|Ahead of print publication
Preoperative neutrophil–lymphocyte ratio/platelet–lymphocyte ratio: A potential and economical marker for renal cell carcinoma
Deepika Chandrasekaran1, Sandhya Sundaram2, K Maheshkumar3, N Kathiresan4, R Padmavathi1
1 Department of Physiology, Sri Ramachandra Institute of Higher Education and Research, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India
2 Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India
3 Department of Physiology and Biochemistry, Government Yoga and Naturopathy Medical College and Hospital, Chennai, Tamil Nadu, India
4 Department of Surgical Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India
|Date of Submission||17-Apr-2020|
|Date of Decision||10-May-2020|
|Date of Acceptance||31-Aug-2020|
|Date of Web Publication||03-Aug-2021|
Department of Physiology, Sri Ramachandra Institute of Higher Education and Research, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Emerging evidences have elucidated the crucial role of inflammation in carcinogenesis and tumor progression. In the recent years, many inflammatory biomarkers showed promising prognostic factors in renal cell carcinoma (RCC). We intended to evaluate the significance of one such inflammatory factor which is potential, noninvasive, simple, as well as economical. The preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in RCC patients have shown favorable results.
Objective: The objective was to assess the prognostic role of NLR/PLR in the advanced stage and high-grade RCC.
Subjects and Methods: This is a retrospective study. Ethical clearance was obtained from the institute ethics committee. One hundred and fifty histopathologically proven RCC cases during the period of January 2010–September 2018 were chosen from the pathology department and corresponding blood reports were obtained from the medical records department. We divided the cases based on their staging and grading. NLR/PLR values were calculated using formulas.
Statistical Analysis: Statistical analysis was done using R software. Data were expressed as mean ± standard deviation, median, and percentage. Independent t-test, Mann–Whitney test, and Chi-square test were used. P < 0.05 was considered statistically significant. The receiver operating characteristic curve (ROC) was plotted to assess the sensitivity of NLR/PLR.
Results: The elevated NLR/PLR values showed a significant relation with high-grade and advanced stage RCC. The ROC curve proved the accuracy of NLR/PLR in the advanced stage and high-grade RCC.
Limitations: A multicentric, prospective study can be planned in the future. Follow-up studies are needed to assess their prognostic role.
Conclusion: NLR/PLR values can become part of routine investigations for all RCC patients. The values may help to estimate pathological outcomes, chance of recovery, recurrence, and survival rates.
Keywords: Biomarker, inflammation, neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, renal cell carcinoma
|How to cite this URL:|
Chandrasekaran D, Sundaram S, Maheshkumar K, Kathiresan N, Padmavathi R. Preoperative neutrophil–lymphocyte ratio/platelet–lymphocyte ratio: A potential and economical marker for renal cell carcinoma. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322906
| > Introduction|| |
Renal cell carcinoma (RCC) is the most common kidney cancer comprising 2%–3% of all adult tumors. It is the sixth most often diagnosed cancer in men and tenth in women. Most cases are diagnosed at the stage of metastasis and the rest develop metastasis after surgery. The GLOBOCAN 2018 data showed the age-standardized rate of kidney cancers in the USA, as 10/100,000/year and mortality 2.3/100,000/year. In European countries, the incidence is 9/100,000/year and mortality is 3/100,000/year. In India, the incidence is increasing at a high rate of around 1/100,000/year and mortality 0.8/100,000/year. Nephrectomy is the only treatment of choice for most RCC as they are resistant to both chemo- and radiotherapy. Many recent studies are going in the field of immunotherapy. The immune system is known to play a rational role in abolishing the malignancy, but the cancer cells develop multiple mechanisms to suppress the immunity and thereby prevent the antitumor response., Inflammation in cancer occurs as a result of the production of immune and nonimmune cells and the molecules secreted by them such as cytokines and chemokines. These attract numerous neutrophils, dendritic cells, macrophages, mast cells, and lymphocytes. Accumulation of inflammatory molecules for a long period causes immunosuppression linked to tumorigenesis.,, This increases the production of reactive oxygen species which in the long term may lead to gene alterations. Thus, inflammation plays a major role in cancer progression. These changes within the body create neutrophilia, thrombocytosis, and lymphocytopenia. Thus, elevated neutrophils create a suitable tumor microenvironment, platelets promote tumor cell adhesion to vascular endothelium and interact with cancer cells through its ligands, and reduced lymphocytes lead to immunosuppression., Hence, the neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) can become potential factors to predict the inflammatory state within the cancer cell. Few studies have analyzed the role of inflammatory markers in various cancers, however its potential and prognostic value in RCC patients are yet to be explored. Hence, in the present study, we aimed to assess the role of NLR/PLR as a prognostic biological marker for advanced stage and high-grade RCC.
| > Subjects and Methods|| |
This retrospective study was conducted after getting the ethical clearance and needed permissions from our institution. Initially, all RCC patients who underwent nephrectomy in our hospital during the period of January 2010–September 2018 were selected. The benign cases were excluded and 150 histopathologically proven RCC cases were included for the study. Complete blood count analysis reports of the study group were obtained from the medical records department. Then, the NLR and PLR values were calculated using the formula: absolute neutrophil count divided by absolute lymphocyte count and platelet count divided by absolute lymphocyte count. Elevated neutrophil and platelet cell counts indicated an inflammatory state which could be a factor favoring tumor progression. The WHO-ISUP grading and tumor, node, metastasis (TNM) staging were done to group the study population as early stage I–II, advanced stage III–IV and low grade I–II, high Grade III–IV.
R software was used for statistical analysis (R Foundation for Statistical Computing, Vienna, Austria). Data were expressed as mean ± standard deviation, median, and percentage. The normal distribution variables were compared using independent t-test, the median variable compared using Mann–Whitney test, and the percentage variables using Chi-square test. P < 0.05 was considered as statistically significant. The receiver operating characteristic curve (ROC) for assessing the sensitivity of NLR/PLR factors as a potential marker for advanced stage and high-grade RCC was analyzed.
| > Results|| |
The study included 150 patients, among which 111 were male and 39 were female. Their mean age in years was 54 ± 12.43. [Table 1] shows the baseline parameters of the study population to be analyzed. The most common type of RCC is the clear cell subtype of RCC. Our study included 109 cases of clear cell renal cell carcinomas and the other subtypes were papillary (14 cases), chromophobe (22 cases), collecting duct (1 case), and sarcomatoid type (4 cases). The median tumor size was 6.5 cm. The TNM Stages III and IV (29.3%) were considered as advanced and Stages I and II (70.7%) as early stage. High-grade cases included WHO-ISUP Grades III and IV (22%) and low grade includes Grades I and II (78%). In [Figure 1], PLR values showed significantly (P < 0.001) higher in the advanced stage (median: 160.02) compared to the early stage (120.17). PLR values also showed greater values in the high-grade (median: 151.06) cases compared to low grade (126.45). In [Figure 2], NLR values also elevated in the advanced stage (median: 2.7) and high-grade (2.55) cases compared to the early stage (median: 1.79) and low grade (1.93). The association between the inflammatory factors and the high-grade RCC (Grades III and IV) also proved to be significant (P = 0.001). Hence, the elevated values of NLR/PLR and their significant association with advanced RCC showed their potential role in assessing the prognosis of RCC. [Figure 3] shows the ROC analysis for advanced stage, followed by ROC analysis for high grade. The NLR and PLR were found to be potential markers for both advanced stage and high-grade RCC. Among the ROC curves, advanced stage NLR (area under the curve [AUC] = 0.94, confidence interval [CI] = 0.89–0.96) and PLR (AUC = 0.94, CI = 0.89–0.99) association was more sensitive than the high-grade NLR (AUC = 0.79, CI = 0.70–0.88 and PLR (AUC = 0.78, CI = 0.696–0.868). Hence, elevated NLR and PLR can become a worthy marker for RCC. The AUC was more for PLR to predict the advanced stage.
|Figure 1: PLR-platelet–lymphocyte ratio; early stage (Stages I and II), advanced stage (Stages III and IV), low grade (Grades I and II), high grade (Grades III and IV). Statistical analysis was done using the Mann–Whitney test. P < 0.05 was considered as statistically significant|
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|Figure 2: NLR-neutrophil–lymphocyte ratio; early stage (Stages I and II), advanced stage (Stages III and IV), low grade (Grades I and II), high grade (Grades III and IV). Statistical analysis was done using the Mann–Whitney test. P < 0.05 was considered as statistically significant|
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|Figure 3: Receiver operating characteristic curve analysis for advanced stage and high grade among the patients with renal cell carcinoma. Advanced stage NLR (area under the curve = 0.94, confidence interval = 0.89–0.96) and PLR (area under the curve = 0.94, confidence interval = 0.89–0.99). High-grade NLR (area under the curve = 0.79, confidence interval = 0.70–0.88 and PLR (area under the curve = 0.78, confidence interval = 0.696–0.868)|
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| > Discussion|| |
The present study was conducted among 150 histopathologically proven RCC cases. The preoperative NLR and PLR were calculated from their blood analysis report. Elevated NLR/PLR values were noted in case of advanced stage (median NLR – 2.7, median PLR – 160.02) and high-grade RCC (median NLR – 2.55, median PLR – 151.06). These values indicate the immune-suppressed nature in these patients and might be less responding to immunotherapy. The prognostic systems validated for RCC were UCLA integrated staging score and Memorial Sloan Kettering Cancer Centre score for metastatic RCC. These included Eastern Cooperative Oncology Group, calcium, hemoglobin, neutrophils, Fuhrman grading, and tumor size. The simple and cost-effective parameter with potential value, the NLR/PLR was never included in these scores. NLR/PLR reflects the activity of the immune system. Several studies have shown the key role of inflammation in tumorigenesis. Cancer-related inflammation creates a local immune response which is the hallmark for malignant tumors. Chronic inflammation favored tumor development by preventing/suppressing the immune response. This underlying inflammation is the root cause of recurrence and metastasis in most RCCs. Inflammatory parameters such as NLR and PLR have been shown to predict the prognosis of various cancers, including RCC. Our study has shown that preoperative NLR and PLR have an independent power to predict advanced RCC patients. Ohno et al., 2010, were the first to assess the vigorous changes in NLR values by analyzing postoperative NLR in nonmetastatic clear cell RCC patients. High levels of neutrophils promote the proliferation, invasion, and metastasis of cancer cells and also develop resistance to targeted therapies.,, The immune response to carcinogenic cell depends mainly on the number of lymphocytes, which can promptly diminish the inflammation. The associated lymphocytopenia lowers the CD4+ T-cells, thereby impairing the cancer immune surveillance. The immune response for stress changes the neutrophil and lymphocyte counts, but the NLR could be even more effective factor in carcinoma patients.,, Otunctemur et al., 2016, analyzed the effects of NLR to be elevated in advanced stage and high-grade tumors, which is very similar to our study results. Dirican et al., 2013, from Turkey found that metastatic RCC patients with elevated PLR had short overall survival. Another study from the UK expressed the association between PLR and high-grade, advanced stage, large tumor size in RCC patients. A meta-analysis done by Wang et al., 2017, suggested the role of PLR as an independent biomarker for predicting overall survival and progression-free survival in RCC. According to Orellana et al., 2015, platelets and ovarian tumor cells were cultivated together and they identified that the platelets assisted the tumor growth and metastasis. Thus, obstructing the platelet receptors delayed the metastasis. NLR/PLR has gained prognostic value in gastric cancer, hepatocellular cancer, breast cancer, and pancreatic cancer. The importance of lymphocytes has been highlighted in several studies in the recent years. The tumor-infiltrating lymphocytes like CD8 have been associated with improved response to targeted therapies and show a better prognosis in most cancer patients.,, The present study showed that elevated NLR and PLR values were associated with advanced stage and high grade similar to the study conducted by Çalışkan S et al., 2019. As the NLR/PLR ratios get elevated, the pathological outcomes become poorer in these patients. A multicentric, prospective study can be planned in the future. Follow-up studies are needed to assess the prognostic role of NLR/PLR.
| > Conclusion|| |
Emerging evidences indicated the role of inflammation in the development and progression of RCC. The cost-effectiveness and easy availability of NLR/PLR assessments in all primary hospitals can make it a part of the routine investigations done to predict the recurrence, progression, and survival in RCC patients, regardless of targeted interventions, stage, grade, and histological subtype of tumor.
We thank the management of Sri Ramachandra Institute of Higher Education and Research for providing the facilities to carry out our research successfully. The research was supported by the Indian Council of Medical Research – Talent Search Scheme Fellowship. We are thankful to our patients and our colleagues who provided expertise that greatly assisted the research.
Financial support and sponsorship
This study was financially supported by the Indian Council of Medical Research – Talent Search Schemes.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]