In the present study, we explored the prognostic value of preoperative SII in non-metastatic RCC patients who underwent nephrectomy. We observed that high SII is likely to be associated with adverse factors, such as age, tumor size, pathological T stage, tumor grade, and necrosis. Multivariate analyses showed SII was an independent predictor of OS and CSS. Moreover, to limit the influence of bias, we performed PSM and demonstrated that high SII was also an unfavorable factor for OS and CSS in the matched cohort.
The association between inflammation and malignancy has been widely explored in the past decades. Immune cells play an essential role in the inflammatory process leading to the production of cytokines and chemokines that promote tumor development, invasion and metastasis8. Therefore, the complex balance between immune cells and substances secreted by inflammation may affect the type of cells detectable in the peripheral circulation. SII, a novel inflammation index, based on the proportion of neutrophil, platelet, and lymphocyte, was found to be associated with the prognosis of several malignancies. A retrospective multicenter cohort study revealed that high SII (>900) is associated with poor CSS (HR=2.32; 95%CI 1.55-3.48) in patients with resectable pancreatic cancer22. Chen et al. included 1383 colorectal cancer patients and found high SII (>340) was an independent predictor of OS and disease-free survival23. Zhang et al. conducted a retrospective analysis of 209 patients with BC undergoing radical cystectomy, finding SII was an independent predictor for OS and provided more accurate prognostic predication than neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein/albumin ratio17. Similarly, Jan et al. observed that SII is superior to NLR, PLR and monocyte-to-lymphocyte ratio (MLR) as a predictor of survival in patients with UTUC24. Besides, a high SII was associated with adverse characteristics such as lymphovascular invasion, positive lymph node and more aggressive phenotype, which is consistent with our findings.
Similarly, SII was also reported to be associated with survival outcomes in patients with RCC. Chrom et al. involved metastatic RCC (mRCC) patients treated with the tyrosine kinase inhibitor and found that high SII was an independent factor for inferior OS25. Besides, they found that the addition of the SII to the International Metastatic Renal Cell Carcinoma Consortium (IMDC) model in place of neutrophil and platelet counts increased the model’s prognostic performance. Lolli et al. also included patients with mRCC treated with sunitinib and observed SII was associated with the OS18. To be noted, the improvement of SII value at 6 weeks (from ≥730 to <730) was correlated to a better prognosis, as a possible effect of sunitinib on peripheral blood cells secondary to decline in inflammation process18. De Giorgi et al. suggested that SII appears superior to the NLR as a prognostic marker in mRCC patients treated with immune check-point inhibitors26. Furthermore, recently, a retrospective study of 176 RCC patients who underwent radical nephrectomy observed that high SII was associated with poor OS (P=0.034)27. SII is also associated with an increased TNM stage, which is similar to our results. However, no significant association was found for CSS(P=0.29). Although their study was limited by the small number of patients and the short duration of follow-up, it was valuable for exploring the prognostic value of SII in the non-metastatic RCC. To the best of our knowledge, there are no other studies focusing on the prognostic impact of SII in surgically treated non-metastatic RCC patients. There is no standard cut-off value of SII, and the cut-off value of SII differs from study to study. Hence, the multicenter study is required to identify standard cut-off value.
The potential mechanism for the prognostic significance of this combination might be explained by the functions of neutrophil, platelet, and lymphocyte. Neutrophils promote angiogenesis and inhibit anti-tumor immune system response, leading to tumor development9,12,28. Neutrophils also play an important role in the lymphangiogenesis29. Furthermore, neutrophils could secret circulating growth factors such as vascular endothelial growth factor, facilitating adhesion and tumor seeding29-30. Huang et al. Observed that neutrophilia is an independent predictor of recurrence in patients with RCC31. Besides, the intratumoral neutrophil is associated with poor prognosis in patients with localized and metastatic RCC32-33. Platelet could protect circulating tumor cells (CTCs) during circulation, induce CTC epithelial-mesenchymal transition, and facilitate the extraction of tumor cells, leading to the metastasis of tumor cells34. Moschini et al. revealed that the platelet count was associated with survival in patients with bladder carcinoma35. Yun et al. also found that decreased mean platelet volume was independently associated with RCC36. Lymphocyte plays an important role in anti-tumor immunity. Lymphocyte could induce cytotoxic cell death and inhibit tumor proliferation and migration by secreting cytokines, leading to a host immune response to malignancy8. A decreased lymphocyte count might result in the attenuation of immunological anti-tumor response. Lymphopenia was found to be associated with lower survival in patients with advanced bladder cancer and RCC37-38. Besides, higher tumor-infiltrating lymphocytes mean more strongly anti-tumor effect and better survival outcomes39. Therefore, the high SII, which reflects thrombocythemia, neutrophilia, or lymphopenia, suggests weak adaptive immune response in patients. All of these could cause more tumor cells to escape from the host immune system, lead to an increase in circulating growth factors and tumor cells, and finally facilitate the tumor invasion and metastasis. Based on the above-mentioned evidence, high SII could serve as an unfavorable factor in cancer patients. However, more large scale studies are required to verify our findings.
SII had significance in clinical practice. SII was calculated based on the neutrophil, platelet, and lymphocyte, which is convenient, easily obtained and commonly tested before the treatment. SII could predict the prognosis of patients, which could be used for risk stratification. It could provide physicians with useful information and guide the treatment, adjuvant therapy and follow-up for patients. However, non-tumor associated inflammation might cause the change of SII. Similarly, the patients with some sort of deficiencies might have more risk of change of SII. Therefore, we need to consider these conditions and might provide supportive treatments. Besides, the individual conditions should be considered during the treatment strategy decision.
Our study is not devoid of limitations. Firstly, the present study is a retrospective study with potential selection bias. To limit the influence of bias, propensity score matching was conducted to balance the baseline. Secondly, the data was extracted from single hospital, and the sample size is moderate. A multicenter study with a large scale is further required. Next, although we excluded the patients with the presence of inflammation, other unknown conditions may have existed which affected the neutrophils, lymphocytes, and platelets. Finally, there is no standard cut-off value of SII. Therefore, we determined the cut-off value based on our data. More studies are necessary to identify the optimal cut-off value.