Preoperative Neutrophil-lymphocyte Ratio as a Predictor of Overall Survival in Patients with Localized
Renal Cell Carcinoma
Damian Widz1*, Przemysław Mitura1, Paweł Buraczyński1, Paweł Płaza1, Marek Bar1, Michał Cabanek1,
Grzegorz Nowak1, Anna Ostrowska2 , Krzysztof Bar1
Purpose: The neutrophil-to-lymphocyte ratio (NLR), as an indicator of the systemic inflammatory response,
predicts adverse outcomes in many malignancies. We investigated its prognostic significance in patients with non-
metastatic renal cell carcinoma.
Materials and Methods: We retrospectively evaluated data of 196 consecutive non-metastatic RCC patients
who underwent radical or partial nephrectomy between 2010 and 2012 at a single center. Overall survival (OS)
was assessed using the Kaplan-Meier method and compared using the log-rank test. We applied univariate and
multivariate Cox regression models to evaluate the prognostic value of dichotomized NLR for OS.
Results: At a median follow up of 68 months, high NLR (≥ 2,69) correlated with worse survival outcome (P = .006
in log-rank test) and higher tumor stage (P = .035). Univariate and multivariate analysis identified elevated NLR
(P = .039), as well as age (P = .002), high Fuhrmann grade (P = .002) and high pathologic T stage (P < .001), as
significantly associated with overall survival.
Conclusion: In our cohort, an elevated neutrophil-to-lymphocyte ratio is significantly associated with worse OS on
univariate and multivariate analysis. Consequently, the NLR is an easily acquired biomarker, which may be useful
in pretreatment patient risk stratification.
Keywords: inflammation, neutrophil-lymphocyte ratio, prognosis, renal cell carcinoma, survival
INTRODUCTION
Renal cell carcinoma, representing 2–3% of malig-nancies worldwide(1), has increased in incidence
over the last two decades. This medical condition is of-
ten identified in Western countries, but the frequency of
its occurrence in western Europe has been stabilized(2).
Also, due to the wide-spread use of ultrasound (US) and
computed tomography (CT) many newly diagnosed re-
nal tumors occur as incidental findings, and are there-
fore smaller and of lower stage(3,4,5).
Kidney cancer therapy is a subject of continuous veri-
fication and incremental modification to improve onco-
logical outcome while reducing the negative implica-
tions of surgical or systemic treatment(6,7,8).
Researchers are constantly attempting to determine
prognostic factors that can accurately predict clinical
outcomes of RCC patients. These features are derived
from anatomical, histological, clinical and molecular
data and are combined into prognostic systems and
nomograms(9,10,11,12,13).
This constant effort to uncover new factors has focused
attention on cancer-associated inflammation, which
has an established role in cancer development and pro-
gression. Pre-operative measurement of inflammatory
response markers, such as elevated C-reactive protein
levels, hypoalbuminemia or increased white cell, neu-
1Department of Urology, Medical University of Lublin, Lublin, Poland.
2Department of Pathology, Medical University of Lublin, Lublin, Poland.
*Correspondence: Department of Urology, Medical University of Lublin, Jaczewskiego 8, Lublin,
E-mail address: damian.widz@gmail.com; damianwidz@umlub.pl.
Received & Accepted
trophil and platelet counts, allows the prediction of
patients’ survival in many cancers(14,15). The neutro-
phil to lymphocyte ratio (NLR) is a cheap and easily
acquired inflammatory marker widely investigated as a
prognostic factor in a number of cancers(14,16), including
urologic tumors(17). The aim of our study was to eval-
uate the prognostic significance of preoperative NLR
in non-metastatic RCC. This is one of the first cohort
studies in this field in our region.
MATERIALS AND METHODS
Study population
A total of 196 consecutive patients with non-metastatic
RCC who had undergone a curative radical or partial
nephrectomy at the Department of Urology at the Med-
ical University of Lublin between January 2010 and
September 2012 were included in this historical cohort
study. Patients suspected of bone marrow disease (1
case) or lost from follow-up (3 cases) were not involved
in the study.
Study design and Evaluations
The research was reviewed and approved by Medical
University of Lublin Ethics Committee. Data regarding
age, sex, body mass index (BMI), history of hyperten-
sion and diabetes were retrieved from medical records
UROLOGICAL ONCOLOGY
Urology Journal/Vol 17 No. 1/ January-February 2020/ pp. 30-35. [DOI: 10.22037/uj.v0i0.4541]
Vol 17 No 01 January-February 2020 31Urological Oncology 349
of the Department of Urology, clinicopathological pa-
rameters including histological RCC subtype, tumor
grade (Fuhrmann grade), presence or absence (not
quantitatively assessed) of histologic tumor necrosis
(TN), and tumor size were obtained from the patholo-
gy reports from the Department of Pathology at Lublin
University Hospital. Laboratory tests, including periph-
eral blood cell counts, were performed at 1–7 days be-
fore surgery.
Overall survival was calculated based on the dates of
individuals' surgery and death from any cause. Dates
of death were obtained from the registry of the Polish
Ministry of Digital Affairs.
The objective of the present study was to examine the
relationship between pretreatment NLR and the clinico-
pathological features of RCC in patients who had re-
ceived radical surgery, as well as the potential effect of
NLR on overall survival.
NLR was calculated by dividing the absolute neutrophil
count by the absolute lymphocyte count.
Statistical Analysis
The cutoff value for the dichotomization of NLR was
calculated using a receiver – operating characteristic
curve with survival (death) as a gold standard. The pro-
NLR as a predictor of overall survival in patients with RCC-Widz et al.
Table 1. Clinicopathological characteristics of the cohort stratified by preoperative NLR.
Clinicopathological features NLR < 2,69 n (%) NLR ≥ 2,69 n (%) P-value a
Age (years) 0.44
< 65 65 (64.4) 56 (58.9)
≥ 65 36 (35.6) 39 (41.1)
Gender 0.95
Male 60 (59.4) 56 (58.9)
Female 41 (40.6) 39 (41.1)
BMI 0.29
< 25 25 (24.75) 30 (31.6)
≥ 25 76 (75.25) 65 (68.4)
Hypertension 0.15
No 48 (47.5) 55 (57.9)
Yes 53 (52.5) 40 (42.1)
Tumor size 0.21
< 7 83 (82.2) 71 (74.7)
≥ 7 18 (17.8) 24 (25.3)
Histologic subtypes 0.18
Clear cell 88 (87.1) 76 (80)
Non-clear cell 13 (12.9) 19 (20)
pT stage 0.04
T1 – T2 73 (72.3) 55 (57.9)
T3 – T4 28 (27.7) 40 (42.1)
Fuhrman grade 0.74
1 – 2 61 (60.4) 54 (58.1)
3 – 4 40 (39.6) 39 (41.9)
Type of surgery 0.27
NSS 27 (26.7) 19 (20)
Nephrectomy 74 (73.3) 76 (80)
Tumor necrosis 0.80
No 75 (74.3) 69 (72.6)
Yes 25 (26.7) 26 (27.4)
a The χ2-test
Abbreviations: BMI – body mass index, NLR – neutrophil-lymphocyte ratio, NSS – nephron-sparing surgery, pT stage – pathological
tumor stage
Figure 1. Linear correlation analysis of the association between
prognosis and NLR values.
Figure 2. Kaplan–Meier curves for overall survival in renal cell
carcinoma patients categorized by the neutrophil–lymphocyte ratio
(low NLR < 2,69; high NLR ≥ 2,69).
posed and finally accepted cut-off point was determined
to be 2.69.
Categorical variables were reported as frequencies and
percentages. Continuous variables were reported as
medians and ranges, and then dichotomized according
to approximate optimal cutoff points. The relationship
between NLR and the clinicopathologic parameters was
evaluated by non-parametric tests - Pearson’s χ2 tests.
Linear correlation analysis was used to determine
the association between prognosis and NLR values.
The time of overall survival was calculated using the
Kaplan-Meier method and compared using the log-rank
test. Cox’s proportional hazard regression model was
used to assess the influence on overall survival (OS)
of age, gender, Fuhrmann grade, histologic subtypes of
RCC, pathologic T (tumor) stage, tumor size. We decid-
ed on a multivariate analysis with variables significant
in univariate analysis, as well as including histological
subtype, due to its acknowledged role as prognostic fac-
tor.
All statistical analyses were performed using STATA
software version 13. P < .05 was considered to be sta-
tistically significant.
RESULTS
Overall, 196 RCC patients, median age 61 years (inter-
quartile range 24-85), were treated with partial nephrec-
tomy – 46 (23.5%) or nephrectomy – 150 (76.5%).
Among all the cases, 165 (84.2%) had clear cells, 14
(7.1%) had papillary, 6 (3.1%) had chromophobe, 4
(2%) had cystic, 1 (0.5%) had collecting duct RCC and
6 (3.1%) were not specified. Pathologic T stage was
T1a in 67 (34.2%), T1b in 52 (26.5%), T2a in 7 (3.6%),
T2b in 2 (1%), T3a in 58 (29.6%), T3b in 7 (3.6%) and
T4 in 3 (0.2%) patients. Tumor Fuhrmann grading was
Grade 1 in 11 cases (5.6%), Grade 2 in 103 (52.6%),
Grade 3 in 55 (28.1%), Grade 4 in 24 (12.2%) and in 3
(1.5%) cases not specified. Histologic tumor necrosis
was reported in 52 (26.5%) patients. The mean neutro-
phil count was 4.94 ± 1.66, mean lymphocyte count was
1.74 ± 0.64 and mean NLR was 3.18 ± 1.66. Using an
ROC curve we determined the cutoff NLR value of 2.69
to be optimal to differentiate patients’ overall survival
and define low (< 2.69) and high NLR (≥ 2.69). Overall,
there were 101 (51.5%) patients with a low NLR and 95
(48.5%) patients with a high NLR. A High NLR was
significantly associated with an advanced tumor stage
(P < .05) but not with any other tested clinicopatholog-
ical feature (Table 1).
Total median follow-up time was 68 months (interquar-
tile range (IQR) 44.5–78). Overall, there were 64 deaths
from all causes. The prognosis of patients was signifi-
cantly associated with NLR values (P < .001) (Figure
1). Kaplan–Meier curves for survival probability shown
on Figure 2 revealed that a high NLR correlates with
poor prognosis in RCC patients (P = .006 in log-rank
test).
For further investigations to determine the prognostic
significance of NLR for OS, univariate and multivariate
Cox proportional hazard analyses were performed. Age
(≥ 65 vs < 65 years, P = .003), gender (male vs female,
P = .004), high tumor Fuhrmann grade (3+4 vs 1+2,
P < .001), high pathologic T stage (T3–T4 vs T1–T2,
P < .001), large tumor size (> 7 cm vs ≤ 7 cm, P <
.001) and a high NLR (≥ 2.69 vs < 2.69, P = .007) were
identified as predictors of poorer outcomes (Table 2).
In multivariable analyses, after adjusting all the varia-
bles, NLR remained significantly associated with OS (P
= .039), as well as age, gender, high Fuhrmann grade,
high pathologic T stage, but not tumor size (Table 3).
DISCUSSION
The challenge presented by the personalized manage-
ment of patient care requires constant research for more
accurate biomarkers characterizing particular tumors.
Continuously updated scientific reports on kidney can-
cer focus to a large extent on molecular research(18). The
complexity of molecular alterations in RCC, as well as
Table 2. Univariate analysis of clinicopathological parameters for the prediction of overall survival in patients with RCC.
Features Overall survival
HR 95% CI P-value
Gender (Male vs Female) 2.287 1.298-4.029 0.004
Age (≥ 65 vs < 65) 2.105 1.286-3.445 0.003
The histologic subtypes (Clear cell vs Non-clear cell) 1.008 0.955-1.064 0.77
pT stage (T3 -T4 vs T1 - T2 ) 5.375 3.200-9.028 0.000
NLR ( ≥ 2.69 vs < 2.69) 2.009 1.211-3.334 0,007
Tumor size (> 7 cm vs ≤ 7 cm) 3.924 2.380-6.473 0.000
Fuhrman grade (3 - 4 vs 1 - 2) 3.377 2.015-5.658 0.000
Abbreviations: BMI – body mass index, NLR – neutrophil-lymphocyte ratio, pT stage – pathological tumor stage
Features Overall survival
HR 95% CI P-value
Gender (Male vs Female) 1.755 0.988-3.116 0.06
Age (≥ 65 vs < 65) 2.187 1.325-3.611 0.002
The histologic subtypes (Clear cell vs Non-clear cell) 1.058 0.995-1.125 0.07
pT stage (T3 -T4 vs T1 - T2 ) 4.817 2.568-9.035 0.00
NLR ( ≥ 2,69 vs < 2,69) 1.718 1.027-2.874 0.04
Tumor size (> 7 cm vs ≤ 7 cm) 1.435 0.819-2.514 0.21
Fuhrman grade (3-4 vs 1-2) 2.230 1.343-3.938 0.002
Abbreviations: BMI – body mass index, NLR – neutrophil-lymphocyte ratio, pT stage – pathological tumor stage
Table 3. Multivariable analysis of clinicopathological parameters for the prediction of overall survival in patients with RCC.
NLR as a predictor of overall survival in patients with RCC-Widz et al.
Urological Oncology 32
Vol 17 No 01 January-February 2020 33
the intratumor heterogeneity of its genomic landscape,
results in time-consuming analyses and is thus associat-
ed with high costs(18,19). As a consequence, none of the
markers are available for routine testing.
NLR is relatively easy to estimate from regularly used
blood – based counts, making it an attractive prognos-
tic factor for further evaluation and treatment of RCC
patients.
NLR has been widely evaluated as an adverse factor for
different human cancers, including colorectal, gastric,
esophageal, pancreatic, liver, urological and gyneco-
logical cancers(1), as well as in non – neoplastic con-
ditions, such as cardiovascular diseases(20,21). Graeme
J.K. Guthrie demonstrated that, regardless of the type
of cancer or required treatment approach, NLR was
elevated in patients with more advanced or aggressive
disease manifested by increased tumor stage, nodal in-
volvement or a higher number of metastatic lesions (14).
You Luo, in his publication dedicated to urologic tum-
ors defined as renal cell carcinoma, upper tract urothe-
lial carcinoma, bladder cancer and prostate cancer, in-
dicated that patients with a higher NLR had a higher
all-cause mortality risk in all the mentioned groups.
In terms of cancer specific survival (CSS) outcome,
results showed significant differences, with inferiority
of a high NLR, in upper tract urothelial carcinoma and
bladder cancer but not in RCC, and no data in prostate
cancer(22).
Renewed interest in the role of NLR as a prognostic
factor in RCC patients has developed as a result of
new scientific reports. Boissier et al. (2017) reviewed
the available literature in August 2016 and found that
NLR has a prognostic value for all stages of localized
or metastatic RCC, including prediction of the response
to systemic treatments or cytoreductive nephrectomy
in metastatic kidney cancer(22). Another study on pa-
tients with advanced disease (locally and metastatic)
performed by Fox et al. showed that the addition of in-
flammatory markers into prognostic models based on
MSKCC allows a more accurate prediction of patient
survival time. According to this improved classifica-
tion 25.8% of patients were more appropriately classi-
fied. The markers of systemic inflammation used in the
study were elevated neutrophil counts, elevated platelet
counts and high NLR, defined as > 3(23).
There are incoming evidence on the potential benefits
of adjuvant systemic therapy in advanced kidney can-
cer (24,25). Due to the fact of a possible toxicity of such
treatment, the search for markers enabling proper quali-
fication of patients is underway. Motzer et al. showed in
their study that nlr may contribute in this field. Accord-
ing to their analysis from the S-TRAC trial, patients
with NLR<3 experienced longer disease free survival
with adjuvant sunitinib compared to placebo(24,25). De-
termining the basis of this relation requires further in-
quiry.
The value of NLR in patients with non-metastatic RCC
remains under investigation. Some studies have already
been published, with conflicting results reported.
In this cohort study, we found that preoperative NLR is
significantly associated with OS in univariate and mul-
tivariable analyses. We demonstrated that an increased
NLR > 2.7 was an independent predictor of poor prog-
nosis. Our findings are in agreement with the large Eu-
ropean validation study of Pichler et al (2013), where
they investigated a group of 678 patients with non –
metastatic clear cell RCC and reported that NLR was
an independent negative predictor for OS. They did not
find the same relation to CSS or metastatic free survival
(26). Their research is in contrast to another prior study
by Ohno et al (2010) on a smaller cohort of 192 pa-
tients with a mean follow-up of 93 months, where they
reported that an increased NLR was an independent
predictor for recurrence-free survival(27). In his analy-
ses Ohno omitted variables such as tumor stage, size,
grade or presence of necrosis which has been proven to
be highly predictive of tumor recurrence(28). Moreover,
their study did not include OS data.
Other research projects also do not provide an unam-
biguous answer about the prognostic role of NLR. Us-
ing a group of 827 non-metastatic clear cell RCC pa-
tients, Boyd et al (2014) demonstrated that NLR is an
independent predictor of cancer-specific and all-cause
mortality. In contrast to many previous studies, and
ours, their multivariable analysis is based on continu-
ous NLR(29). This approach, perceived by the authors to
be an advantage of the analysis, allows the avoidance
of inaccurate setting of the cut-off value and receiving
misleading results. However, everyday clinical practice
usually requires the establishing of a certain point by
which a clinician can identify significant abnormality in
a diagnostic test. Combination of information received
from analyses based on continuous NLR with tests on
dichotomized NLR would make it possible to identify a
group of patients with a worse prognosis and gradation
of their risk.
Lastly, Bazzi et al (2016) evaluated 1970 patients un-
dergoing partial or radical nephrectomy for localized
clear cell RCC and found that NLR, as a continuous
variable, was significantly associated with worse re-
currence free survival (RFS), CSS, and OS; however,
in contrast to Boyd’s research NLR independently pre-
dicted only worse OS(30).
Attempts to explain the relationship between NLR and
prognosis, on a pathophysiological basis, lead to the
role of inflammation. The interaction between inflam-
mation and carcinogenesis has been studied over the
past decades. Through various mechanisms, inflamma-
tion is involved in oncogenesis. A tumor is not merely a
line of cancer cells dividing in an uncontrolled manner.
On the contrary, there are many accompanying cells,
including those derived from the immune system, in-
fluencing tumor behavior. Cancer-associated inflam-
mation induces the up-regulation of the innate immune
response. It is manifested as a heightened neutrophil
dependent reaction, increased tumor macrophage infil-
tration with concomitant suppression of lymphocytes.
Elevated proinflammatory cytokines modify the tumor
microenvironment, allowing its intense growth and
overcoming consecutive barriers in tumor expansion,
promoting aggressive tumor behavior(31,32). An elevat-
ed neutrophil–lymphocyte ratio reflects, in part, the in-
creased role of the innate immune system; moreover, it
is often associated with higher values of proinflamma-
tory cytokines(33,34).
Our study, as being the historical cohort, is limited by
its non-randomized character. No data were availa-
ble about the cause of death. Moreover, NLR is not a
disease-specific biomarker and may be influenced by
many factors interacting with the immune system. The
NLR cut-off point used in our study differs slightly
from those used in previous research, as it is always set
NLR as a predictor of overall survival in patients with RCC-Widz et al.
for a certain evaluated cohort.
CONCLUSIONS
Nevertheless, considering the limitations, our data show
that elevated NLR may be recognized as an independ-
ent prognostic factor for OS in non-metastatic RCC
patients undergoing surgical resection of tumors. The
NLR might be an easily available and inexpensive bi-
omarker predicting clinical outcomes of RCC patients.
However, to establish an accurate NLR value, useful for
clinical practice, further prospective research is needed.
CONFLICT OF INTEREST
None declared.
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NLR as a predictor of overall survival in patients with RCC-Widz et al.