Elevated neutrophil to lymphocyte and platelet to lymphocyte ratios predict high grade and advanced stage renal cell carcinoma

Abstract

Introduction:

Renal cell carcinoma is the most common malignancy of the kidney, which accounts 85% of all renal tumors. In recent years, the incidence of renal cell carcinoma was increased due to the widespread use of imaging techniques. The aim of this study is to investigate the clinical significance of pretreatment neutrophil to lymphocyte and platelet to lymphocyte ratios in patients with renal cell carcinomas.

Methods:

The patients who underwent nephrectomy for renal tumor between 2010 and 2018 in two centers were reviewed retrospectively. The age, sex, complete blood test, and pathological results were recorded. The patients who were diagnosed with other carcinomas, benign renal tumors, and missing data of age, complete blood test, and pathological results, were excluded. The patients were divided into two groups according to the T stage and Fuhrman grade, T1-2 and T3-4, G1-2 and G3-4.

Results:

There were 271 patients in the current study. The male to female ratio was 1.97 and the mean age of the patients was 59.37±11.62 years. Clear cell renal cell carcinoma was the most common subtype in 72.7% of the patients. Both the neutrophil to lymphocyte ratio and the platelet to lymphocyte ratio were significantly higher in patients with high-grade and advanced-stage disease than in the others. The receiver operating characteristic curve showed no significant difference between platelet to lymphocyte ratio and neutrophil to lymphocyte ratio to diagnose the high grade and stage of renal cell carcinoma.

Conclusion:

The neutrophil to lymphocyte and platelet to lymphocyte ratios are easily accessible biomarkers which are used for the prognosis of malignancy. The current study found that these biomarkers may predict the pathological results during the preoperative period.

Keywords

Neutrophil to lymphocyte ratio renal cell carcinoma platelet to lymphocyte ratio

Introduction

Kidney and renal pelvis cancers account for 3% of all adult tumors.¹ Renal cell carcinoma (RCC) is the seventh and ninth most common cancer in male and female patients, respectively.² RCC is predominantly seen in males and is diagnosed between 50 and 70 years of age.³ Studies have shown that inflammation plays an important role in the pathogenesis and progression of RCC,² and that neutrophils and platelets have a prominent role in the inflammation of tumors and immunology.⁴ Neutrophils can induce tumor growth and remodel the extracellular matrix for metastasis. In addition, reactive oxygen species, nitric oxide, and arginase are released by neutrophils. Tumor cells produce hematopoietic cytokines that increase the neutrophil levels. Platelets release a vascular endothelial growth factor, which is important in angiogenesis for tumor growth. Platelets may also protect cancer cells from the immune system and secrete thrombospondin to facilitate tumor adhesion and extravasation.⁵

The platelet to lymphocyte ratio (PLR) and the neutrophil to lymphocyte ratio (NLR) are useful biomarkers to predict survival in patients with malignant neoplasm.¹ These biomarkers have been found to be associated with the oncologic outcomes in some malignancies including colorectal, ovarian, testicular, and renal cell cancers.^6–9 In this study, I investigated the relationship between PLR, NLR, and the pathological results of the patients with RCC.

Materials and methods

The patients who underwent radical or partial nephrectomy for renal tumor between 2010 and 2018 in two centers; Haydarpaşa Numune Training and Research Hospital and Hitit University, Çorum Erol Olçok Training and Research Hospital, were reviewed retrospectively. The age, sex, complete blood test before surgery, and the pathological results were recorded. The PLR and the NLR were calculated by dividing the platelet count by the lymphocyte, and the neutrophil count by the lymphocyte count, respectively. Normal hematological reference values for neutrophils, platelets, and lymphocytes were 2–7, 100–300 and 1–4 *10⁹/l, respectively. Venous blood samples were taken by antecubital venipuncture containing ethylenediaminetetraacetic acid as an anticoagulant. A full blood count was measured as standard laboratory procedure using an LH780 automated cell counter (Beckman Coulter, Pasadena, CA, USA).

The patients who had a diagnosis of (a) benign renal tumor; (b) other kidney cancers such as squamous and transitional; (c) hematologic disease; (d) received anticoagulant drugs; and (e) active infection, were excluded from the study.

The surgical specimens were evaluated by genitourinary pathologists. The Fuhrman grade system, TNM classification (7th edition from American Joint Committee, 2017) and histologic subtype (World Health Organization, 2016) were used for pathological result. The patients were divided into two groups according to the low and high T-stage and Fuhrman grade, as T1-T2 and T3-T4, G1-2 and G3-4, respectively. The platelet to lymphocyte ratio and neutrophil to lymphocyte ratio were compared between T1-T2 and T3-T4, G1-G2 and G3-G4. The receiver operating characteristic (ROC) curves were analyzed to assess the diagnostic efficacy of PLR, NLR, platelet, neutrophil, and lymphocyte for advanced stage and high grade.

Distribution normality was analyzed with the Kolmogorov-Smirnov test. The normal distribution variable was compared with independent t test and the others were compared with Mann-Whitney U test. The chi-squared test was used for percentage values. Data were expressed as mean ± standard deviation for age, median for the others, and P < 0.05 as considered with statistical significance. Statistical analyses were performed using the demo version of MedCalc Statistical Software version 17.6 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2017).

Results

There were 271 patients in the study. Of these patients, 180 were male and 91 were female. The mean age of the patients was 59.37±11.62 years. Table 1 shows the characteristics and pathological results of the patients. The advanced stage (T3-T4) was reported in 64 patients (23.61%), and the Fuhrman grading system was reported in 258 patients: 48.83% had high grade (G3-G4). Table 2 shows the hematological parameters according to the grade and T stage classification. Both PLR and NLR were higher in patients with a more advanced stage and a higher grade than the others. The platelet was significantly higher in patients with T3-T4. The tumor size was correlated with T stage and Fuhrman grade.

Table 1.

The characteristics of the patients.

Number of patients (%)	271 (100)
Age, years	59.37±11.62
Gender
Male n, (%)	180 (66.42)
Female n, (%)	91 (33.58)
Histological subtype
Clear cell n, (%)	197 (72.7)
Chromophobe n, (%)	30 (11.07)
Papiller n, (%)	31 (11.44)
Unclassified n, (%)	9 (3.30)
Multilocular cystic renal neoplasm n, (%)	2 (0.73)
Renal medullary carcinoma n, (%)	1 (0.37)
Mucinous tubular and spindle cell carcinoma n, (%)	1 (0.37)
T Stage
T1-T2 n, (%)	207 (76.38)
T3-T4 n, (%)	64 (23.61)
Fuhrman Grade
G1-G2 n, (%)	132 (51.16)
G3-G4 n, (%)	126 (48.83)

Table 2.

The hematological parameters and patients’ characteristics according to the grade and T stage classification.

	T1-T2	T3-T4	P value	G1-G2	G3-G4	P value
Number of patients n, (%)	207 (76.38)	64 (23.61)		132 (51.16)	126 (48.83)
Male n, (%)	132 (63.76)	48 (75)	0.09	83 (62.87)	88 (69.84)	0.07
Female n, (%)	75 (36.23)	16 (25)		49 (37.12)	38 (30.15)
Age, years	58.66±12.24	61.67±9.03	0.07	56.83±12.29	62.03+9.60	<0.05
Tumor size, cm (median)	5	8	<0.05	5	6.5	<0.05
Neutrophil (median) *10⁶	4780	6360	<0.05	4740	5220	<0.05
Lymphocyte (median) *10⁶	2000	1615	<0.05	2100	1775	<0.05
Platelet (median) *10⁶	254,000	290,000	<0.05	261,500	260,000	0.84
NLR (median)	2.22	3.75	<0.05	2.2	2.69	<0.05
PLR (median)	122.22	197.61	<0.05	117.12	142.46	<0.05

NLR: neutrophil to lymphocyte ratio; PLR: platelet to lymphocyte ratio. The independent t test was used for the mean, the Mann-Whitney U test for the median, and the chi-squared test for percentage values.

The ROC analysis is shown in Figure 1. There was no significant difference between NLR and PLR to predict the stage and grade (P=0.07). The area under curve (AUC) was greater for PLR to predict the advanced stage than for the others. There was a significant difference between PLR and lymphocyte (P=0.001). The lymphocyte had the biggest AUC for advanced stage diagnosis (0.605), and a significant difference was detected between PLR and platelet (P=0.01). The AUC of the hematological parameters are seen in Table 3.

Figure 1.

The ROC of the parameters. ROC: receiver operating characteristic.

Table 3.

The AUC of the hematological parameters in advanced stage and high grade.

	Advanced T stage			High grade
	AUC	SE	95% CI	AUC	SE	95% CI
Lymphocyte	0.631	0.0420	0.570 to 0.688	0.572	0.0360	0.509 to 0.633
Neutrophil	0.633	0.0409	0.573 to 0.691	0.605	0.0353	0.542 to 0.665
Platelet	0.635	0.0411	0.574 to 0.692	0.507	0.0364	0.444 to 0.570
NLR	0.668	0.0418	0.608 to 0.723	0.595	0.0358	0.533 to 0.656
PLR	0.718	0.0372	0.660 to 0.771	0.598	0.0356	0.536 to 0.659

	Advanced T stage	High grade
	P value	P value
Lymphocyte-neutrophil	0.96	0.49
Lymphocyte-platelet	0.95	0.07
Lymphocyte-NLR	0.23	0.75
Lymphocyte-PLR	0.001*	0.79
Neutrophil-platelet	0.97	0.13
Neutrophil-NLR	0.24	0.34
Neutrophil-PLR	0.05	0.52
Platelet-NLR	0.55	0.06
Platelet-PLR	0.05	0.01*
PLR-NLR	0.07	0.92

AUC: area under curve; NLR: neutrophil to lymphocyte ratio; PLR: platelet to lymphocyte ratio; SE: standard error.

Significant difference: lymphocyte and PLR for T stage, platelet, and PLR for High grade.

Discussion

The incidence of RCC has increased in the last three decades.¹⁰ The widespread use of radiologic imaging techniques may be one of the reasons for this increase.¹¹ The other factors are environmental exposures, smoking, obesity, and changes in lifestyle. Surgery is the gold standard treatment for patients with localized disease, but 10%–60% of the patients develop recurrence after surgery.¹⁰ Although several prognostic factors have been reported for RCC, the stage and grade are the most important factors.¹¹

In the pathophysiology of the cancer-associated systemic inflammation, the distribution of circulating inflammatory cells changes.¹² The main change is neutrophilia with relative lymphocytopenia or thrombocytosis. Neutrophils secrete some cytokines including tumor necrosis factor (TNF), interleukin 1 (IL-1), IL-6, and vascular endothelial growth factor (VEGF), which is a proangiogenic factor.¹⁰ They also release reactive oxygen species, nitric oxide, and arginase.⁴ The neutrophils promote tumor growth and metastasis by remodeling the extracellular matrix and suppressing the T-cell response. Additionally, tumor cells produce immunosuppressive cytokines, which decrease the cytotoxic T lymphocytes.¹³ As a result, the decreased lymphocyte count causes suboptimal defense in the lymphocyte-mediated immune system against cancer. The platelets have a prominent role in cancer progression. They promote tumor growth and angiogenesis by VEGF cytokine.⁴ VEGF induces the formation of blood vessels and facilitates metastasis.¹⁴ Solid tumors produce IL-6, which contributes to the thrombocytosis. The IL-6 stimulates thrombopoietin that increases the platelet count in patients with malignancy.¹⁵ The other cytokines are IL-11, stem cell factor, and granulocyte-macrophage colony-stimulating factor.¹⁶

Some prognostic factors, such as NLR and PLR, which came from the blood cells, have been defined as valuable biomarkers to predict the prognosis in solid tumors.¹⁷ These biomarkers are cheap and easily acquired when compared with other markers such as C-reactive protein.¹⁸ The authors investigated the NLR in patients with metastatic RCC and found NLR>4 was independently associated with overall survival.¹⁹ The other study showed that high NLR (⩾1.7) was correlated both worse overall and disease-free survival in non-metastatic RCC.²⁰ In addition, the authors found that preoperative NLR was associated with increased risk of death and all-cause mortality in patients with localized clear cell RCC.¹⁰ Most of the studies about NLR and RCC are about the prognosis, the clinical diagnosis and importance is limited in the literature. Otunctemur et al.³ reported that NLR was higher in patients with advanced stage and high grade (T3-4, G3-4) than the others. The authors found similar results; NLR value was significantly higher in patients with advanced disease and high grade of RCC.²¹ The current study showed that NLR was significantly higher in patients with advanced stage and high-grade disease (P<0.05).

In a meta-analysis; the authors reported that elevated PLR was associated with poor overall survival and disease-free survival in renal cancer.¹⁸ The other meta-analysis indicated that elevated PLR is an independent predictor of poor overall survival and progression-free survival in RCC.¹⁷ Baum et al. found that elevated PLR was associated with short survival.²² Dirikan et al., from Turkey, revealed that patients diagnosed with metastatic RCC with high PLR had shorter overall survival than the others without significant difference.²³ In another study from the UK, the investigators found that high PLR was associated with high grade (G3), high T stage (T2+), and large tumor size (⩾3 cm).¹² The authors reported that elevated PLR was associated with high grade (G3-4) and advanced T stage (T3-4) of RCC.²¹ In addition, PLR was found to be significantly increased in the advanced stage (III-IV) of ovarian cancer.⁵ The current study showed that elevated PLR was associated with high grade and advanced stage disease (P<0.05).

There are some limitations in the current study. The retrospective design, which is associated with selection bias and incomplete data collection, is the main limitation. Also, overall survival and cancer-specific survival was not evaluated. These limitations include a relatively large series of RCCs from Turkey regarding the clinical significance of PLR and NLR for the pathology of RCC.

In conclusion, the neutrophil to lymphocyte ratio and the platelet to lymphocyte ratio may predict the pathological outcome for patients with RCCs. Further studies are needed to understand the role of these ratios in the pathology of RCCs.

Footnotes

Authors’ Note

Selahattin Çalışkan is now affiliated with Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey.

Declaration of conflicting interest

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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