Schreiber SS. Serum albumin. Hepatology. 1988;8:385–401.CrossRefPubMedGoogle Scholar
  28. 28.
    Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach: the ALBI grade. J Clin Oncol. 2015;33:550–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Vazeille C, Jouinot A, Durand JP, Neveux N, Boudou-Rouquette P, Huillard O, et al. Relation between hypermetabolism, cachexia, and survival in cancer patients: a prospective study in 390 cancer patients before initiation of anticancer therapy. Am J Clin Nutr. 2017;105:1139–47.CrossRefPubMedGoogle Scholar
  30. 30.
    Kaida T, Nitta H, Kitano Y, Yamamura K, Arima K, Higashi T, et al. Preoperative platelet-to-lymphocyte ratio can predict recurrence beyond the Milan criteria after hepatectomy for patients with hepatocellular carcinoma. Hepatol Res. 2016. doi: 10.1111/hepr.12835.PubMedGoogle Scholar
  31. 31.
    Xia W, Ke Q, Wang Y, Wang W, Zhang M, Shen Y, et al. Predictive value of pretransplant platelet-to-lymphocyte ratio for hepatocellular carcinoma recurrence after liver transplantation. World J Surg Oncol. 2015;13:60.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59:1295–300.PubMedGoogle Scholar
  33. 33.
    Meikle CK, Kelly CA, Garg P, Wuescher LM, Ali RA, Worth RG. Cancer and thrombosis: the platelet perspective. Front Cell Dev Biol. 2016;4:147.PubMedGoogle Scholar
  34. 34.
    Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–57.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Sideras K, Biermann K, Verheij J, Takkenberg BR, Mancham S, Hansen BE, et al. PD-L1, galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma. Oncoimmunology. 2017;6:e1273309.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016;4:419–30.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhao Y, Si G, Zhu F, Hui J, Cai S, Huang C, et al. Prognostic role of platelet-to-lymphocyte ratio in hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget. 2017;8:22854–62.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Choo SP, Tan WL, Goh BK, Tai WM, Zhu AX. Comparison of hepatocellular carcinoma in Eastern versus Western populations. Cancer. 2016. doi: 10.1002/cncr.30237.PubMedCentralGoogle Scholar
  39. 39.
    Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60:1767–75.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Makarova-Rusher OV, Altekruse SF, McNeel TS, Ulahannan S, Duffy AG, Graubard BI, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Cancer. 2016;122:1757–65.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2017

Authors and Affiliations

  • Jian Zheng
    • 1
  • Ken Seier
    • 2
  • Mithat Gonen
    • 2
  • Vinod P. Balachandran
    • 1
  • T. Peter Kingham
    • 1
  • Michael I. D’Angelica
    • 1
  • Peter J. Allen
    • 1
  • William R. Jarnagin
    • 1
  • Ronald P. DeMatteo
    • 1
  1. 1.Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkUSA

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