BJC 201328
BJC 201328
Background: The neutrophil–lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response.
Several studies suggest a negative impact of increased NLR for patient’s survival in different types of cancer. However, previous
findings from small-scale studies revealed conflicting results about its prognostic significance with regard to different clinical end
points in non-metastatic renal cell carcinoma (RCC) patients. Therefore, the aim of our study was the validation of the prognostic
significance of NLR in a large cohort of RCC patients.
Methods: Data from 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 at a single centre,
were evaluated retrospectively. Cancer-specific, metastasis-free, as well as overall survival (OS) were assessed using the Kaplan–
Meier method. To evaluate the independent prognostic significance of NLR, multivariate Cox regression models were applied for
all three different end points. Influence of the NLR on the predictive accuracy of the Leibovich prognosis score was determined by
Harrell’s concordance index.
Results: Multivariate analysis identified increased NLR as an independent prognostic factor for overall (hazard ratio (HR) ¼ 1.59,
95% confidence interval (CI) ¼ 1.10–2.31, P ¼ 0.014), but not for cancer-specific (HR ¼ 1.59, 95% CI ¼ 0.84–2.99, P ¼ 0.148), nor for
metastasis-free survival (HR ¼ 1.39, 95% CI ¼ 0.85–2.28, P ¼ 0.184). The estimated concordance index was 0.79 using the Leibovich
risk score and 0.81 when NLR was added.
Conclusion: Regarding patients’ OS, an increased NLR represented an independent risk factor, which might reflect a higher risk
for severe cardiovascular and other comorbidities. Adding the NLR to well-established prognostic models such as the Leibovich
prognosis score might improve their predictive ability.
The worldwide incidence rates of renal cell carcinoma (RCC) have tumours has been observed (Pichler et al, 2012). The use of
slightly increased within the last three decades (Siegel et al, 2012). prognostic factors and models that can accurately predict clinical
However, because of the widespread use of radiological imaging outcomes of RCC patients are of paramount interest, not only for
techniques, a migration towards small and organ-confined patients’ individualised risk assessment but also for the comparison
of the results from international clinical multicentre trials partial nephrectomy at the Department of Urology at the Medical
(Meskawi et al, 2012). Several prognostic models have been University of Graz, between January 2000 and December 2010. Of
established to predict patient’s clinical outcome. Kattan et al (2001) this data set, we excluded 195 cases with non-clear cell histology
integrated disease-related symptoms, histologic subtype, tumour and restricted our analyses to clear cell RCC only, as the evaluated
size and pathologic tumour-node-metastasis (pTNM) stage into prognostic model (i.e., Leibovich prognosis score) has been
their model to predict 5-year treatment failure. The University of previously established on clear cell RCC (Leibovich et al, 2003).
California Integrated Staging System (UISS) incorporated perfor- All of the clinicopathological data were retrieved from medical
mance status, pTNM stage and Fuhrman grade to predict overall records from the Department of Urology, as well as from pathology
survival (OS) in RCC patients (Zisman et al, 2001). The Leibovich reports from the Institute of Pathology at the same institution. As
prognosis score integrates five clinicopathological features trans- the TNM classification system for RCC changed during the
lated into a score and categorises patients into eight-score observational period, pathologic T stages were uniformly adjusted
categories, which are then assigned to one of three different risk according to the seventh edition of the TNM classification system
groups. According to this score, patients’ assignment into the low-, (Novara et al, 2010). Other documented clinicopathological
intermediate- or high-risk group can accurately assess the risk for parameters included histological RCC subtype, tumour grade,
the occurrence of metastatic disease after radical nephrectomy presence or absence (not quantitatively assessed) of histologic
(Leibovich et al, 2003). The accuracy of these models may be coagulative tumour necrosis (TN), as well as patients’ age and
further improved by the incorporation of different prognostic gender. The laboratory data, including neutrophil and lymphocyte
biomarkers (Lam et al, 2008). In addition to individual’s risk counts, were obtained by preoperative exploration one day before
assessment, considering high costs and often toxic side-effects of surgical intervention. Patients’ postoperative surveillance included
novel drugs, an accurate identification and validation of prognostic routine clinical and laboratory examination; regarding imaging
factors will enable a better risk-stratified patient selection for methods, X-rays of the chest and abdominal ultrasound were
adjuvant treatment modalities (Crispen et al, 2008). External predominantly used, especially in patients with a low relapse risk
validation of prognostic risk assessment tools using independent (pT-1 G1–2), whereas computed tomography or magnetic
cohorts of patients is paramount before the general applicability of resonance imaging was performed in all other patients as
a prognostic marker or model (Altman and Royston, 2000; Bleeker previously reported (Pichler et al, 2011). Follow-up evaluations
et al, 2003). were performed every 6 months for the first 5 years and annually
The systemic inflammatory response, which is usually measured thereafter for locally advanced tumours. In organ-confined cancers,
by surrogate blood-based parameters, such as C-reactive protein, imaging was performed twice in the first year after surgery and
neutrophil or platelet count, has been shown to independently annually thereafter. No neoadjuvant or adjuvant treatment was
predict the clinical outcome of various human cancer types administered. Dates of death were obtained from the central
(Roxburgh and McMillan, 2010). Of these inflammatory para- registry of the Austrian Bureau of Statistics. Cancer-specific
meters, an increased neutrophil–lymphocyte ratio (NLR) has been survival was defined as the time (in months) from date of surgery
proposed as an easily accessible and reliable marker to predict to a cancer-related death. Metastasis-free survival (MFS) was
cancer patients survival (Roxburgh and McMillan, 2010). Cumu- defined as the time (in months) from date of surgery to the
lating evidence in metastatic RCC suggests that a high NLR might recurrence of radiologically or histologically confirmed distant
represent an independent adverse prognostic factor in interferon- metastases. Overall survival was defined as the time (in months)
treated (Atzpodien et al, 2003), interleukin-2-treated (Donskov and from date of surgery to individuals’ death of any cause. The study
von der Maase, 2006), as well as in sunitinib-treated (Keizman was approved by the local ethical committee of the Medical
et al, 2012) patients. However, data regarding the prognostic University of Graz (no. 24-330 ex 11/12).
significance of the NLR in non-metastatic RCC are sparse, and
controversy still exists about how discriminating the NLR might
Statistical analyses. The primary study end point was CSS, which
potentially be as an independent risk factor in non-metastatic RCC.
was calculated from the date of diagnosis to the date of patients’
For instance, in a prospective cohort study including 83 localised
cancer-related death. Secondary end points included OS (the time
RCCs, Ramsey et al (2008) found no statistically significant
between diagnosis and death of any cause) and MFS (the time
association of preoperative neutrophil count and patients’ relapse-
between diagnosis and occurrence of distant metastases). The ideal
free or CSS. In addition, when evaluating 228 non-metastatic RCC
cutoff value for the continuous NLR was calculated by testing all
patients, Jagdev et al (2010) also failed to demonstrate an increased
possible cutoffs that would discriminate between survival and
NLR to be of independent prognostic value in their cohort study.
cancer-related death by Cox proportional analyses. The ideal cutoff
In contrast, a study from Japan including 192 patients with non-
value was then rounded to clinically relevant (convenient) values as
metastatic RCC, identified a high preoperative NLR as an
previously reported (Atzpodien et al, 2003).
independent prognostic indicator of patients’ relapse-free survival
The relationship between NLR and other clinicopathologic
(Ohno et al, 2010). These previously published reports analysed
parameters was studied by non-parametric tests. Patients’ clinical
relatively small numbers of patients, heterogeneously histologic
subtypes and examined the NLR with regard to different clinical end points were calculated using the Kaplan–Meier method and
end points. Therefore, the aim of our study was to further clarify compared by the log-rank test. Backward stepwise multivariate Cox
the prognostic significance of the preoperative NLR in non- proportion analysis was performed to determine the influence of
metastatic clear cell RCC and to evaluate whether this parameter pathologic T stage, grade, age, gender and histologic TN on CSS,
provides additional prognostic information to well-established MFS and OS. Hazard ratios (HRs) estimated from the Cox analysis
clinicopathological parameters and to the Leibovich prognosis were reported as relative risks with corresponding 95% confidence
score (Leibovich et al, 2003). intervals (CIs). The patients were categorised according to the
Leibovich prognosis risk groups developed for M0 clear cell RCC
patients (Leibovich et al, 2003). Harrell’s concordance index (c-
index) was calculated using the individual Leibovich risk groups
PATIENTS AND METHODS followed by the addition of the NLR (Harrell et al, 1982). All
statistical analyses were performed using the Statistical Package for
This retrospective analysis included data from 873 consecutive Social Sciences version 17.0 (SPSS Inc., Chicago, IL, USA). A two-
non-metastatic RCC patients who underwent a curative radical or sided Po0.05 was considered statistically significant.
Cancer-specific survival
RESULTS
1.0
Of the 843 consecutive RCC patients, 678 (80.4%) had clear cell,
108 (12.8%) had papillary, 43 (5.1%) had chromophobe, 3 (0.4%)
had collecting duct RCC and 11 (1.3%) were not otherwise
specified. For all further analyses, we excluded non-clear cell 0.8
histology cases resulting in 678 patients with clear cell RCC.
Pathologic T stage was T1a in 334 (49.3%), T1b in 117 (17.3%), T2a
Probability to survive
in 32 (4.7%), T2b in 5 (0.7%), T3a in 170 (25.1%), T3b in 16 (2.4%), 0.6
T3c in 2 (0.3%) and T4 in 2 (0.3%) patients. Tumour grading was
G1 in 170 (25.1%), G2 in 411 (60.6%) G3 in 92 (13.6%) and G4 in 5
(0.7%) cases. Overall, the presence of histologic TN was noted in
165 (24.3%) patients with a mean age of 63.7±11.9 years, a mean 0.4
neutrophil count of 4828±1974, a mean lymphocyte count of
1580±581 and a mean NLR of 3.51±2.49. Applying the criteria
mentioned above, we determined a cutoff value of 3.3 for the NLR
to be optimal to discriminate between patients’ CSS that prompted 0.2
us to select 3.3 as the optimal cutoff value for all subsequent
analyses to differentiate between low (o3.3) and high (X3.3) NLR. Low NLR P < 0.001
Overall, there were 398 (58.7%) patients with a low NLR and 280 0.0 High NLR
(41.3%) patients with a high NLR. A high NLR was statistically
significantly correlated with older age, high tumour grade, large 0.00 20.00 40.00 60.00 80.00 100.00 120.00
tumour size, as well as with advanced tumour stage (all Po0.05), Time (months)
but not with gender (P ¼ 0.552), the presence of histologic TN
(P ¼ 0.107) or positive lymph node disease (P ¼ 0.136). Figure 1. Kaplan–Meier curves for renal cell carcinoma patients cancer-
To investigate whether the NLR is associated with the clinical specific survival groups categorised by the neutrophil-lymphocyte ratio
outcome of RCC patients, univariable and multivariable analyses (NLR).
for all three end points were performed. Mean follow-up was 44
(range 0–130) months. Of the 678 clear cell RCC patients, 76 Metastases-free survival
(11.2%) developed metastatic disease, of which 49 (7.2%) died
because of their advanced disease state. Overall, 123 (18.1%) 1.0
patients died by their most recent follow-up visit for any cause.
Among the 678 RCC patients, metastatic disease was diagnosed in
29 out of 398 (7.3%) patients with a low NLR and in 47 out of 280
Probability to metastases-free survival
0.8
(16.8%) patients with a high NLR (Po0.001). Regarding survival,
cancer-related and overall deaths occurred in 26 (4.0%) and 52
(13.1%) patients with low NLR and in 33 (11.8%) and 71 (25.4%)
patients with high NLR (Po0.001). Figures 1, 2 and 3 show the 0.6
Kaplan–Meier curves for CSS, MFS and OS and reveal that a high
NLR is a consistent factor for poor prognosis in RCC patients
(Po0.001 for all three tested end points, log-rank test).
Univariate analysis identified age (X65 vs o65 years, 0.4
P ¼ 0.044), high tumour grade (G3 þ G4 vs G1 þ G2, Po0.001),
histologic TN (presence vs absence, Po0.001), high pathologic T
stage (XpT3 vs opT3, Po0.001) and a high NLR (X3.2 vs o3.2,
0.2
Po0.001) as prognosticators of poor outcome for patients’ CSS,
whereas gender (male vs female, P ¼ 0.124) was not statistically
significantly associated with CSS (Table 1). Low NLR P < 0.001
To determine the independent prognostic significance of the 0.0 High NLR
NLR for CSS, a multivariate analysis using a Cox proportional
hazard model was performed. In our multivariate analysis that 0.00 20.00 40.00 60.00 80.00 100.00 120.00
included age, pathologic T stage, tumour grade, NLR and presence Time (months)
of histologic TN, we identified age, pathologic T stage, tumour
grade, as well as histologic TN as independent prognostic factors Figure 2. Kaplan–Meier curves for renal cell carcinoma patients
for CSS and MFS, whereas the NLR was not statistically metastasis-free survival groups categorised by the neutrophil-
significantly associated with either CSS (HR ¼ 1.59, 95% lymphocyte ratio (NLR).
CI ¼ 0.84–2.99, P ¼ 0.148, Table 1) or MFS (HR ¼ 1.39, 95%
was 0.83 compared with 0.86 when NLR was supplemented. Finally
CI ¼ 0.85–2.28, P ¼ 0.184, Table 2). Regarding OS, a high NLR was
for OS, the c-index improved from 0.63 compared with 0.67 when
identified as an independent prognostic factor for poor survival
the NLR was added to the Leibovich prognosis groups.
(HR ¼ 1.59, 95% CI ¼ 1.10–2.31, P ¼ 0.014, Table 3). Before
analysing the addition of the NLR to the Leibovich prognosis
model, patients were categorised into risk groups (low, inter-
mediate and high risk) according to Leibovich et al (2003). For DISCUSSION
MFS, the c-index was 0.79 when assessed with each individual
Leibovich risk score and improved to 0.81 when the NLR was Despite recent progress in the identification of genetic, epigenetic
added. Regarding CSS, the c-index of the original Leibovich model and common molecular alterations in RCC has been made
(Al-Ali et al, 2012; Gerlinger et al, 2012), the routine diagnostic these newly discovered molecular markers influence diagnostic or
and prognostic assessment of RCC currently relies on pathological therapeutic decisions have rendered none of the markers available
tissue examination and traditional clinicopathological prognostic for routine testing. Regularly used blood-based parameters, such as
variables (Ficarra et al, 2010). The complexity of these molecular the neutrophil or lymphocyte count and the resultant-derived
changes, as well as high costs of analyses, the time-consuming NLR, are relatively easy to assess without additional laborious
preparation required and the lack of evidence demonstrating how efforts, making them attractive parameters for patients’ improved
individualised risk assessment in RCC (Zahorec, 2001).
Heng et al (2009) detected 11.7% of patients with an increased
blood neutrophil count (i.e., cutoff value defined as greater than
Overall survival
the upper limit of normal range) and showed that the blood
1.0 neutrophils only represent an independent prognostic factor in
metastatic RCC patients. However, in our study we only could
identify 15 (2.2%) patients with an increased blood neutrophil
count only (i.e., greater than the upper limit of normal range),
0.8 which represents a too low number of patients to perform a reliable
multivariate prognostic analysis.
Beyond the neutrophil count only, an increased pre-treatment
Probability to survive
Table 1. Univariate and multivariate analysis of clinicopathological parameters for the prediction of cancer-specific survival in patients with clear cell
renal cell carcinoma (n ¼ 678)
Gender
Female 1 (Referent) 0.124
Male 1.55 (0.88–2.72)
T stage
pT1–2 1 (Referent) o0.001 1 (Referent) o0.001
pT3–4 6.47 (3.48–12.04) 3.77 (1.93–7.36)
Tumour grade
G1 þ G2 1 (Referent) o0.001 1 (Referent) 0.003
G3 þ G4 6.91 (3.89–12.29) 2.66 (1.40–5.04)
Neutrophil–lymphocyte ratio
o3.3 1 (Referent) o0.001 1 (Referent) 0.148
X3.3 2.89 (1.59–5.22) 1.59 (0.84–2.99)
Table 2. Univariate and multivariate analysis of clinicopathological parameters for the prediction of metastasis-free survival in patients with clear cell
renal cell carcinoma (n ¼ 678)
Gender
Female 1 (Referent) 0.072
Male 1.51 (0.96–2.37)
T stage
pT1–2 1 (Referent) o0.001 1 (Referent) o0.001
pT3–4 5.69 (3.52–9.19) 3.47 (2.06–5.84)
Tumour grade
G1 þ G2 1 (Referent) o0.001 1 (Referent) o0.001
G3 þ G4 6.08 (3.83–9.64) 2.69 (1.61–4.49)
Neutrophil–lymphocyte ratio
o3.3 1 (Referent) o0.001 1 (Referent) 0.184
X3.3 2.37 (1.49–3.76) 1.39 (0.85–2.28)
Table 3. Univariate and multivariate analysis of clinicopathological parameters for the prediction of overall survival in patients with clear cell renal cell
carcinoma (n ¼ 678)
Gender
Female 1 (Referent) 0.894
Male 1.02 (0.71–1.47)
T stage
pT1–2 1 (Referent) o0.001 1 (Referent) 0.048
pT3–4 1.92 (1.34–2.75) 1.47 (1.00–2.18)
Tumour grade
G1 þ G2 1 (Referent) o0.001 1 (Referent) 0.027
G3 þ G4 2.50 (1.64–3.84) 1.72 (1.16–2.78)
Neutrophil–lymphocyte ratio
o3.3 1 (Referent) o0.001 1 (Referent) 0.014
X3.3 1.93 (1.35–2.77) 1.59 (1.10–2.31)
that an increased NLR was an independent predictor for relapse- used prognostic factors in their multivariate model, such as tumour
free survival in a smaller cohort of 192 RCC patients from Japan. grade or histologic TN (Sun et al, 2011). Interestingly, we found
However, in addition to the significantly smaller sample size and a that the NLR was an independent prognostic factor for OS, which
different ethnic background, Ohno et al did not include commonly might possibly reflect a higher overall mortality rate for patients
with increased systemic inflammatory responses. However, a population, we excluded patients with non-clear cell histology,
definitive explanation for this observation remains speculative. hereditary RCC, patients with metachronous secondary RCC and
Nevertheless, several studies evaluating the NLR as an adverse those with competitive invasive cancers originating from other sites
factor in cardiovascular diseases included several thousands of if metastatic spread was not assessed through histologic examina-
patients and have clearly established an increased NLR as a tion. In addition to the evaluation of the integration of the NLR to
negative prognostic predictor for cardiovascular events. For the Leibovich prognosis score, other prognostic models such as the
instance, Tsai et al (2007) demonstrated in 1872 subjects that the Kattan nomogram (Kattan et al, 2001) or the UISS model (Zisman
NLR, in addition to metabolic syndrome, is strongly associated et al, 2001) should be evaluated.
with the risk of ischaemic cardiovascular diseases. Other studies Nonetheless, even considering these limitations, our data clearly
have indicated an increased NLR to be associated with poor indicate that an increased pre-treatment NLR might represent an
survival after coronary artery bypass grafting (Gibson et al, 2007), independent prognostic factor for OS in non-metastatic clear cell
to be an independent predictor of in-hospital and 6-month RCC patients.
mortality in patients with acute coronary syndrome (Tamhane In conclusion, an increased NLR seems to represent an
et al, 2008) and to be an independent predictor of in-hospital independent predictor with respect to patients’ OS in non-
major adverse cardiac events in patients with ST-segment elevation metastatic RCC. As the NLR improves the prognostic accuracy
myocardial infarction (Akpek et al, 2012). Imtiaz et al (2012) of the Leibovich prognosis score, this parameter warrants further
described an increased NLR in patients with hypertension and validation as a selection criterion for risk factor-stratified patient
diabetes, and Terradas et al (2012) found that an increased NLR management in non-metastatic RCC.
was an independent marker of mortality in patients with
bacteraemia. Furthermore, one recently published report demon-
strated that stage 4 chronic kidney disease patients with a high ACKNOWLEDGEMENTS
NLR had a worse prognosis and a significantly faster progression to
dialysis compared with those with a low NLR (Kocyigit et al, 2012). None of the contributing authors have any conflicts of interest,
In this context, Sun et al (2012) demonstrated that the status of including specific financial interests and relationships and affilia-
chronic kidney disease is getting worse after nephrectomy, which tions relevant to the subject matter or materials discussed in the
might contribute to a higher overall mortality in patients with an manuscript.
increased systemic inflammatory response found in our study.
Evidence also exists that an increased NLR might represent a
marker for more severe gastrointestinal conditions, such as a
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treated for renal cell carcinoma: are further improvements needed? the license terms will switch to a Creative Commons Attribution-
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