In this study, we evaluated the prognostic value of several systemic inflammatory markers in patients with localized or locally advanced renal cell carcinoma. We showed a comprehensive comparison of eight different blood count-derived markers (NLR, PLR, LMR, NER, HPR, SIRI SII), which all stratified RCC patients according to CSS.
There is a growing number of studies focusing on the involvement of inflammatory markers in the clinical practice of individuals that developed RCC [4, 6, 7, 9, 14]. The available papers, however, emphasize the role of particular parameters (e.g. NLR, PLR, LMR) derived from peripheral blood counts, but direct comparisons between different markers are lacking. Recently, novel inflammatory indices such as systemic SIRI and SII were also reported as prognostic for RCC oncological outcomes [4, 15]. Furthermore, hematological parameters have a well-documented prognostic role in the setting of metastatic RCC, in which IMDC and MSKCC models are mainly used [16, 17].
In the present paper, we found that patients treated surgically for localized or locally advanced RCC, who presented preoperatively with higher NLR, PLR, SIRI, SII, NER, dNLR, and lower LMR and HPR, had a significantly worse CSS. Multivariate analysis showed that tumour stage, grade, age and inflammatory markers constituted independent factors predicting CSS. As the markers of systemic inflammatory response demonstrate a strong correlation between each other, we decided to create three alternative models using a single systemic inflammatory marker for each multivariate model. The model based on clinicopathologic features, which did not include any inflammatory markers was characterized by already high accuracy (C-index 0.877). Further addition of inflammatory indices provided more accurate prognostic information. The CSS predictive model with the highest accuracy included SIRI values and achieved a C-index of 0.903, while alternative multivariate models included SII and NLR and were characterized by C-index 0.902 and 0.890, respectively. Therefore, different inflammatory markers seem to provide the same prognostic information, as they show a strong correlation with each other (SIRI, SII and NLR) and their incorporation into the model results in similar accuracy increment.
A variety of papers pinpoint the observation that preoperative blood count-derived parameters reflecting the systemic inflammatory response can help in the estimation of the prognosis in patients with RCC [14, 18–21]. Here, we focused on the role of the markers of the well-established usefulness (NLR, dNLR, PLR, LMR) in the survival analysis, together with the new tools that are easily calculated from peripheral blood count (SII and SIRI), and, finally, the implementation of red blood cells lineage derivatives (HPR and NER). NLR seems to be the most extensively studied marker shown to be predictive for survival in RCC patients . A meta-analysis of 25 studies (24 retrospective, 1 prospective), including 6461 patients showed that pretreatment increased NLR is associated with worse OS in non-metastatic (localized) RCC (pooled HR = 1.90, p < 0.001) . In patients treated surgically for RCC plenty of studies revealed the association between NLR and adverse pathologic tumour features (advanced staging, grading, depth of invasion, the presence of metastasis, tumour size [6, 7]). In our analysis, higher values of inflammatory markers (NLR, SIRI and SII) were associated with more advanced stage and radical nephrectomy as for the surgery type. Higher SII was also related to higher grade and larger tumour diameter.
Cut-off values for the categorization of particular markers into elevated or decreased largely differ between studies. In cases of localized or locally advanced tumors, NLR above 3 was proven to be predictive of a higher risk of recurrence, shorter overall and progression-free survival and response to systemic treatment . In the paper by Elghiaty et al. patients with non-metastatic RCC up to 7 cm in diameter, who presented with higher MLR (cut-off value of 0.21), were at greater risk of recurrence and had worse CSS . Then, Hu et al. evaluated the prognostic significance of NLR (cut-off 2.78), dNLR (cut-off 2.05) and PLR (cut-off 185) in RCC cases treated with nephrectomy . Firstly, there was an association between poorer OS and increased values of NLR, dNLR and PLR. Secondly, only NLR was found to be an independent risk factor for shorter survival. On the contrary, Lucca et al. enrolled localized RCC cases and described MLR as potentially the best prognostic tool (when compared to NLR and PLR) that reflects the systemic inflammatory response and enables the estimation of disease-free survival . Conversely, another study proposed PLR as the most reliable marker for overall and cancer-specific survival prediction in patients with non-metastatic clear cell RCC, who underwent nephrectomy . To sum up, conflicting reports on the superiority of different inflammatory markers exist and none could be clearly chosen as of highest prognostic value yet.
Here, we grouped the parameters in the analysis of survival, so as to determine their value in the prognosis of OS, CSS and RFS. In the present paper, the Kaplan-Meier curves revealed that higher NLR (≥ 2.76), PLR (> 170), NER (> 0.95) and dNLR (> 1.8), and lower LMR (< 2.0) and HPR (≤ 0.53) were associated with worse CSS, while only elevated NLR from the markers mentioned above was found to be an independent factor for CSS in multivariate analysis. Similarly, high NLR (but not dNLR) and PLR and lower LMR were associated with OS, but none of the above-mentioned, well-known markers constituted an independent predictor of OS. We also observed associations between increased PLR and worse RFS, while no influence was observed in the case of NLR, dNLR and LMR.
There is still limited evidence on the prognostic value of the novel markers of systemic inflammation such as systemic inflammatory response index and systemic immune-inflammation index [4, 15, 25]. Interestingly, in our study the novel markers of systemic inflammation i.e. higher SIRI and SII, occurred to be associated with worse CSS and represented independent predictors of CSS, comparably to NLR. CSS prognostic models including SIRI and SII outperformed the model that based on staging, grading and age alone. Moreover, in the multivariate analysis these inflammatory markers were also significant predictors of OS but did not prove to be an independent tool for RFS estimations. This observation complies with the paper by Chen et al., in which the authors reported worse CSS and OS in individuals with elevated SIRI . Worth emphasizing is the fact that AUC for SIRI was far greater, when compared to NLR, PLR and MLR . Furthermore, in our study SII exhibited superior AUC compared to other markers (including SIRI) for all investigated outcomes. Another retrospective study reported that elevated SII is associated with OS and CSS in non-metastatic RCC even after propensity score matching but the authors did not provide data on other inflammatory markers that could be obtained simultaneously . A study by Ozbek et al. showed that high SII is prognostic for worse overall, but not disease-specific survival in patients treated with nephrectomy due to RCC .
Some other researchers used the term SIRI for additional calculations, incorporating hemoglobin values [26, 27]. In the recent paper by Mao et al., one outlined similar results: SIRI proved to be an independent prognostic risk factor for OS and CSS with greater impact on prognostic nomograms when compared to LMR and hemoglobin . In the current study, we also included hematological biomarkers derived from red blood cell lineage, i.e. HPR and NER. Among the potential mechanisms involved in the association between red blood cells and RCC, other authors listed e.g. anemia, systemic inflammation leading to iron deficiency or decrease in renal erythropoietin production . Here, elevated NER was related to shorter recurrence-free, cancer-specific and overall survival in univariate analysis. Moreover, NER proved to be an independent risk factor for shorter overall survival, together with age and tumour grade in multivariate analysis. Decreased HPR was associated with poorer OS and CSS in univariate analysis, as well. To the best of our knowledge, the prognostic values of HPR and NER in RCC were hardly studied, and only few studies were performed that were focused on red blood cell derivatives [28, 29]. Tang et al. described that low HPR (< 0.615) was associated with worse CSS, OS and PFS, but not RFS in bladder cancer patients . To the best of our knowledge, neutrophil to red blood cell ratio (called NER in our study) has not been investigated in renal cell cancer, but was shown to be associated with worse disease-free survival and OS in breast cancer patients . In our previous paper, we found that NER > 0.93 was a predictor of poorer oncological outcomes (BCG failure) in high-risk non-muscle invasive bladder cancer .
None of the studied inflammatory markers were independently associated with recurrence-free survival. Although higher SIRI, SII, NER, PLR and lower HPR were related to shorter time to reccurence, only tumour diameter and grade served as independent predictors for RFS in the multivariable model. This corresponds with the majority of prognostic scores, which rely solely on histopathologic (staging, grading, necrosis, tumour diameter) and clinical features (age, symptoms) . On the other hand, one of the meta-analysis reported the predictive value of elevated NLR for RFS/PFS in RCC (HR = 2.18) . Further studies investigating the role of inflammatory markers on the recurrence risk are warranted.
We are conscious of several limitations of our study that are listed below. It was a single-center retrospective analysis and selection bias could not be excluded. Some clinical data were not collected, and some other biomarkers easily obtained from peripheral blood count were not included e.g. lymphocyte to red blood cell ratio (LRR) . Furthermore, no data on the postoperative values to be used in the follow-up were collected. Local and distant RCC recurrences were not analyzed separately. Nevertheless, we managed to analyse in the relatively large contemporary cohort the impact of several markers of the inflammatory response, easy to adopt in the patients with RCC for clinical purposes.