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Retrospective Evaluation and Significance of Neutrophil-to-Lymphocyte Ratio Prior to and 1 month Following Microwave Ablation of Hepatocellular Carcinoma

  • Clinical Investigation
  • INTERVENTIONAL ONCOLOGY
  • Published:
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Abstract

Purpose

Neutrophil-to-lymphocyte ratio (NLR) recently demonstrated predictive value for hepatocellular carcinoma (HCC) recurrence after thermal ablation. Microwave ablation (MWA) has been shown to induce changes in the immune landscape after HCC treatment. This study aims at identifying predictors of local tumor progression (LTP) and post-treatment NLR kinetics after MWA.

Materials and Methods

Data from 108 consecutive patients who underwent percutaneous MWA of 119 HCCs with a 2450 Hz/100 W generator in two institutions from October 2014 to September 2021 were retrospectively reviewed. Forty-five HCCs (42 patients) met inclusion criteria for analysis (technique efficacy, pre- and post-treatment NLR availability, follow-up > 6 months, absence of complications). NLR was analyzed prior to therapy and at 1-month follow-up; difference between the two time points was defined as ΔNLR1stFU.

Results

After a median follow-up of 25 months, LTP occurred in 18 HCCs (40%) and 18 patients (42.9%). Multivariate competing risk regression comprising ΔNLR1stFU > 0, cirrhosis etiology and subcapsular location showed that the only independent predictor of LTP was ΔNLR1stFU > 0, on both a per-patient (HR = 2.7, p = 0.049) and per-tumor (HR = 2.8, p = 0.047) analysis. ΔNLR1stFU > 0 occurred in 24/42 patients (57.1%). In this subgroup, higher rates of female patients (p = 0.026), higher mean baseline NLR (p < 0.0001) and lower mean energy/size (p = 0.006) were observed. Upon ROC curve analysis, energy/size < 1414 J/mm predicted ΔNLR1stFU > 0 with 76% sensitivity and 70% specificity (AUC = 0.74).

Conclusion

NLR increase after ablation was the only independent predictor of LTP, supporting the role of balance between systemic inflammation and immunity in recurrence after MWA. Ablation energy/tumor size predicted NLR increase, reinforcing the concept of immune ablation.

Level of Evidence

III.

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References

  1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.

    Article  Google Scholar 

  2. Grandhi MS, Kim AK, Ronnekleiv-Kelly SM, Kamel IR, Ghasebeh MA, Pawlik TM. Hepatocellular carcinoma: from diagnosis to treatment. Surg Oncol. 2016;25:74–85.

    Article  Google Scholar 

  3. Xu XL, Di LX, Liang M, Luo BM. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Radiology. 2018;287:461–72.

    Article  Google Scholar 

  4. Di Sandro S, Benuzzi L, Lauterio A, Botta F, De Carlis R, Najjar M, et al. Single hepatocellular carcinoma approached by curative-intent treatment: a propensity score analysis comparing radiofrequency ablation and liver resection. Eur J Surg Oncol. 2019;45(9):1691–9.

    Article  Google Scholar 

  5. Kim JS, Kim W, So YH, Yu SJ, Kim BG. Topographical impact of hepatitis B-related hepatocellular carcinoma on local recurrence after radiofrequency ablation. J Clin Gastroenterol. 2014;48:66–72.

    Article  CAS  Google Scholar 

  6. Lai ZC, Liang JY, Da CL, Wang Z, Ruan SM, Xie XY, et al. Do hepatocellular carcinomas located in subcapsular space or in proximity to vessels increase the rate of local tumor progression? A meta-analysis Life Sci. 2018;207:381–5.

    CAS  Google Scholar 

  7. Kang TW, Lim HK, Lee MW, Kim YS, Rhim H, Lee WJ, et al. Long-term therapeutic outcomes of radiofrequency ablation for subcapsular versus nonsubcapsular hepatocellular carcinoma: a propensity score matched study. Radiology. 2016;280:300–12.

    Article  Google Scholar 

  8. Kono M, Inoue T, Kudo M, Chishina H, Arizumi T, Takita M, et al. Radiofrequency ablation for hepatocellular carcinoma measuring 2 cm or smaller: results and risk factors for local recurrence. Dig Dis. 2014;32:670–7.

    Article  Google Scholar 

  9. Chen Y, Yang Y, Xyuan Z, Qsheng F, Li X, Xin YJ, et al. Nomogram based on neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio to predict recurrence in patients with hepatocellular carcinoma after radiofrequency ablation. Cardiovasc Intervent Radiol. 2021;44:1551–60.

    Article  Google Scholar 

  10. An C, Li WZ, Huang ZM, Yu XL, Han YZ, Liu FY, et al. Small single perivascular hepatocellular carcinoma: comparisons of radiofrequency ablation and microwave ablation by using propensity score analysis. Eur Radiol. 2021;31:4764–73.

    Article  Google Scholar 

  11. Glassberg MB, Ghosh S, Clymer JW, Qadeer RA, Ferko NC, Sadeghirad B, et al. Microwave ablation compared with radiofrequency ablation for treatment of hepatocellular carcinoma and liver metastases: a systematic review and metaanalysis. Onco Targets Ther. 2019;12:6407–38.

    Article  CAS  Google Scholar 

  12. Nie Y, Yang D, Oppenheim JJ. Alarmins and antitumor immunity. Clin Ther. 2016;38:1042–53.

    Article  CAS  Google Scholar 

  13. Rodriguez-Ruiz ME, Vitale I, Harrington KJ, Melero I, Galluzzi L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat Immunol. 2020;21:120–34.

    Article  CAS  Google Scholar 

  14. Zerbini A, Pilli M, Penna A, Pelosi G, Schianchi C, Molinari A, et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res. 2006;66:1139–46.

    Article  CAS  Google Scholar 

  15. Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013;57:1448–57.

    Article  CAS  Google Scholar 

  16. Chernyak V, Fowler KJ, Kamaya A, Kielar AZ, Elsayes KM, Bashir MR, et al. Liver imaging reporting and data system (LI-RADS) version 2018: imaging of hepatocellular carcinoma in at-risk patients. Radiology. 2018;289:816–30.

    Article  Google Scholar 

  17. Ahmed M. Image-guided tumor ablation: standardization of terminology and reporting criteria-A 10-year update. Radiology. 2014;273:241–60.

    Article  Google Scholar 

  18. Teratani T, Yoshida H, Shiina S, Obi S, Sato S, Tateishi R, et al. Radiofrequency ablation for hepatocellular carcinoma in so-called high-risk locations. Hepatology. 2006;43:1101–8.

    Article  Google Scholar 

  19. Wang X, Sofocleous CT, Erinjeri JP, Petre EN, Gonen M, Do KG, et al. Margin size is an independent predictor of local tumor progression after ablation of colon cancer liver metastases. Cardiovasc Intervent Radiol. 2013;36:166–75.

    Article  CAS  Google Scholar 

  20. Puijk RS, Ahmed M, Goldberg SN, Meijerink MR. Consensus guidelines for the definition of time-to-event end points in image-guided tumor ablation: results of the SIO and DATECAN initiative. Radiology. 2021;301:533–40.

    Article  Google Scholar 

  21. Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014. https://doi.org/10.1093/jnci/dju124.

    Article  Google Scholar 

  22. Hung HC, Lee JC, Cheng CH, Wu TH, Wang YC, Lee CF, et al. Impact of neutrophil to lymphocyte ratio on survival for hepatocellular carcinoma after curative resection. J Hepatobiliary Pancreat Sci. 2017;24:559–69.

    Article  Google Scholar 

  23. Johnson PJ, Dhanaraj S, Berhane S, Bonnett L, Ma YT. The prognostic and diagnostic significance of the neutrophil-to-lymphocyte ratio in hepatocellular carcinoma: a prospective controlled study. Br J Cancer. 2021;125:714–6.

    Article  CAS  Google Scholar 

  24. Masucci MT, Minopoli M, Carriero MV. Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis Prognosis and Therapy. Front Oncol. 2019. https://doi.org/10.3389/fonc.2019.01146.

    Article  Google Scholar 

  25. Li Y, Wang W, Yang F, Xu Y, Feng C, Zhao Y. The regulatory roles of neutrophils in adaptive immunity. Cell Commun Signal. 2019;17:1–11.

    Article  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. Li XF, Chen DP, Ouyang FZ, Chen MM, Wu Y, Kuang DM, et al. Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma. J Hepatol. 2015;62:131–9.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. 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(3):58184.

    Article  Google Scholar 

  30. Zhang H, Hou X, Cai H, Zhuang X. Effects of microwave ablation on T-cell subsets and cytokines of patients with hepatocellular carcinoma. Minim Invasive Ther Allied Technol. 2017;26:207–11.

    Article  Google Scholar 

  31. Leuchte K, Staib E, Thelen M, Gödel P, Lechner A, Zentis P, et al. Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2021;70:893–907.

    Article  CAS  Google Scholar 

  32. Nijkamp MW, Van Der Bilt JDW, De Bruijn MT, Molenaar IQ, Voest EE, Van Diest PJ, et al. Accelerated perinecrotic outgrowth of colorectal liver metastases following radiofrequency ablation is a hypoxia-driven phenomenon. Ann Surg. 2009;249:814–23.

    Article  Google Scholar 

  33. Rozenblum N, Zeira E, Bulvik B, Gourevitch S, Yotvat H, Galun E, et al. Radiofrequency ablation: inflammatory changes in the periablative zone can induce global organ effects, including liver regeneration. Radiology. 2015;276:416–25.

    Article  Google Scholar 

  34. Nikfarjam M, Muralidharan V, Christophi C. Altered growth patterns of colorectal liver metastases after thermal ablation. Surgery. 2006;139:73–81.

    Article  Google Scholar 

  35. Rozenblum N, Zeira E, Scaiewicz V, Bulvik B, Gourevitch S, Yotvat H, et al. Oncogenesis: an “off-target” effect of radiofrequency ablation. Radiology. 2015;276:426–32.

    Article  Google Scholar 

  36. Markezana A, Ahmed M, Kumar G, Zorde-Khvalevsky E, Rozenblum N, Galun E, et al. Moderate hyperthermic heating encountered during thermal ablation increases tumor cell activity. Int J Hyperth. 2020;37:119–29.

    Article  CAS  Google Scholar 

  37. Mehta A, Oklu R, Sheth RA. Thermal ablative therapies and immune checkpoint modulation: can locoregional approaches effect a systemic response? Gastroenterol Res Pract. 2016;2016:1–11.

    Article  Google Scholar 

  38. Ahmad F, Gravante G, Bhardwaj N, Strickland A, Basit R, West K, et al. Changes in interleukin-1β and 6 after hepatic microwave tissue ablation compared with radiofrequency, cryotherapy and surgical resections. Am J Surg. 2010;200:500–6.

    Article  CAS  Google Scholar 

  39. Velez E, Goldberg SN, Kumar G, Wang Y, Gourevitch S, Sosna J, et al. Hepatic thermal ablation: effect of device and heating parameters on local tissue reactions and distant tumor growth. Radiology. 2016;281:782–92.

    Article  Google Scholar 

  40. Alonzo M, Bos A, Bennett S, Ferral H. The Emprint™ Ablation system with thermosphere™ technology: one of the newer next-generation microwave ablation technologies. Semin Intervent Radiol. 2015;32:335–8.

    Article  Google Scholar 

  41. Jilma B, Eichler HG, Breiteneder H, Wolzt M, Aringer M, Graninger W, et al. Effects of 17 beta-estradiol on circulating adhesion molecules. J Clin Endocrinol Metab. 1994;79:1619–24.

    CAS  Google Scholar 

  42. Bouman A, Jan Heineman M, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11:411–23.

    Article  CAS  Google Scholar 

  43. Gardini AC, Marisi G, Canale M, Foschi FG, Donati G, Ercolani G, et al. Radiofrequency ablation of hepatocellular carcinoma: a meta-analysis of overall survival and recurrence-free survival. Onco Targets Ther. 2018;11:6555–67.

    Article  CAS  Google Scholar 

  44. Sumie S, Nakashima O, Okuda K, Kuromatsu R, Kawaguchi A, Nakano M, et al. The significance of classifying microvascular invasion in patients with hepatocellular carcinoma. Ann Surg Oncol. 2014;21:1002–9.

    Article  Google Scholar 

  45. Liu WR, Tian MX, Tang Z, Fang Y, Zhou YF, Song SS, et al. Nine-factor-based immunohistochemistry classifier predicts recurrence for early-stage hepatocellular carcinoma after curative resection. Br J Cancer. 2020;123:92–100.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Radiology, IRCCS San Raffaele Hospital, Via Olgettina 60, 20132, Milan, Italy

    Angelo Della Corte, Simone Gusmini, Renato Pennella, Domenico Santangelo & Francesco De Cobelli

  2. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy

    Angelo Della Corte & Francesco De Cobelli

  3. University Vita-Salute San Raffaele, 20132, Milan, Italy

    Angelo Della Corte, Andrea Casadei-Gardini, Luca Aldrighetti & Francesco De Cobelli

  4. Radiology Department, Fondazione Poliambulanza Istituto Ospedaliero, 25124, Brescia, Italy

    Claudio Sallemi & Lorenzo Monfardini

  5. Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, 20132, Milan, Italy

    Francesca Ratti, Federica Cipriani & Luca Aldrighetti

  6. Unit of Oncology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy

    Valentina Burgio & Andrea Casadei-Gardini

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  1. Angelo Della Corte
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Correspondence to Angelo Della Corte.

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Della Corte, A., Sallemi, C., Ratti, F. et al. Retrospective Evaluation and Significance of Neutrophil-to-Lymphocyte Ratio Prior to and 1 month Following Microwave Ablation of Hepatocellular Carcinoma. Cardiovasc Intervent Radiol 46, 49–59 (2023). https://doi.org/10.1007/s00270-022-03288-8

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