Renal cell carcinoma (RCC) accounts for 3-4% of all adult malignancies, and its incidence rate has been steadily increasing worldwide [
Inflammation has an impact on tumorigenesis and tumor progression [
Of the many hematological and biochemical markers for systemic inflammatory response, neutrophil-to-lymphocyte ratio (NLR) has been introduced relatively recently [
Multiple studies suggested that NLR might be a prognostic factor in mRCC, irrespective of the treatment method [
Main characteristics of recently published studies on prognostic value of neutrophil-to-lymphocyte ratio in patients with nonmetastatic renal cell carcinoma.
Study cohort | Study cases | Histologic subtype | TNM stage | NLR | ||||
---|---|---|---|---|---|---|---|---|
Value | Cut-off | Prognostic significanc | Adjustment variables | |||||
RFS# | CSS | |||||||
Lucca et al. [ | 430 | Clear cell | T1–3 | Median 2.9 | 4.2 | Yes | NA | Stage, grade, tumor size, necrosis |
Pichler et al. [ | 678 | Clear cell | T1–4 | Mean 3.51 | 3.3 | No | No | Age, gender, stage, grade, necrosis |
Viers et al. [ | 827 | Clear cell | M0 | Median 3.51 | 4.0 | No | Yes | Age, gender, ECOG PS, tumor size, Sx, stage, grade, necrosis |
Huang et al. [ | 218 | Papillary | T1–3Nx | Median 3.1 | 3.6 | Yes | NA | Age, gender, Sx, DM, HTN, stage, node, TNM group, grade, necrosis, ANC, ALC |
De Martino et al. [ | 281 | Papillary and chromophobe | T1–3Nx | Median 2.6 | 3.6 | Yes | NA | Age, gender, ECOG PS, stage, TNM group, grade, MVI, ANC, ALC |
Wen et al. [ | 327 | All | T1–4 | Mean 2.72 | 1.7 | Yes | NA | Age, gender, tumor size, stage, subtype |
Forget et al. [ | 227 | All | M0 | Median 3.01 | 5.0 | Yes | NA | Age, gender, stage, grade, node |
Jagdev et al. [ | 228 | 3 major subtypes | M0 | NA | NA | No | NA | NA |
Present study | 1,284 | 3 major subtypes | T1–4 | Mean 2.2 | 3.7 | Yes | Yes | Age, gender, BMI, ECOG PS, Sx, tumor size, stage, grade, subtype, sarcomatoid differentiation, necrosis |
#RFS stands for disease-free, progression-free, and metastasis-free survival as well as recurrence-free survival.
TNM, tumor-node-metastasis; NLR, neutrophil-to-lymphocyte ratio; RFS, recurrence-free survival; CSS, cancer-specific survival; necrosis, tumor necrosis; NA, not available; ECOG PS, Eastern Cooperative Oncology Group performance status; MVI, microvascular invasion; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; Sx, symptoms at presentation; DM, diabetes mellitus; HTN, hypertension.
We assessed the prognostic significance of NLR in a large, multicenter cohort of non-mRCC patients. To our knowledge, this is the largest scale study conducted in the field, which also included the most widely accepted prognostic factors.
Approval for the study was obtained from the relevant institutional ethics committee. A total of 3,410 patients with RCC underwent curative partial or radical nephrectomy at six institutions between 2000 and 2014. We consecutively excluded 239 patients with lymph node and/or distant metastasis immediately after surgery, 574 patients who did not have any of the three major RCC subtypes (clear cell, papillary, and chromophobe variants), 351 patients with postoperative follow-up durations within 3 months, and 962 patients with unavailable data on at least one of the relevant parameters. Only patients with complete absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) data within the 2 weeks before surgery were included in the study. Finally, 1,284 non-mRCC patients (pathologically, TxN0M0) from any of the three major RCC subtypes were included in this study and retrospectively reviewed.
The characteristics of RCC and patients are detailed in Table
Association of different clinical and pathological characteristics with neutrophil-to-lymphocyte ratio in patients with nonmetastatic renal cell carcinoma.
Variable | All | Low NLR | High NLR | |
---|---|---|---|---|
Number of subjects | 1,284 | 1,168 | 116 | |
NLR, mean ± SD | | | | <0.00 |
Age, mean ± SD, year | | | | 0.00 |
Gender | 0.23 | |||
Male, | 913 (71.1) | 825 (70.6) | 88 (75.9) | |
Female, | 371 (28.9) | 343 (29.4) | 28 (24.1) | |
BMI, mean ± SD, kg/m2 | | | | 0.00 |
ECOG PS ≥ 1, | 180 (14.0) | 148 (12.7) | 32 (27.6) | <0.00 |
Symptoms at presentation | 0.00 | |||
No symptom, | 975 (75.9) | 900 (77.1) | 75 (64.7) | |
Symptom, | 309 (24.1) | 268 (22.9) | 41 (35.3) | |
Tumor size | ||||
(1) mean ± SD, cm | | | | <0.00 |
(2) Category | <0.00 | |||
<4 cm, | 748 (58.3) | 701 (60.0) | 47 (40.5) | |
4–7 cm, | 351 (27.3) | 321 (27.5) | 30 (25.9) | |
≥7 cm, | 185 (14.4) | 146 (12.5) | 39 (33.6) | |
Side | 1.00 | |||
Unilateral, | 1,268 (98.8) | 1,153 (98.7) | 115 (99.1) | |
Bilateral, | 16 (1.2) | 15 (1.3) | 1 (0.9) | |
Type of nephrectomy | <0.00 | |||
Radical, | 634 (49.4) | 552 (47.3) | 82 (70.7) | |
Partial, | 650 (50.6) | 616 (52.7) | 34 (29.3) | |
Method of surgery | 0.04 | |||
Open, | 697 (54.3) | 628 (53.8) | 69 (59.5) | |
Laparoscopic, | 316 (24.6) | 283 (24.2) | 33 (28.4) | |
Robot, | 271 (21.1) | 257 (22.0) | 14 (12.1) | |
T stage | <0.00 | |||
T1, | 1,016 (79.1) | 945 (80.9) | 71 (61.2) | |
T2, | 89 (6.9) | 75 (6.4) | 14 (12.1) | |
T3-4, | 179 (13.9) | 148 (12.7) | 31 (26.7) | |
Fuhrman’s grade | 0.56 | |||
G1-2, | 664 (51.7) | 607 (52.0) | 57 (49.1) | |
G3-4, | 620 (48.3) | 561 (48.0) | 59 (50.9) | |
Histologic subtype | 0.04 | |||
Clear cell, | 1,114 (86.8) | 1,017 (87.1) | 97 (83.6) | |
Papillary, | 87 (6.8) | 73 (6.3) | 14 (12.1) | |
Chromophobe, | 83 (6.5) | 78 (6.7) | 5 (4.3) | |
Sarcomatoid differentiation, yes, | 29 (2.3) | 22 (1.9) | 7 (6.0) | 0.00 |
Tumor necrosis, yes, | 208 (16.2) | 174 (14.9) | 34 (29.3) | <0.00 |
Recurrence, | 142 (11.1) | 114 (9.8) | 28 (24.1) | <0.00 |
RCC-specific death, | 56 (4.4) | 40 (3.4) | 16 (13.8) | <0.00 |
NLR, neutrophil-to-lymphocyte ratio; low NLR, <3.7; high NLR, ≥3.7; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; RCC, renal cell carcinoma;
For most patients, postoperative follow-up was scheduled every 3 months for 6 months, every 6 months for the next 3 years, and yearly thereafter. NLR was defined as the ANC divided by the ALC. The general health status was determined by the Eastern Cooperative Oncology Group performance status (ECOG PS). Tumor size was measured as the greatest diameter of the pathologic specimen. Pathologic staging was performed using the 2002 tumor-node-metastasis (TNM) classification system, and grading was performed using Fuhrman nuclear grading system. The histologic subtype was determined using the 2004 World Health Organization (WHO) international histological classification of tumors. For all specimens, urologic pathologists of each institution determined the pathologic features of the tumor. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were calculated from the date of surgery to the date of recurrence and RCC-specific death, respectively, and were confirmed by imaging studies.
The primary endpoints were RFS and CSS. The ideal cut-off level of NLR was estimated by testing all possible cut-off levels that were likely to discriminate between survival and recurrence and RCC-specific death, using the Cox proportional hazard model. The ideal cut-off level determined was then rounded to clinically relevant levels [
The RFS and CSS rates were calculated using the Kaplan-Meier method stratified by NLR, and the log-rank test was used to compare the groups. The prognostic significance of NLR as a continuous and categorical variable was evaluated using variables entered into the Cox proportional hazards model. The variables analyzed included patient age, gender, body mass index (BMI), ECOG PS, symptoms at presentation, tumor size, pathologic T stage, Fuhrman grade, histologic subtype, sarcomatoid differentiation, and tumor necrosis. The accuracy of NLR in predicting RFS and CSS was reflected by Harrell concordance index (c-index) calculated using the Cox proportional hazard models with and without the incorporation of NLR.
All tests were two-sided, and
A cut-off NLR level of 3.7 was estimated to be the optimal cut-off level for discriminating between patients’ recurrences (hazard ratio (HR) = 3.049, 95% confidence interval (CI) = 2.015–4.614, and
The mean follow-up period was 46.8 months for all patients (median 39 months; interquartile range, 19–69 months). The mean NLRs of patients with low and high NLR were
During follow-up, 142 (11.1%) patients had recurrence (Table
Kaplan-Meier curve for recurrence-free survival (a) and cancer-specific survival (b) for patients with nonmetastatic renal cell carcinoma according to neutrophil-to-lymphocyte ratio. NLR, neutrophil-to-lymphocyte ratio.
Multivariate analysis identified NLR to be an independent predictor of RFS (HR of NLR as a continuous variable = 1.081,
Multivariate analyses predicting probability of cancer recurrence in relation to the neutrophil-to-lymphocyte ratio in patients with nonmetastatic renal cell carcinoma.
Variables | NLR as a continuous variable | NLR as a categorical variable | ||||
---|---|---|---|---|---|---|
HR | 95% CI | | HR | 95% CI | | |
Age | 1.011 | 0.997–1.025 | 0.134 | 1.011 | 0.997–1.026 | 0.123 |
Gender | ||||||
Female versus male | 0.873 | 0.588–1.296 | 0.502 | 0.876 | 0.591–1.299 | 0.510 |
BMI | 0.959 | 0.907–1.015 | 0.146 | 0.959 | 0.907–1.014 | 0.146 |
ECOG PS | ||||||
≥1 versus 0 | 1.936 | 1.270–2.950 | 0.002 | 1.900 | 1.244–2.902 | 0.003 |
Symptoms at presentation | 1.185 | 0.811–1.731 | 0.380 | 1.208 | 0.830–1.758 | 0.325 |
Tumor size | 1.011 | 1.005–1.017 | 0.001 | 1.011 | 1.004–1.017 | 0.001 |
T stage | 0.009 | 0.010 | ||||
T2 versus T1 | 1.384 | 0.745–2.571 | 0.303 | 1.376 | 0.743–2.550 | 0.310 |
T3-4 versus T1 | 2.068 | 1.281–3.340 | 0.003 | 2.050 | 1.267–3.314 | 0.003 |
Fuhrman’s grade | ||||||
G3-4 versus G1-2 | 1.974 | 1.352–2.882 | <0.001 | 1.958 | 1.340–2.863 | 0.001 |
Histologic subtype | 0.012 | 0.019 | ||||
pRCC versus cRCC | 1.044 | 0.582–1.872 | 0.886 | 1.029 | 0.575–1.841 | 0.924 |
chRCC versus cRCC | 0.104 | 0.023–0.467 | 0.003 | 0.132 | 0.032–0.545 | 0.005 |
Sarcomatoid differentiation | 2.095 | 1.061–4.137 | 0.033 | 2.004 | 1.010–3.977 | 0.047 |
Tumor necrosis | 1.255 | 0.817–1.927 | 0.300 | 1.265 | 0.825–1.939 | 0.282 |
NLR | ||||||
(1) Continuous | 1.081 | 1.009–1.160 | 0.028 | |||
(2) High versus low NLR | 1.788 | 1.153–2.771 | 0.009 |
NLR, neutrophil-to-lymphocyte ratio; low NLR, <3.7; high NLR, ≥3.7; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; cRCC, clear cell renal cell carcinoma; pRCC, papillary renal cell carcinoma; chRCC, chromophobe renal cell carcinoma; HR, hazard ratio; CI, confidence interval.
During follow-up, 56 (4.4%) patients died of RCC-related causes (Table
Multivariate analysis identified NLR to be an independent predictor of CSS (HR of NLR as a continuous variable = 1.156,
Multivariate analyses predicting probability of cancer-specific death in relation to the neutrophil-to-lymphocyte ratio in patients with nonmetastatic renal cell carcinoma.
Variables | NLR as a continuous variable | NLR as a categorical variable | ||||
---|---|---|---|---|---|---|
HR | 95% CI | | HR | 95% CI | | |
Age | 1.042 | 1.016–1.069 | 0.002 | 1.044 | 1.018–1.072 | 0.001 |
Gender | ||||||
Female versus male | 0.652 | 0.324–1.313 | 0.231 | 0.648 | 0.323–1.300 | 0.222 |
BMI | 0.916 | 0.832–1.009 | 0.074 | 0.924 | 0.840–1.017 | 0.105 |
ECOG PS | ||||||
≥1 versus 0 | 2.820 | 1.498–5.309 | 0.001 | 2.672 | 1.408–5.071 | 0.003 |
Symptoms at presentation | 1.029 | 0.558–1.897 | 0.927 | 1.056 | 0.577–1.932 | 0.860 |
Tumor size | 1.012 | 1.002–1.022 | 0.015 | 1.012 | 1.002–1.022 | 0.018 |
T stage | 0.022 | 0.020 | ||||
T2 versus T1 | 0.665 | 0.198–2.233 | 0.509 | 0.662 | 0.198–2.215 | 0.503 |
T3-4 versus T1 | 2.175 | 1.025–4.617 | 0.043 | 2.209 | 1.041–4.688 | 0.039 |
Fuhrman’s grade | ||||||
G3-4 versus G1-2 | 2.155 | 1.141–4.072 | 0.018 | 2.101 | 1.110–3.977 | 0.023 |
Histologic subtype | 0.854 | 0.860 | ||||
pRCC versus cRCC | 1.268 | 0.551–2.919 | 0.576 | 1.257 | 0.554–2.850 | 0.584 |
chRCC versus cRCC | 0.001 | <0.001–5.496 | 0.959 | 0.001 | <0.001–6.687 | 0.962 |
Sarcomatoid differentiation | 3.355 | 1.230–9.148 | 0.018 | 3.092 | 1.123–8.514 | 0.029 |
Tumor necrosis | 1.054 | 0.509–2.181 | 0.888 | 1.097 | 0.537–2.242 | 0.799 |
NLR | ||||||
(1) Continuous | 1.156 | 1.037–1.289 | 0.009 | |||
(2) High versus low NLR | 2.566 | 1.348–4.887 | 0.004 |
NLR, neutrophil-to-lymphocyte ratio; low NLR, <3.7; high NLR, ≥3.7; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; cRCC, clear cell renal cell carcinoma; pRCC, papillary renal cell carcinoma; chRCC, chromophobe renal cell carcinoma; HR, hazard ratio; CI, confidence interval.
In this study, NLR was identified to be a significant prognostic factor of both RFS and CSS in patients with non-mRCC, even when the models were adjusted for other well-known prognostic factors. The predictive accuracy of the multivariate models for RFS and CSS increased by 2.2% and 4.2%, respectively, with NLR inclusion.
The present study had several strengths, compared to the previous studies in the field (Table
In terms of clinical and pathologic characteristics at diagnosis, patients with high NLR differed significantly from those with low NLR in various parameters. Patients with high NLR had a larger tumor, a higher T stage, worse ECOG PS, worse symptoms, sarcomatoid differentiation, and tumor necrosis. These results are similar to those reported in previous studies [
NLR was shown to be a possible prognostic factor for mRCC in multiple studies, irrespective of the treatment method [
An important point is that most of the previous studies incorporated NLR as a categorical variable in their models. The use of a continuous variable reflects an intrinsic effect, whereas that of a categorical variable seems to adjust itself and to be created [
It is well known that inflammation affects tumorigenesis and progression [
In contrast to our findings, some studies did not show a relationship between NLR and non-mRCC prognosis [
This study also had a few limitations. Firstly, data were retrospectively collected. Secondly, preoperative conditions such as chronic infection and chronic disease, which might affect the level of NLR, were not included. However, it is impossible to identify all the conditions associated with the NLR level in the clinical setting. Therefore, this study may be a better representation of the prognostic significance of NLR in actual practice. Lastly, this study lacked a central review of pathology, although most of the previous large multicenter studies did. Instead, urologic pathologists determined all pathologic features at each institution.
Despite limitations, it is noted that this study is the largest in the field, incorporating the most widely accepted independent prognostic factors of non-mRCC and evaluating both RFS and CSS.
This study showed that patients with high NLR differed significantly from those with low NLR in various clinical and pathologic parameters, suggesting that higher NLR may indicate worse clinical behavior of non-mRCC. In addition, NLR was a significant prognostic factor of both RFS and CSS, and incorporation of NLR into conventional prognostic predictors increased the predictive accuracy by 2.2% and 4.2%, respectively. This study suggests that the use of preoperative NLR may be helpful in counseling and clinical trial design in patients with non-mRCC.
Nonmetastatic renal cell carcinoma
Neutrophil-to-lymphocyte ratio
Absolute neutrophil count
Absolute lymphocyte count
Eastern Cooperative Oncology Group performance status
Tumor-node-metastasis
World Health Organization
Recurrence-free survival
Cancer-specific survival
Body mass index
Hazard ratio
Confidence interval.
The authors have nothing to disclose.
Seok-Soo Byun participated in the study’s design, coordination, treatment of patients, and data collection. Eu Chang Hwang, Seok Ho Kang, Sung-Hoo Hong, Jinsoo Chung, Tae Gyun Kwon, Hyeon Hoe Kim, Cheol Kwak, and Yong-June Kim were members of the research group and participated in the treatment of patients and data collection. Won Ki Lee conceived the study, participated in its design, performed the statistical analysis, and drafted the manuscript. All authors read and approved the final manuscript.