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Preoperative lymphocyte/C-reactive protein ratio and its correlation with CD8+ tumor-infiltrating lymphocytes as a predictor of prognosis after resection of intrahepatic cholangiocarcinoma

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Abstract

Purpose

To clarify whether the preoperative lymphocyte/C-reactive protein (CRP) ratio (LCR) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (IHCC), and investigate its mechanism via tumor-infiltrating lymphocytes.

Methods

The subjects of this retrospective study were 42 patients who had undergone hepatectomy for IHCC. We divided the patients into low LCR and high LCR groups (cutoff value: 8780) and analyzed their overall survival (OS) and disease-free survival (DFS) with respect to LCR and other clinicopathological factors. We also investigated the levels of stromal tumor-infiltrating lymphocytes (TILs) and CD8+ TILs in surgical specimens, and the relationship between LCR and TILs.

Results

A low LCR was identified in 21 patients and was significantly correlated with older age, a high CRP-albumin ratio, and advanced disease stage, and was a prognostic factor for OS and DFS. Multivariate analysis revealed that a low LCR was an independent prognostic factor for worse OS (HR 10.40, P = 0.0077). Although the LCR and levels of stromal TILs were not significantly related, LCR and levels of CD8+ TILs were significantly related (P = 0.0297).

Conclusion

The preoperative LCR may predict the postsurgical prognosis of patients with IHCC and reflect the CD8+ TILs.

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Abbreviations

ANC:

Absolute neutrophil count

CAFs:

Cancer associated fibroblasts

CRP:

C-reactive protein

CAR:

C-reactive protein–albumin ratio

DFS:

Disease-free survival

H.E:

Hematoxylin and eosin

IHCC:

Intrahepatic cholangiocarcinoma

im:

Intrahepatic metastasis

LCR:

Lymphocyte–C-reactive protein ratio

LMR:

Lymphocyte–monocyte ratio

LNM:

Lymph-node metastasis

LPBC:

Lymphocyte-predominant breast cancer

mGPS:

Modified Glasgow Prognostic Score

NLR:

Neutrophil–lymphocyte ratio

OS:

Overall survival

PLR:

Platelet–lymphocyte ratio

PNI:

Prognostic nutrition index

PD-L1:

Programmed death ligand 1

ROC:

Receiver-operating characteristics

SII:

Systemic immune inflammation index

TLC:

Total lymphocyte count

TILs:

Tumor-infiltrating lymphocytes

TMB:

Tumor mutation burden

vp:

Portal vein invasion

vv:

Hepatic vein invasion

References

  1. Ishikawa D, Nishi M, Takasu C, Kashihara H, Tokunaga T, Higashijima J, et al. The role of neutrophil-to-lymphocyte ratio on the effect of CRT for patients with rectal cancer. In Vivo. 2020;34:863–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lin G, Liu Y, Li S, Mao Y, Wang J, Shuang Z, et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget. 2016;7(32):50963–71.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mcmilan DC, Crozier JE, Canna K, Angerson W, McArdle CS. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis. 2007;22(8):881–6.

    Article  Google Scholar 

  4. Okuno M, Ebata T, Yokoyama Y, Igami T, Sugawara G, Mizuno T, et al. Appraisal of inflammation-based prognostic scores in patients with unresectable perihilar cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2016;23(10):636–42.

    Article  PubMed  Google Scholar 

  5. Chan AWH, Chan SL, Wong GLH, Wong VWS, Chong CCN, Lai PBS, 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.

    Article  PubMed  Google Scholar 

  6. Akgül Ö, Bagante F, Olsen G, Cloyd JM, Weiss M, Merath K, et al. Preoperative prognostic nutritional index predicts survival of patients with intrahepatic cholangiocarcinoma after curative resection. J Surg Oncol. 2018;118(3):422–30.

    PubMed  Google Scholar 

  7. Chen Q, Dai Z, Yin D, Yang LX, Wang Z, Xiao YS, et al. Negative impact of preoperative platelet–lymphocyte ratio on outcome after hepatic resection for intrahepatic cholangiocarcinoma. Medicine (Baltimore). 2015. https://doi.org/10.1097/MD.0000000000000574.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tsiimigras D, Moris D, Mehta R, Paredes AZ, Sahara K, Guglielmi A, et al. The systemic immune-inflammation index predicts prognosis in intrahepatic cholangiocarcinoma: an international multi-institutional analysis. HBP (Oxford). 2020. https://doi.org/10.1016/j.hpb.2020.03.011.

    Article  Google Scholar 

  9. Wu Y, Ren F, Chai Y, Xue Z, Shen C, Zhang X, et al. Prognostic value of inflammation-based indexes for intrahepatic cholangiocarcinoma following curative resection. Oncol Lett. 2019;17(1):165–74.

    CAS  PubMed  Google Scholar 

  10. Nakao Y, Yamashita Y, Arima K, Miyata T, Itoyama R, Yusa T, et al. Clinical usefulness of perioperative C-reactive protein/albumin ratio in patients with intrahepatic cholangiocarcinoma: a retrospective single institutional study. Anticancer Res. 2019;39(5):2641–6.

    Article  CAS  PubMed  Google Scholar 

  11. Okugawa Y, Toiyama Y, Yamamoto A, Shigemori T, Ide S, Kitajima T, et al. Lymphocyte–C-reactive protein ratio as promising new marker for predicting surgical and oncological outcomes in colorectal cancer. Ann Surg. 2020;272(2):342–51.

    Article  PubMed  Google Scholar 

  12. Okugawa Y, Toiyama Y, Yamamoto A, Shigemori T, Ichikawa T, Yin C, et al. Lymphocyte-to-C-reactive protein ratio and score are clinically feasible nutrition-inflammation markers of outcome in patients with gastric cancer. Clin Nutr. 2020;39(4):1209–17.

    Article  CAS  PubMed  Google Scholar 

  13. Fan Z, Luo G, Gong Y, Xu H, Qian Y, Deng S, et al. Prognostic value of the C-reactive protein/lymphocyte ratio in pancreatic cancer. Ann Surg Oncol. 2020;27(10):4017–25.

    Article  PubMed  Google Scholar 

  14. Okugawa Y, Toiyama Y, Fujikawa H, Ide S, Yamamoto A, Omura Y, et al. Prognostic potential of lymphocyte–C-reactive protein ratio in patients with rectal cancer receiving preoperative chemoradiotherapy. J Gastrointest Surg. 2020. https://doi.org/10.1007/s11605-019-04495-4 (online ahead of print).

    Article  PubMed  Google Scholar 

  15. Sata A, Fukui R, Miyagawa Y, Bun A, Ozawa H, Fujimoto Y, et al. C-reactive protein and absolute lymphocyte count can predict overall survival of patients treated with eribulin. Anticancer Res. 2020;40(7):4147–56.

    Article  PubMed  Google Scholar 

  16. Lu LH, Zhong C, Wei W, Li SH, Mei J, Zou JW, et al. Lymphocyte–C-reactive protein ratio as a novel prognostic index in intrahepatic cholangiocarcinoma: a multicentre cohort study. Liver Int. 2020. https://doi.org/10.1111/liv.14567 (online ahead of print).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ohtani H, Mori K, Nakajima M, Ueki H. Defining lymphocyte-predominant breast cancer by the proportion of lymphocyte-rich stroma and its significance in routine histopathological diagnosis. Pathol Int. 2015;65(12):644–51.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lee YY, Choi CH, Sung CO, Do IG, Hub SJ, Kim HJ, et al. Clinical significance of changes in peripheral lymphocyte count after surgery in early cervical cancer. Gynecol Oncol. 2012;127(1):107–13.

    Article  PubMed  Google Scholar 

  19. Yoon CI, Park S, Cha YJ, Lee HS, Bae SJ, Cha C, et al. Associations between absolute neutrophil count and lymphocyte-predominant breast cancer. Breast. 2020;50:141–8.

    Article  PubMed  Google Scholar 

  20. Zhu Y, Wang XY, Zhang Y, Xu D, Dong J, Zhang Z, et al. Programmed death ligand 1 expression in human intrahepatic cholangiocarcinoma and its association with prognosis and CD8+ T-cell immune responses. Cancer Manag Res. 2018. https://doi.org/10.2147/CMAR.S172719.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Asahi Y, Hatanaka KC, Hatanaka Y, Kamiyama T, Orimo T, Shimada S, et al. Prognostic impact of CD8+ T cell distribution and its association with the HLA class I expression in intrahepatic cholangiocarcinoma. Surg Today. 2020;50(8):931–40.

    Article  CAS  PubMed  Google Scholar 

  22. Yamada S, Morine Y, Imura S, Ikemoto T, Arakawa Y, Saito Y, et al. Prognostic prediction of apparent diffusion coefficient obtained by diffusion-weighted MRI in mass-forming intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2020;27(7):388–95.

    Article  PubMed  Google Scholar 

  23. Morine Y, Shimada M. The value of systematic lymph node dissection for intrahepatic cholangiocarcinoma from the viewpoint of liver lymphatics. J Gastroenterol. 2015;50(9):913–27.

    Article  CAS  PubMed  Google Scholar 

  24. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71.

    Article  CAS  PubMed  Google Scholar 

  25. Ishikawa D, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, et al. Effect of Twist and Bmi1 on intraductal papillary mucinous neoplasm of the pancreas. J Gastroenterol Hepatol. 2014;29(12):2032–7.

    Article  CAS  PubMed  Google Scholar 

  26. Takasu C, Nishi M, Yoshikawa K, Tokunaga T, Kashihara H, Yoshimoto T, et al. Impact of sidedness of colorectal cancer on tumor immunity. PLoS One. 2020. https://doi.org/10.1371/journal.pone.0240408.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gerhardt T, Milz S, Schepke M, Feldmann G, Wolff M, Sauerbruch T, et al. C-reactive protein is a prognostic indicator in patients with perihilar cholangiocarcinoma. World J Gastroenterol. 2006;12(34):5495–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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(4):510–3.

    Article  CAS  PubMed  Google Scholar 

  29. Kishi T, Nakamura A, Itasaka S, Shibuya K, Matsumoto S, Kanai M, et al. Pretreatment C-reactive protein level predicts outcome and patterns of failure after chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology. 2015;15(6):694–700.

    Article  CAS  PubMed  Google Scholar 

  30. Yang J, Wezeman M, Zhang X, Lin P, Wang M, Qian J, et al. Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell. 2007;12(3):252–65.

    Article  PubMed  Google Scholar 

  31. Yang J, Liu Z, Liu H, He J, Yang J, Lin P, et al. C-reactive protein promotes bone destruction in human myeloma through the CD32-p38 MAPK-Twist axis. Sci Signal. 2017. https://doi.org/10.1126/scisignal.aan6282.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Iseki Y, Shibutani M, Maeda K, Nagahara H, Tamura T, Ohira G, et al. The impact of the preoperative peripheral lymphocyte count and lymphocyte percentage in patients with colorectal cancer. Surg Today. 2017;47(6):743–54.

    Article  CAS  PubMed  Google Scholar 

  33. Liang L, Zhu J, Jia H, Huang L, Li D, Li Q, et al. Predictive value of pretreatment lymphocyte count in stage II colorectal cancer and in high-risk patients treated with adjuvant chemotherapy. Oncotarget. 2016;7(1):1014–28.

    Article  PubMed  Google Scholar 

  34. Loupakis F, Depetris I, Biason P, Intini R, Prete AA, Leone F, et al. Prediction of benefit from checkpoint inhibitors in mismatch repair deficient metastatic colorectal cancer: role of tumor infiltrating lymphocytes. Oncologist. 2020;25(6):481–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ozaki Y, Muto S, Takagi H, Inoue T, Watanabe Y, Fukuhara M, et al. Prognostic impact of tumor mutation burden in patients with completely resected non-small cell lung cancer: brief report. J Thorac Oncol. 2018;13(8):1217–21.

    Article  Google Scholar 

  36. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kato T, Noma K, Ohara T, Kashima H, Katsura Y, Sato H, et al. Cancer-associated fibroblasts affect intratumoral CD8 + and FoxP3 + T cells via IL6 in the tumor microenvironment. Clin Cancer Res. 2018;24(19):4820–33.

    Article  CAS  PubMed  Google Scholar 

  38. Mitchell KG, Daio L, Karpinets T, Negrao MV, Tran TH, Parra ER, et al. Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2019-000405.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kinoshita F, Tagawa T, Akamine T, Takada K, Yamada Y, Oku Y, et al. Interleukin-38 promotes tumor growth through regulation of CD8 + tumor-infiltrating lymphocytes in lung cancer tumor microenvironment. Cancer Immunol Immunother. 2021;70(1):123–35.

    Article  CAS  PubMed  Google Scholar 

  40. Yoshida T, Ichikawa J, Giuroiu I, Laino AS, Hao Y, Krogsgaard M, et al. C reactive protein impairs adaptive immunity in immune cells of patients with melanoma. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2019-000234.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Lee KH, Kim EY, Yun JS, Park YL, Do SI, Chae AW, et al. The prognostic and predictive value of tumor-infiltrating lymphocytes and hematologic parameters in patients with breast cancer. BMC Cancer. 2018;18(1):938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhu Y, Li M, Bo C, Liu X, Zhang J, Li Z, et al. Prognostic significance of the lymphocyte-to-monocyte ratio and the tumor-infiltrating lymphocyte to tumor-associated macrophage ratio in patients with stage T3N0M0 esophageal squamous cell carcinoma. Cancer Immunol Immunother. 2017;66:343.

    Article  CAS  PubMed  Google Scholar 

  43. Okadome K, Baba Y, Yagi T, Kiyozumi Y, Ishimoto T, Iwatsuki M, et al. Prognostic nutritional index, tumor-infiltrating lymphocytes, and prognosis in patients with esophageal cancer. Ann Surg. 2020;271(4):693–700.

    Article  PubMed  Google Scholar 

  44. Shirasawa M, Yoshida T, Horinoucho H, Kitano S, Arakawa S, Matsumoto Y, et al. Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment. Br J Cancer. 2020. https://doi.org/10.1038/s41416-020-01188-7 (online ahead of print).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Nakamura M, Ueno M, Hayami S, Kawai M, Miyamoto A, Suzaki N, et al. Effective response of intrahepatic cholangiocarcinoma to Pembrolizumab: a case report. Anticancer Res. 2020;40(7):4123–9.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Katsuki Miyazaki, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yu Saito, Shinichiro Yamada, Kazunori Tokuda, Shohei Okikawa, Shoko Yamashita & Mitsuo Shimada

  2. Department of Molecular Pathology, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Takeshi Oya

  3. Department of Pathology and Laboratory Medicine, Tokushima Univercity, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Shoko Yamashita & Koichi Tsuneyama

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  1. Katsuki Miyazaki
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Correspondence to Mitsuo Shimada.

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Miyazaki, K., Morine, Y., Imura, S. et al. Preoperative lymphocyte/C-reactive protein ratio and its correlation with CD8+ tumor-infiltrating lymphocytes as a predictor of prognosis after resection of intrahepatic cholangiocarcinoma. Surg Today 51, 1985–1995 (2021). https://doi.org/10.1007/s00595-021-02295-5

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