Kaohsiung Journal of Medical Sciences (2016) 32, 327e333

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ORIGINAL ARTICLE

Can the neutrophil-to-lymphocyte ratio be used

to predict recurrence and progression of
non-muscle-invasive bladder cancer?
Sebahattin Albayrak a, Kursad Zengin a, Serhat Tanik a,*, Muhittin Atar a,
Serhat Haluk Unal b, M. Abdurrahim Imamoglu a, Mesut Gurdal a

a
Department of Urology, Bozok University, School of Medicine, Yozgat, Turkey
b
Department of Urology, Amasya Serafeddin Sabuncuoglu Education and Research Hospital,
Amasya, Turkey

Received 29 January 2016; accepted 23 March 2016

Available online 2 June 2016

KEYWORDS Abstract The aim of our study was to evaluate whether neutrophil-to-lymphocyte ratio (NLR)
Age; is a predictor of disease progression and recurrence in patients with primary non-muscle-
Bladder cancer; invasive bladder cancer (NMIBC). This was a prospective study of 86 patients with newly diag-
Neutrophil-to- nosed NMIBC. The patients were classified by the number of points assigned by the European
lymphocyte ratio; Organization for Research and Treatment of Cancer risk tables. The correlation between pro-
Progression; gression score, recurrence score, age, mean platelet volume, red blood cell distribution width
Recurrence and NLR was assessed statistically. The same parameters were compared between the risk
groups. A significant difference in NLR and age values was observed between recurrence and
progression risk score groups. The relationships between NLR and recurrence and progression
risk scores were no longer significant after correcting for the statistical effect of age on scores.
Age was significantly different between groups after adjusting for NLR. Our study revealed that
NLR and age were associated with patient age and bladder tumor progression and recurrence
risk scores. After correcting for age, the significant relationship with NLR was lost, in contrast
to some previous studies. We recommend that patient age should be corrected to avoid
misleading results in NLR studies.
Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

Conflicts of interest: All authors declare no conflicts of interest.

* Corresponding author. Department of Urology, Bozok University, School of Medicine, Adnan Menderes Avenue, No: 42, 66000, Yozgat,
Turkey.
E-mail address: [email protected] (S. Tanik).

http://dx.doi.org/10.1016/j.kjms.2016.05.001
1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
328 S. Albayrak et al.

Introduction patients were followed up until September 2015. The study

data were collected from 2010 to 2015. All specimens were
The overall incidence of urinary bladder cancer (BC) was reviewed by a pathologist, and the urothelial carcinoma of
about 429,200 cases in 2012. Most (75%) BC is non-muscle the bladder diagnosis was confirmed. Tumors were staged
invasive (NMI) at the first diagnosis [Ta, T1, and carcinoma according to the 2002 American Joint Committee on Cancer
in situ (CIS)] and usually has a good prognosis. Between 30% TNM (tumorenodeemetastasis) staging system [18], and
and 80% of cases will relapse as NMI tumors and 1e45% will graded according to the 1973 World Health Organization
progress to muscle invasion (MI) within 5 years [1e3]. The grading system [19].
difficulty of treating non-muscle-invasive bladder cancer The patients were classified by the number of points
(NMIBC) is to protect the bladder and its function for as long assigned by the EORTC risk tables. Patients with a pro-
as possible, accepting the risk of recurrence while mini- gression risk score of 0, 2e6, 7e13, and > 13 were cate-
mizing the possibility of progression to muscle-invasive gorized as Group 1, 2, 3, and 4, respectively. Furthermore,
disease. The European Organization for Research and scores of 0, 2e6, and > 6 were considered low, interme-
Treatment of Cancer (EORTC) risk stratification can be used diate, and high risk for progression, respectively, according
to measure these risks [1,3]. The aim has been to divide to the European Association of Urology (EAU) guidelines.
patients into risk groups of good, intermediate, and poor Patients with a recurrence risk score of 0, 1e4, 5e9, and >
prognosis. After transurethral resection of bladder tumor 9 were Groups 1, 2, 3, and 4, respectively. Similarly, 0, 1e9,
(TURBT) and one immediate instillation of chemotherapy, and > 9 were low, intermediate, and high risk of recur-
treatment can be modified according to the patient’s rence, respectively according to the EAU guidelines [20].
prognosis. Patients with a good prognosis receive either no A second TURBT was routinely performed in patients who
more instillations or intravesical chemotherapy. The had a T1 tumor or the important risk of residual tumor after
treatment of choice for poor prognosis patients is Bacillus the first TURBT of Ta or G3 tumor in initial TURBT. Patients
CalmetteeGuérin with maintenance. Treatments for received postoperative intravesical instillations based on
intermediate-risk patients are controversial [4]. tumor characteristics, and according to the choice of the
According to recent theories, the systemic inflammatory treating urologist. Maintenance chemotherapy or immuno-
response induced by cancer causes relative neutrophilia therapy was administered to medium- and high-risk pa-
and lymphocytopenia, producing a protumor inflammatory tients according to the selection of treating urologist.
state [5]. The neutrophil-to-lymphocyte ratio (NLR), as a Postoperative follow-up was designed according to EAU
marker of the systemic inflammatory response, has been guidelines and the selection of the treating urologist, for
studied as a valuable prognostic biomarker in various types instance, high-risk patients underwent cystoscopy every 3
of tumors including BC [6e8]. Among patients with BC, a months for 2 years, and every 6 months in the following
high NLR is related to muscle-invasive disease, extravesical years. Low-risk patients were monitored after 3 months,
disease, and poorer cancer-specific and overall survival and if the result was negative, the next cystoscopy was
[8e12]. Nonsteroidal anti-inflammatory drugs have been planned for 9 months and subsequently once yearly [3].
suggested to decrease the risk of evolving BC by 19%, sug- Recurrence of bladder tumor was defined as the first his-
gesting a critical correlation between BC and inflammation tologically confirmed tumor relapse in the bladder,
[13]. Mean platelet volume (MPV) is also related with the regardless of its stage. Progression of bladder tumor was
pathophysiological characteristics of various types of can- defined as an advance in T category from CIS or Ta to T1
cer and inflammation [14,15]. Red blood cell distribution (invasion), development of T2 or an increase in grade of
width (RDW) is a strong predictor of all-cause mortality, tumor from low to high [21]. The study endpoints were
including cancer-related death and cancer progression defined as immunotherapy requirement or T2 disease. The
[16,17]. follow-up average was 29 months.
The aim of our study was to evaluate whether NLR is a This study was approved by the Institutional Ethics
predictor of disease progression and recurrence in patients Committee of Bozok University. The correlation between
with primary NMIBC. progression score, recurrence score, patient age, MPV,
RDW, and NLR was assessed statistically. Similar parameters
were compared between the recurrence and progression
Methods risk groups.

Study population
Statistical analysis
This was a prospective study of 86 patients with newly
diagnosed NMIBC (72 men and 14 women) who presented ShapiroeWilk’s and Levene’s tests were used to test for
consecutively at the Urology Clinic of Bozok University normality and homogeneity of the data. Values are
Research Hospital, Yozgat, Turkey. We selected patients expressed as frequencies and percentages, mean -
using our laboratory information system database to  standard deviation, or median and 25e75th percentiles.
retrieve data regarding NLR, RDW, hemoglobin, MPV, and Student t test and one way analysis of variance were used
age. Clinical and pathological data were recorded. The NLR to compare parametric continuous variables, and the
ratio was calculated using the neutrophil and lymphocyte ManneWhitney U test was used to compare nonparametric
values obtained from the complete blood counts. Patients continuous variables. Categorical data were compared
with newly diagnosed urothelial carcinoma underwent using the c2 distribution. Pearson’s test was used for the
TURBT at a single institute between 2010 and 2014. These correlation analysis. A multiple linear regression model was
Bladder cancer and neutrophil-to-lymphocyte ratio 329

used to identify independent predictors of recurrence and

Table 1 Characteristics and follow-up data of patients
progression scores. Statistical analyses were performed
with bladder cancer.
using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). A p
value < 0.05 was considered to indicate significance. Variables of 86 patients Mean  SD or n (%)
Age (y) 65.8  12
Results Sex
Male 72 (84)
The baseline characteristics and follow-up data of the pa- Female 14 (16)
tients are summarized in Table 1. The mean age of the NLR 2.64  0.51
patients was 65.8  12 years. NLR was positively correlated MPV (fL) 8.12  1.2
with patient age (p Z 0.018, r Z 0.315), recurrence risk Hemoglobin (g/dL) 14  1.4
score (p Z 0.001, r Z 0.421), and progression risk score RDW (%) 15.8  1.9
(p Z 0.004, r Z 0.375; Figure 1AeC, respectively). Patient Recurrence risk score 5.1  1.3
age was positively correlated with recurrence risk score Progression risk score 7.68  1.9
(p Z 0.018, r Z 0.313), and progression risk score Pathological stage
(p Z 0.001, r Z 0.443; Figure 1D and 1E, respectively). No Ta 50 (58)
other significant correlations were detected. We showed T1 36 (42)
that NLR increased relative to the increase in risk score in Grading
the comparison of NLR and recurrence risk scores of pa- G1 11 (13)
tients. Similarly, a significant difference in NLR values was G2 48 (56)
observed between recurrence risk score groups G3 27 (31)
(p Z 0.041). Risk score increased significantly with the in- Concomitant CIS 13 (15)
crease in age (p Z 0.003). No significant differences were No. of tumors
detected between the other variables (Table 2). NLR values 1 59 (69)
increased with the increase in progression risk scores. In 2e7 18 (21)
addition, a significant difference in NLR values was 8 9 (10)
observed between the groups (p Z 0.042). Progression risk Tumor size (mm)
score increased with the increase in patient age  10 29 (34)
(p Z 0.001). No significant differences were found between 10e30 36 (42)
any other variables (Table 3). The relationships between  30 21 (24)
NLR and progression and recurrence risk scores were no Tumor morphology
longer significant after correcting for the statistical effect Papillary 68 (79)
of age on the progression and recurrence risk scores. NLR Nonpapillary 18 (21)
did not differ statistically between the recurrence or pro- EORTC recurrence risk
gression risk score groups after adjusting for age (p Z 0.229 Low 10 (12)
and p Z 0.146, respectively). Age was significantly Medium 55 (64)
different between the recurrence risk score and progres- High 21 (24)
sion risk score groups after adjusting for NLR (p < 0.001 and EORTC progression risk
p < 0.003, respectively). The results of performed multiple Low 14 (16)
linear regression also were similar (Tables 4 and 5). Medium 21 (25)
High 51 (59)
Recurrence
Discussion No 50 (58.2)
1st year 25 (29)
We found that NLR was significantly associated with After 1 year 11 (12.8)
recurrence risk score, progression risk score, and patient Progression
age. However, the significant differences were lost after No 67 (77.9)
adjusting for age. 1st year 10 (11.6)
NLR has been recommended as a simple systemic in- After 1 year 9 (10.5)
flammatory response marker in patients with a variety of
EORTC Z European Organization for Research and Treatment of
diseases and can be easily obtained from the differential
Cancer; MPV Z mean platelet volume; NLR Z neutrophil-to-
white blood cell count [22,23]. BC is often related to lymphocyte ratio; RDW Z red blood cell distribution width;
chronic or recurrent inflammation, and a high number of SD Z standard deviation.
inflammatory cells are found in the tumor field [24]. The
numbers of T lymphocytes and natural killer cells are
significantly lower in patients with invasive bladder carci-
noma than those in patients with superficial carcinoma linked to a poor prognosis in certain cancers, including that
[25]. Several inflammatory parameters obtained from blood of the bladder [10,27,28]. Furthermore, several studies
tests, including C-reactive protein, NLR, plate- have reported that a high NLR is associated with worse
letelymphocyte ratio, and albumin level are related to recurrence-free, disease-specific, and overall survival in
treatment outcomes from primary operable malignancies patients with BC and upper urinary tract cancers [12,29].
[26]. A higher NLR during the preoperative period has been NLR level is significantly associated with disease
330 S. Albayrak et al.

Figure 1. (A) Correlation between age and NLR. (B) Correlation between NLR and recurrence score. (C) Correlation between NLR
and progression score. (D) Correlation between age and recurrence score. (E) Correlation between age and progression score.
NLR Z neutrophil-to-lymphocyte ratio.
Bladder cancer and neutrophil-to-lymphocyte ratio 331

Table 2 Comparison of NLR, MPV and RDW between groups of recurrence risk.
Variables Group 1 (Low risk; Group 2 (Intermediate risk; Group 3 (Intermediate risk; Group 4 (High risk; p*
Score 0; n Z 10) Score 1e4; n Z 24) Score 5e9; n Z 31) Score > 9; n Z 21)
NLR 1.93  0.3a 2.18  0.4b 2.68  0.5bc 3.17  0.5c 0.041
MPV (fL) 7.88  1.6a 7.97  1.6a 8.38  1a 8.56  1.17a 0.607
RDW (%) 15.6  1a 16.2  1.7a 15.5  1.7a 16.3  2.4a 0.517
Age (y) 45.2  8a 59.9  11ab 68.8  13b 69.9  15b 0.003
Values are expressed as mean  standard deviation.
* Different subscripts letters in a row indicate statistically significant difference. Bold values indicate statistically significant (p < 0.05).
MPV Z mean platelet volume; NLR Z neutrophil-to-lymphocyte ratio; RDW Z red blood cell distribution width.

Table 3 Comparison of NLR, MPV and RDW between groups of progression risk.
Variables Group 1 (Low risk; Group 2 (Intermediate risk; Group 3 (High risk; Group 4 (High risk; p*
Score 0; n Z 14) Score 2e6; n Z 21) Score 7e13; n Z 27) Score > 13; n Z 24)
NLR 2.12  0.4a 2.23  0.4a 2.63  0.5ab 3.25  0.6b 0.019
MPV (fL) 7.68  0.7a 7.95  0.9a 8.24  1.3a 8.67  1.7a 0.186
RDW (%) 17.1  1.8a 15.3  1a 15.8  1.6a 15.7  2.5a 0.171
Age (y) 55.8  9a 62.9  12a,b 68.6  13b 71.7  15b 0.001
Values are expressed as mean  standard deviation.
*Different subscripts letters in a row indicate statistically significant difference. Bold value indicates statistically significant (p < 0.05).
MPV Z mean platelet volume; NLR Z neutrophil-to-lymphocyte ratio; RDW Z red blood cell distribution width.

Table 4 Independent predictors of recurrence risk scores patients undergoing radical cystectomy is associated with
by multiple linear regression analysis. cancer-specific and all-cause mortality [12]. Higher pre-NLR
Factors B S.E. b t p* is an independent risk factor of disease recurrence and
NLR 0.094 0.039 0.301 2.413 0.064 cancer-specific mortality in patients with upper tract uro-
MPV (fL) 0.057 0.393 0.020 0.144 0.886 thelial carcinoma treated with radical nephroureter-
RDW (%) 0.400 0.293 0.208 1.366 0.178 ectomy. In addition, an elevated pre-NLR is significantly
Age (y) 1.544 0.510 0.439 3.029 0.004 associated with worse pathological features and patient
age [31]. According to Li et al [32], the eldest age group has
* Bold value indicates statistically significant (p < 0.05).
the highest NLR, and the youngest age group possesses the
B Z unstandardized coefficients; b Z standardized coefficients;
lowest NLR. Healthy elderly people have a high NLR [32]. In
MPV Z mean platelet volume; NLR Z neutrophil-to-lymphocyte
ratio; RDW Z red blood cell distribution width; SE Z standard our study, we evaluated patient age, NLR, RDW, and MPV
error. according to the EORTC risk score. Patient age and NLR
were correlated with recurrence risk score and each other.
Patient age and NLR may be related to the recurrence risk
score. Additionally, NLR and age increased significantly
Table 5 Independent predictors of progression risk scores according to recurrence risk group. NLR was no different
by multiple linear regression analysis. between the risk score groups after adjusting for age.
Factors B S.E. b t p* However, age was significantly different in the recurrence
risk score groups after adjusting for NLR. Our results show
NLR 2.366 0.821 0.396 2.883 0.064 that recurrence risk was affected by age, in contrast to NLR
MPV (fL) 0.697 0.633 0.141 1.100 0.276 in other studies [12,30,31]. Studies that evaluate recur-
RDW (%) 0.663 0.471 0.204 1.407 0.166 rence risk in patients with BC should consider age as a
Age (y) 0.204 0.063 0.386 3.268 0.002 factor.
* Bold value indicates statistically significant (p < 0.05). Tumor size, hydronephrosis, and hemoglobin levels in
B Z unstandardized coefficients; b Z standardized coefficients; patients with BC are the most important preoperative
MPV Z mean platelet volume; NLR Z neutrophil-to-lymphocyte prognostic factors [33]. Hilmy et al [34] advised that the
ratio; RDW Z red blood cell distribution width; SE Z standard preoperative systemic inflammatory response is more
error.
nearly related to outcome in patients with BC treated
with radical cystectomy and reported the usefulness of
CRP as an important prognostic factor for disease-specific
progression and recurrence in patients with NMIBC [30]. survival. A previous study reported that patients with a
Elevated preoperative NLR is associated with increased higher NLR display relative lymphocytopenia and may
risks of extravesical tumor extension and disease recur- show a poorer lymphocyte-mediated immune response to
rence. Furthermore, a higher preoperative NLR among malignancy; thus, deteriorating their prognosis and
332 S. Albayrak et al.

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