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Perioperative Lymphopenia is Associated with Increased Risk of Recurrence and Worse Survival Following Hepatectomy for Hepatocellular Carcinoma

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Immune dysregulation may be associated with cancer progression. We sought to investigate the prognostic value of perioperative lymphopenia on short- and long-term outcomes among patients undergoing resection of hepatocellular carcinoma (HCC).

Methods

Patients undergoing resection of HCC between 2000 and 2020 were identified using an international database. The incidence and impact of perioperative lymphopenia [preoperative, postoperative day (POD) 1/3/5], defined as absolute lymphocyte count (ALC) <1000/μL, on short- and long-term outcomes was assessed.

Results

Among 1448 patients, median preoperative ALC was 1593/μL [interquartile range (IQR) 1208–2006]. The incidence of preoperative lymphopenia was 14.0%, and 50.2%, 45.1% and 35.6% on POD1, POD3 and POD5, respectively. Preoperative lymphopenia predicted 5-year overall survival (OS) [lymphopenia vs. no lymphopenia: 49.1% vs. 66.1%] and 5-year disease-free survival (DFS) [25.0% vs. 41.5%] (both p < 0.05). Lymphopenia on POD1 (5-year OS: 57.1% vs. 71.2%; 5-year DFS: 30.0% vs. 41.1%), POD3 (5-year OS: 57.3% vs. 68.9%; 5-year DFS: 35.4% vs. 42.7%), and POD5 (5-year OS: 53.1% vs. 66.1%; 5-year DFS: 32.8% vs. 42.3%) was associated with worse long-term outcomes (all p < 0.05). Patients with severe lymphopenia (ALC <500/μL) on POD5 had worse 5-year OS and DFS (5-year OS: 44.7% vs. 54.3% vs. 66.1%; 5-year DFS: 27.8% vs. 33.3% vs. 42.3%) [both p < 0.05], as well as higher incidence of overall (45.5% vs. 25.3% vs. 30.9%; p = 0.013) and major complications (18.2% vs. 3.4% vs. 4.5%; p < 0.001) versus individuals with moderate (ALC 500–1000/μL) or no lymphopenia following hepatectomy for HCC. After adjusting for competing risk factors, prolonged lymphopenia was independently associated with higher hazards of death [hazard ratio (HR) 1.38, 95% CI 1.11–1.72] and recurrence (HR 1.22, 95% CI 1.02–1.45).

Conclusion

Perioperative lymphopenia had short- and long-term prognostic implications among individuals undergoing hepatectomy for HCC.

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References

  1. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68(3):526–49.

    Article  PubMed  Google Scholar 

  2. Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of hepatocellular carcinoma incidence in the United States Forecast Through 2030. J Clin Oncol. 2016;34(15):1787–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tsilimigras DI, Bagante F, Moris D, et al. Defining the chance of cure after resection for hepatocellular carcinoma within and beyond the Barcelona Clinic Liver Cancer guidelines: a multi-institutional analysis of 1010 patients. Surgery. 2019;166(6):967–74.

    Article  PubMed  Google Scholar 

  4. Pinna AD, Yang T, Mazzaferro V, et al. Liver transplantation and hepatic resection can achieve cure for hepatocellular carcinoma. Ann Surg. 2018;268(5):868–75.

    Article  PubMed  Google Scholar 

  5. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.

    Article  PubMed  Google Scholar 

  6. Tsilimigras DI, Bagante F, Moris D, et al. Recurrence patterns and outcomes after resection of hepatocellular carcinoma within and beyond the Barcelona clinic liver cancer criteria. Ann Surg Oncol. 2020;27(7):2321–31.

    Article  PubMed  Google Scholar 

  7. Tsilimigras DI, Ntanasis-Stathopoulos I, Moris D, Pawlik TM. Liver tumor microenvironment. Adv Exp Med Biol. 2020;1296:227–41.

    Article  CAS  PubMed  Google Scholar 

  8. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  10. Ceze N, Thibault G, Goujon G, et al. Pre-treatment lymphopenia as a prognostic biomarker in colorectal cancer patients receiving chemotherapy. Cancer Chemother Pharmacol. 2011;68(5):1305–13.

    Article  CAS  PubMed  Google Scholar 

  11. De Giorgi U, Mego M, Scarpi E, et al. Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer. Clin Breast Cancer. 2012;12(4):264–9.

    Article  PubMed  Google Scholar 

  12. Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009;69(13):5383–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Aizawa M, Yabusaki H, Matsuki A, Bamba T, Nakagawa S. Predictive significance of surgery-induced lymphopenia on the survival after curative resection for locally advanced gastric cancer: a retrospective cohort analysis. World J Surg Oncol. 2023;21(1):7.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cohen JT, Charpentier KP, Miner TJ, Cioffi WG, Beard RE. Lymphopenia following pancreaticoduodenectomy is associated with pancreatic fistula formation. Ann Hepatobiliary Pancreat Surg. 2021;25(2):242–50.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev. 2010;21(1):3–10.

    Article  CAS  PubMed  Google Scholar 

  16. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137–48.

    Article  CAS  PubMed  Google Scholar 

  17. Alwarawrah Y, Kiernan K, MacIver NJ. Changes in nutritional status impact immune cell metabolism and function. Front Immunol. 2018;9:1055.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hogan BV, Peter MB, Shenoy HG, Horgan K, Hughes TA. Surgery induced immunosuppression. Surgeon. 2011;9(1):38–43.

    Article  PubMed  Google Scholar 

  19. Chiarelli M, Achilli P, Tagliabue F, et al. Perioperative lymphocytopenia predicts mortality and severe complications after intestinal surgery. Ann Transl Med. 2019;7(14):311.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Toft P, Tonnesen E, Helbo-Hansen HS, Lillevang ST, Rasmussen JW, Christensen NJ. Redistribution of granulocytes in patients after major surgical stress. APMIS. 1994;102(1):43–8.

    Article  CAS  PubMed  Google Scholar 

  21. Zidar DA, Al-Kindi SG, Liu Y, et al. Association of lymphopenia with risk of mortality among adults in the US general population. JAMA Netw Open. 2019;2(12):e1916526.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Romo EM, Munoz-Robles JA, Castillo-Rama M, et al. Peripheral blood lymphocyte populations in end-stage liver diseases. J Clin Gastroenterol. 2007;41(7):713–21.

    Article  PubMed  Google Scholar 

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Acknowledgement

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Funding

No sources of funding were received to assist in the preparation of this study.

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Authors and Affiliations

  1. Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Diamantis I. Tsilimigras MD, Yutaka Endo MD & Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.)

  2. Department of Surgery, Ospedale San Raffaele, Milan, Italy

    Francesca Ratti MD & Luca Aldrighetti MD

  3. Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal

    Hugo P. Marques MD

  4. Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France

    François Cauchy MD

  5. Department of Surgery, Westmead Hospital, Sydney, NSW, Australia

    Vincent Lam MD

  6. Department of Surgery, Stanford University, Stanford, CA, USA

    George A. Poultsides MD

  7. Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania

    Irinel Popescu MD & Sorin Alexandrescu MD

  8. Department of Surgery, University of Ottawa, Ottawa, ON, Canada

    Guillaume Martel MD

  9. Department of Surgery, Keio University, Tokyo, Japan

    Minoru Kitago MD

  10. Department of Surgery, University of Verona, Verona, Italy

    Alfredo Guglielmi MD

  11. Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia

    Tom Hugh MD

  12. Department of Surgery, University of Colorado, Denver, CO, USA

    Ana Gleisner MD

  13. Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

    Feng Shen MD

  14. Yokohama City University School of Medicine, Yokohama, Japan

    Itaru Endo MD, PhD

Authors
  1. Diamantis I. Tsilimigras MD
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  2. Yutaka Endo MD
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  3. Francesca Ratti MD
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  6. Vincent Lam MD
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  7. George A. Poultsides MD
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  8. Irinel Popescu MD
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  9. Sorin Alexandrescu MD
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  10. Guillaume Martel MD
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  11. Minoru Kitago MD
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  12. Alfredo Guglielmi MD
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  13. Tom Hugh MD
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  14. Luca Aldrighetti MD
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  15. Ana Gleisner MD
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  16. Feng Shen MD
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  17. Itaru Endo MD, PhD
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  18. Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.)
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Corresponding author

Correspondence to Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.).

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Disclosures

Guillaume Martel has received speakers honorarium from Incyte Biosciences. Diamantis I. Tsilimigras, Yutaka Endo, Francesca Ratti, Hugo P. Marques, François Cauchy, Vincent Lam, George A. Poultsides, Irinel Popescu, Sorin Alexandrescu, Minoru Kitago, Alfredo Guglielmi, Tom Hugh, Luca Aldrighetti, Ana Gleisner, Feng Shen, Itaru Endo, and Timothy M. Pawlik have no conflicts of interest to declare in relation to this work.

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Tsilimigras, D.I., Endo, Y., Ratti, F. et al. Perioperative Lymphopenia is Associated with Increased Risk of Recurrence and Worse Survival Following Hepatectomy for Hepatocellular Carcinoma. Ann Surg Oncol 31, 2568–2578 (2024). https://doi.org/10.1245/s10434-023-14811-7

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