Top

International Journal of Clinical Oncology

Published in:

01-10-2021 | Hepatocellular Carcinoma | Original Article

Lymphocyte-to-C-reactive protein ratio as a prognostic factor for hepatocellular carcinoma

Authors: Norifumi Iseda, Shinji Itoh, Tomoharu Yoshizumi, Takahiro Tomiyama, Akinari Morinaga, Tomonari Shimagaki, Huanlin Wang, Takeshi Kurihara, Takeo Toshima, Yoshihiro Nagao, Noboru Harada, Yoshinao Oda, Masaki Mori

Published in: International Journal of Clinical Oncology | Issue 10/2021

Abstract

Background

Systemic inflammation has been correlated with worse survival for some cancers. We evaluated prognostic values of various inflammatory factor combinations in patients who underwent resections for hepatocellular carcinoma (HCC).

Methods

We retrospectively analysed 306 consecutive patients with HCC who underwent curative liver resections. After assessing eight combinations of inflammatory markers for predictive value for recurrence, we focused on lymphocyte-to-C-reactive protein ratio (LCR) to elucidate its associations with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). We also used immunohistochemical CD34 and CD8 staining to investigate the mechanism of LCR elevation.

Results

LCR showed the highest association with RFS in HCC patients among the compared indices. High preoperative LCR correlated with a high serum albumin concentration, small tumour size, early Barcelona Clinic Liver Cancer stage and low rates of microscopic vascular invasion and microscopic intrahepatic metastasis. Higher preoperative LCR was an independent predictor of longer RFS and OS in this cohort. High LCR patients had fewer vessels encapsulating tumour clusters, and higher intratumoural CD8⁺ T-cell counts than low LCR patients.

Conclusions

Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status.

Available only for authorised users

Villanueva A (2019) Hepatocellular carcinoma. N Engl J Med 380(15):1450–1462. https://doi.org/10.1056/NEJMra1713263CrossRefPubMed

Itoh S, Morita K, Ueda S et al (2009) Long-term results of hepatic resection combined with intraoperative local ablation therapy for patients with multinodular hepatocellular carcinomas. Ann Surg Oncol 16(12):3299–3307. https://doi.org/10.1245/s10434-009-0721-0CrossRefPubMed

Itoh S, Shirabe K, Taketomi A et al (2012) Zero mortality in more than 300 hepatic resections: validity of preoperative volumetric analysis. Surg Today 42(5):435–440. https://doi.org/10.1007/s00595-011-0108-2CrossRefPubMed

Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. https://doi.org/10.1016/j.cell.2010.01.025CrossRefPubMedPubMedCentral

Pichler M, Hutterer GC, Stoeckigt C et al (2013) Validation of the pre-treatment neutrophil-lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients. Br J Cancer 108(4):901–907. https://doi.org/10.1038/bjc.2013.28CrossRefPubMedPubMedCentral

Porrata LF, Ristow K, Habermann TM et al (2012) Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte-predominant Hodgkin lymphoma. Br J Haematol 157(3):321–330. https://doi.org/10.1111/j.1365-2141.2012.09067.xCrossRefPubMed

Smith RA, Bosonnet L, Raraty M et al (2009) Preoperative platelet-lymphocyte ratio is an independent significant prognostic marker in resected pancreatic ductal adenocarcinoma. Am J Surg 197(4):466–472. https://doi.org/10.1016/j.amjsurg.2007.12.057CrossRefPubMed

Ranzani OT, Zampieri FG, Forte DN et al (2013) C-reactive protein/albumin ratio predicts 90-day mortality of septic patients. PLoS ONE 8(3):e59321. https://doi.org/10.1371/journal.pone.0059321CrossRefPubMedPubMedCentral

Pinato DJ, North BV, Sharma R (2012) A novel, externally validated inflammation-based prognostic algorithm in hepatocellular carcinoma: the prognostic nutritional index (PNI). Br J Cancer 106(8):1439–1445. https://doi.org/10.1038/bjc.2012.92CrossRefPubMedPubMedCentral

10.

Diakos CI, Charles KA, McMillan DC et al (2014) Cancer-related inflammation and treatment effectiveness. Lancet Oncol 15(11):e493-503. https://doi.org/10.1016/s1470-2045(14)70263-3CrossRefPubMed

11.

Chang Y, An H, Xu L et al (2015) Systemic inflammation score predicts postoperative prognosis of patients with clear-cell renal cell carcinoma. Br J Cancer 113(4):626–633. https://doi.org/10.1038/bjc.2015.241CrossRefPubMedPubMedCentral

12.

Okugawa Y, Toiyama Y, Yamamoto A et al (2020) Lymphocyte-C-reactive protein ratio as promising new marker for predicting surgical and oncological outcomes in colorectal cancer. Ann Surg 272(2):342–351. https://doi.org/10.1097/sla.0000000000003239CrossRefPubMed

13.

Itoh S, Yoshizumi T, Yugawa K et al (2020) Impact of immune response on outcomes in hepatocellular carcinoma: association with vascular formation. Hepatology 72(6):1987–1999. https://doi.org/10.1002/hep.31206CrossRefPubMed

14.

Fang JH, Zhou HC, Zhang C et al (2015) A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner. Hepatology 62(2):452–465. https://doi.org/10.1002/hep.27760CrossRefPubMed

15.

Itoh S, Yoshizumi T, Kitamura Y et al (2021) Impact of metabolic activity in hepatocellular carcinoma: association with immune status and vascular formation. Hepatol Commun. https://doi.org/10.1002/hep4.1715CrossRefPubMedPubMedCentral

16.

Yamamoto A, Toiyama Y, Okugawa Y et al (2020) Clinical implications of the preoperative lymphocyte C-reactive protein ratio in esophageal cancer patients. Surg Today. https://doi.org/10.1007/s00595-020-02166-5CrossRefPubMedPubMedCentral

17.

Cheng CB, Zhang QX, Zhuang LP et al (2020) Prognostic value of lymphocyte-to-C-reactive protein ratio in patients with gastric cancer after surgery: a multicentre study. Jpn J Clin Oncol 50(10):1141–1149. https://doi.org/10.1093/jjco/hyaa099CrossRefPubMed

18.

Lu LH, Wei W, Li SH et al (2021) The lymphocyte-C-reactive protein ratio as the optimal inflammation-based score in patients with hepatocellular carcinoma underwent TACE. Aging (Albany NY) 13(4):5358–5368. https://doi.org/10.18632/aging.202468CrossRef

19.

Mantovani A, Allavena P, Sica A et al (2008) Cancer-related inflammation. Nature 454(7203):436–444. https://doi.org/10.1038/nature07205CrossRefPubMed

20.

Crusz SM, Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol 12(10):584–596. https://doi.org/10.1038/nrclinonc.2015.105CrossRefPubMed

21.

Zhang J, Zhang HY, Li J et al (2017) The elevated NLR, PLR and PLT may predict the prognosis of patients with colorectal cancer: a systematic review and meta-analysis. Oncotarget 8(40):68837–68846. https://doi.org/10.18632/oncotarget.18575CrossRefPubMedPubMedCentral

22.

Chan JC, Chan DL, Diakos CI et al (2017) The lymphocyte-to-monocyte ratio is a superior predictor of overall survival in comparison to established biomarkers of resectable colorectal cancer. Ann Surg 265(3):539–546. https://doi.org/10.1097/sla.0000000000001743CrossRefPubMed

23.

Wu SJ, Lin YX, Ye H et al (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(2):202–210. https://doi.org/10.1002/jso.24297CrossRefPubMed

24.

Lin ZX, Ruan DY, Li Y et al (2015) Lymphocyte-to-monocyte ratio predicts survival of patients with hepatocellular carcinoma after curative resection. World J Gastroenterol 21(38):10898–10906. https://doi.org/10.3748/wjg.v21.i38.10898CrossRefPubMedPubMedCentral

25.

Zheng J, Seier K, Gonen M et al (2017) Utility of serum inflammatory markers for predicting microvascular invasion and survival for patients with hepatocellular carcinoma. Ann Surg Oncol 24(12):3706–3714. https://doi.org/10.1245/s10434-017-6060-7CrossRefPubMedPubMedCentral

26.

Yang T, Zhu J, Zhao L et al (2017) Lymphocyte to monocyte ratio and neutrophil to lymphocyte ratio are superior inflammation-based predictors of recurrence in patients with hepatocellular carcinoma after hepatic resection. J Surg Oncol 115(6):718–728. https://doi.org/10.1002/jso.24549CrossRefPubMed

27.

Mano Y, Shirabe K, Yamashita Y et al (2013) Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann Surg 258(2):301–305. https://doi.org/10.1097/SLA.0b013e318297ad6bCrossRefPubMed

28.

Yoshizumi T, Ikegami T, Yoshiya S et al (2013) Impact of tumor size, number of tumors and neutrophil-to-lymphocyte ratio in liver transplantation for recurrent hepatocellular carcinoma. Hepatol Res 43(7):709–716. https://doi.org/10.1111/hepr.12016CrossRefPubMed

29.

Itoh S, Yugawa K, Shimokawa M et al (2019) Prognostic significance of inflammatory biomarkers in hepatocellular carcinoma following hepatic resection. BJS Open 3(4):500–508. https://doi.org/10.1002/bjs5.50170CrossRefPubMedPubMedCentral

30.

Imai D, Maeda T, Shimokawa M et al (2020) Prognostic nutritional index is superior as a predictor of prognosis among various inflammation-based prognostic scores in patients with hepatocellular carcinoma after curative resection. Hepatol Res 50(1):101–109. https://doi.org/10.1111/hepr.13431CrossRefPubMed

31.

Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148. https://doi.org/10.1016/j.immuni.2004.07.017CrossRefPubMed

32.

Hoffmann TK, Dworacki G, Tsukihiro T et al (2002) Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res 8(8):2553–2562PubMed

33.

Väyrynen JP, Tuomisto A, Klintrup K et al (2013) Detailed analysis of inflammatory cell infiltration in colorectal cancer. Br J Cancer 109(7):1839–1847. https://doi.org/10.1038/bjc.2013.508CrossRefPubMedPubMedCentral

34.

Nagaoka S, Yoshida T, Akiyoshi J et al (2007) Serum C-reactive protein levels predict survival in hepatocellular carcinoma. Liver Int 27(8):1091–1097. https://doi.org/10.1111/j.1478-3231.2007.01550.xCrossRefPubMed

35.

Hashimoto K, Ikeda Y, Korenaga D et al (2005) The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer 103(9):1856–1864. https://doi.org/10.1002/cncr.20976CrossRefPubMed

36.

Renne SL, Woo HY, Allegra S et al (2020) Vessels encapsulating tumor clusters (VETC) is a powerful predictor of aggressive hepatocellular carcinoma. Hepatology 71(1):183–195. https://doi.org/10.1002/hep.30814CrossRefPubMed

37.

Xue G, Romano E, Massi D et al (2016) Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights. Cancer Treat Rev 49:1–12. https://doi.org/10.1016/j.ctrv.2016.06.009CrossRefPubMed

Title: Lymphocyte-to-C-reactive protein ratio as a prognostic factor for hepatocellular carcinoma
Authors: Norifumi Iseda
Shinji Itoh
Tomoharu Yoshizumi
Takahiro Tomiyama
Akinari Morinaga
Tomonari Shimagaki
Huanlin Wang
Takeshi Kurihara
Takeo Toshima
Yoshihiro Nagao
Noboru Harada
Yoshinao Oda
Masaki Mori
Publication date: 01-10-2021
Publisher: Springer Singapore
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: International Journal of Clinical Oncology / Issue 10/2021
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-021-01985-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2021

Impact of osteopenia on surgical and oncological outcomes in patients with pancreatic cancer

Lymphocyte–C-reactive protein ratio as a prognostic marker associated with the tumor immune microenvironment in intrahepatic cholangiocarcinoma

Prognosis of Japanese metastatic renal cell carcinoma patients in the targeted therapy era

Osteogenic and brain metastases after non-small cell lung cancer resection

Surgical margin clearance and extended chemotherapy defines survival for synchronous oligometastatic liver lesions of the ductal adenocarcinoma of the pancreas

Retrospective analysis of neoadjuvant chemotherapy followed by surgery versus definitive chemoradiotherapy with proton beam for locally advanced esophageal squamous cell carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer