Review

The Clinical Use of the Neutrophil to

Lymphocyte Ratio (NLR) in Urothelial Cancer:
A Systematic Review
Michele Marchioni,1 Giulia Primiceri,1 Manuela Ingrosso,1 Roberta Filograna,2
Pietro Castellan,3 Piergustavo De Francesco,1 Luigi Schips3
Abstract
The neutrophil to lymphocyte ratio (NLR) is an inflammatory index that has been considered as a potential prognostic
factor in human cancer. The aim of this study was to evaluate the available evidence regarding the NLR as a prog-
nostic value in patients affected by urothelial cancer. This literature review, including papers on NLR in urothelial
cancers, was done on PubMed/Medline and Cochrane libraries in November 2015. The selection of the articles fol-
lowed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses process. Twenty-three of 99 articles
fulfilled all the inclusion criteria, including data on 6240 patients affected by urothelial cancers. Overall, cancer-
specific, and recurrence-free survival were evaluated as the main oncological outcomes. There was significant het-
erogeneity among studies, and the majority of studies were of poor quality. Overall, NLR was considered as a
prognostic marker in 87.5%, 80%, and 60% of the studies on upper tract urothelial cancer, urothelial bladder cancer,
and metastatic and advanced disease, respectively. The NLR cut-off value ranged between 2 and 5. A high NLR was
associated with worse overall, cancer-specific, and recurrence-free survival. NLR is a widely available, easy-to-collect,
costless, prognostic marker in urothelial cancers. Its clinical use still remains under investigation, especially for the
need for cut-off values, particularly in different subsets of patients.

Clinical Genitourinary Cancer, Vol. 14, No. 6, 473-84 ª 2016 Elsevier Inc. All rights reserved.
Keywords: Bladder cancer, Neutrophil to lymphocyte ratio, Oncologic outcome, Prognostic value, Upper tract urothelial cancer

Introduction survival, and migration in the tumor microenvironment.4 Addi-

Urothelial carcinoma (UC) is the fourth most common form of
tumor.1 The 2 most common forms of UC are urothelial bladder
cancer (UBC) and upper tract urothelial carcinoma (UTUC), which
involve the lower and upper part of the urinary tract, respectively.
UBC represents about 90% to 95% of UC cases, whereas UTUC is
relatively rare and affects only 5% to 10% of patients with UC.1,2
In the past decades, several studies have highlighted the role of
inflammation as a critical component in tumor progression.3
Indeed, it has been shown that inflammatory cells are indispens-
able participants in the neoplastic process, promoting proliferation,
1
Department of Urology, SS. Annunziata Hospital, “G.D’Annunzio” University of
Chieti, Chieti, Italy
2
Division of Molecular Metabolism, Department of Medical Biochemistry and
Biophysics, Karolinska Institutet, Stockholm, Sweden
3
Department of Urology, Robotic Unit, ASL Abruzzo 2, “SS. Annunziata” Hospital,
Chieti, Italy
Submitted: Feb 29, 2016; Revised: Apr 9, 2016; Accepted: Apr 11, 2016; Epub:
Apr 22, 2016
Address for correspondence: Michele Marchioni, MD, Via Silvio Pellico 33, Cantalice
(RI) 02014, Italy
E-mail contact: mic.marchioni@gmail.com
tionally, systemic inflammation elevates the C-reactive protein
(CRP) and changes the proportion of white blood cells, increasing
the neutrophil count and decreasing the lymphocyte count. Thus,
some inflammatory indices such as platelet-lymphocyte ratio,
lymphocyte-monocyte ratio, and neutrophil-lymphocyte ratio
(NLR) have been consistently studied as potential prognostic factors
in cancer.5 Among the various biomarkers, it has been previously
reported that an elevated NLR is a valuable predictive indicator of
various cancer types, including pancreatic cancer, epithelial ovarian
cancer, gastric cancer, colorectal cancer, and UC.6-9 Moreover, NLR
appears to be a prognostic value not only for these cancer conditions
but also for acute pancreatitis10 or cardiac events.11
Therefore, the aim of this review is to evaluate and summarize the
data currently reported in the literature concerning the use of NLR
as a prognostic value in patients affected by UC.
Materials and Methods
Searching Strategy
Bibliographic research was conducted using the Medline
(PubMed) and Cochrane Libraries databases in November, 2015 to

1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.clgc.2016.04.008 Clinical Genitourinary Cancer December 2016 - 473
 NLR Clinical Use in Urothelial Cancer
identify all studies reporting the prognostic role of the NLR ratio in
patients affected by UC. The authors undertook a PubMed search
using the following terms in combination: “neutrophil to lympho-
cyte ratio,” “urothelial,” “bladder,” “cancer,” “tumor,” and “onco-
logical outcome.” Subsequently, the references of the retrieved
articles were also used to identify any other relevant studies. Two
preliminary selections were performed to discard obviously irrele-
vant articles and retain potentially pertinent articles concerning the
NLR by 2 independent review authors. For the Medline search, we
used the following filters: Languages (English), Species (Humans),
Text availability (full-text availability). No filters were applied for
the date of publication. Three authors independently analyzed all
the aspects of the research strategy by reviewing the full text articles
in detail and eventually resolving discrepancies by consensus.
they were not deemed to be methodologically appropriate. Figure 1
sums up the process of the selection (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses).12
Studies and Patient Characteristics
For each selected article, the features taken into account included
the year of publication, study design, measured oncologic outcomes,
patient number and gender distribution in examined populations,
major examined variables, main conclusions, NLR (value and cut-
off), follow-up duration, and exclusion criteria. Variables not
directly correlated with oncologic features that might affect the
NLR value were identified by carefully reading all the studies.
Finally, information regarding age, gender, stage, grade, and size of
tumor were collected.

Selection of Studies Results

Inclusion and exclusion criteria were defined before the literature
search. Only studies that explored the role of NLR as a prognostic
factor for UC were included. To be included, studies had to
explicitly investigate main oncologic outcomes, in particular, cancer-
specific survival (CSS), overall survival (OS), and recurrence-free
survival (RFS). Conference abstracts were not considered because
Studies and Patient Characteristics
A total of 99 articles were found in accordance with the afore-
mentioned strategy. In particular, 75 records were identified
through database searching, whereas 24 works were identified
through the reference lists of relevant articles. Thirty-eight of 99
articles were retained after removing duplicates. Thirty-two full-text

Figure 1 Flow Chart of Study Selection Process

IdenƟficaƟon

Records idenƟfied through AddiƟonal records idenƟfied

database searching through other sources
(n = 75) (n = 24 )

Records aŌer duplicates removed

(n = 61)
Screening

Records screened Records excluded by Ɵtle

(n = 38) and abstract
(n = 6)
Eligibility

Full-text arƟcles excluded

Full-text arƟcles assessed
because OS, CSS, RFS
for eligibility
not evaluated
(n = 32)
(n = 9)
Included

Studies included in
qualitaƟve synthesis
(n = 23)

Abbreviations: CSS ¼ Cancer-specific survival; OS ¼ overall survival; PRISMA ¼ Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RFS ¼ recurrence-free survival.

474 - Clinical Genitourinary Cancer December 2016

 Table 1 Studies and Baseline Patient Characteristics

Outcome
Author (Study) Year Study Design Patients (M/F) Age (years) T Stage (No.) Grade (No.) Variables Measured
Upper tract urothelial
cancer (UTUC)
Azuma (13)a 2013 Retrospective single 137 (106/31) 69.4 (40-88) pTa-pT2 (79) G1-G2 (78) Age, gender, stage, LVI, RFS
center pT3-pT4 (58) G3 (59) CRP, pyuria CSS
Cheng (14)a 2015 Retrospective single 195 (79/116) 68  10.3 pTa-pTis-pT1 (76) Low (32) Age, gender, smoking, type OS
center pT2 (45) High (163) of nephroureterectomy, CSS
pT3 (59) eGFR, preoperative
pT4 (15) hemodialysis, tumor side
and location, stage, grade,
anemia, adjuvant CT and RT,
LN metastasis, RDW, WBC,
PLT
Dalpiaz (15)a 2014 Retrospective single 202 (122/80) 69.3 (32-85) pT1 (91) G1 (19) Age, gender, stage, tumor side and OS
center pT2 (33) G2 (91) location, grade, tumor necrosis, LVI, CSS
pT3 (70) G3 (88) ECOG-PS, age-adjusted CCI
pT4 (8) G4 (4)
Hashimoto (16)b 2013 Retrospective single 84 (59/25) 68.8  9.9 cT2 (40) NA Age, number of recurrence, RFS
center cT3 (44) gender, side, tumor
location, performance
status, presentation, clinical
stage, hydronephrosis,
voided urine cytology, HGB,
CRP
Kim (17)b 2015 Retrospective single 277 (218/59) 63.7 (IQR, 57.4-70.6) pTa (42) Low (96) Gender, age, BMI, year CSS
center pTis (1) High (181) of surgery, previous or RFS
Clinical Genitourinary Cancer December 2016

pT1 (69) concomitant bladder

Michele Marchioni et al
pT2 (49) cancer, bladder cuff
pT3 (112) excision, stage, grade,
pT4 (4) concomitant CIS, LVI, tumor
necrosis, margin status,
tumor location, multifocality,
hydronephrosis, CT,
albumin, WBC, red cell
count, serum creatinine,
PLT, prognostic nutrition
index, PLR, dNLR
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NLR Clinical Use in Urothelial Cancer

Table 1 Continued
Clinical Genitourinary Cancer December 2016

Outcome
Author (Study) Year Study Design Patients (M/F) Age (years) T Stage (No.) Grade (No.) Variables Measured
Luo (18)a 2014 Retrospective single 234 (102/132) High NLR, 67.7  9.5 pTis (99) High (208) Age, gender, end stage CSS
center Low NLR, 66.5  11.5 pT0 (58) renal desease, smoking, MFS
pT1 (61) grade, multifocality, tumor CSM
pT2 (48) necrosis, stage, LVI,
pT3 (67) concomitant CIS, bladder
cuff excision, presence of
variant form, localization,
previous bladder cancer,
LND, intravescical
recurrence, systemic
recurrence
Sung (19)b 2014 Retrospective single 410 (312/98) 64 (IQR, 55-72) pTa (74) G1-2 (219) Age, gender, ASA score, CSS
center pT1 (89) G3 (182) site, side, multifocality, OS
pT2 (69) previous bladder tumor, PFS
pT3-4 (178) preoperative URS, bladder
cuff excision, stage, grade,
CIS, size, margin, LVI,
presence of variant form,
adjuvant CT, ESR
Tanaka (20)b 2014 Retrospective multicenter 665 (493/172) 70 (IQR, 62-76) pTa-PT1 (228) G1-G2 (259) Age, gender, site, CSS
pT2 (100) G3 (406) multifocality, grade, RFS
pT3 (311) stage, LVI, concomitant CIS,
pT4 (26) CT, WBC
Urothelial bladder
cancer (UBC)
Demirtaş (21)a 2013 Retrospective single 201 (175/26) 62.03  9.42 (34-82) pT1 (35) NA Age, gender, stage, CT, RT, OS
center >pT1 (166) CTþRT, No. LN removed,
No. LN positive, LN
density (%)
Gondo (22)a 2012 Retrospective single 189 (158/31) 68.4  0.72 (38-85) pT1 (62) G1-G2 (21) Age, gender, stage, CSS
center pT2 (76) G3 (168) grade, no. of tumors,
pT3 (38) size, tumor shape,
pT4 (13) concomitance CIS, history of
intravesical therapy, number
of TURBT, hydronephrosis, HGB,
PLT, LDH, CRP
Hermanns (23)b 2014 Retrospective single 424 (325/99) 70.1 (IQR, 60.6-76.3) pT0 (25) NA Age, gender, HGB, WBC, OS
center pTa-pT1-pT2-CIS (205) PLT, smoker; CCI, CSS
pT3-pT4 (194) hydronephrosis, concomitant RFS
CIS, stage, PSM, LVI, total
node count, NAC/primary CT,
salvage CT
 Table 1 Continued

Outcome
Author (Study) Year Study Design Patients (M/F) Age (years) T Stage (No.) Grade (No.) Variables Measured
Kang (24)a 2015 Retrospective single 385 (333/52) 66 (59-72) pT2 (246) Low (69) Age, gender, ASA, BMI, OS
center pT3 (139) High (315) preop-NLR, postop-NLR, CSS
NLR change, stage, grade,
LVI, presence of variant form,
PSM, no. of LNs removed,
adjuvant CT
Krane (25)a 2013 Retrospective single 68 (55/13) 67.4  10.1 pT1 (10) NA Age, gender, BMI, surgical OS
center pt2 (58) technique, serum albumin, CSS
serum creatinine, WBC, PLT, Extravescical disease
HGB, comorbidities, BCG
refractory, stage,
hypoalbuminemia, serum
creatinine
Ku (26)b 2015 Retrospective single 419 (362/57) 65.1 (IQR, 58.3-70.4) pT0 (55) G0 (55) Gender, age, BMI, ASA OS
center pTa (14) Low (17) score, year of surgery, CSS
pTis (35) High (347) stage, grade, LVI, margin
pT1 (69) status, CRP, albumin, WBC,
pT2 (69) PLT
pT3 (111)
pT4 (66)
Mano (27)b 2014 Retrospective single center 107 (91/16) 68 (IQR, 61-78) pTa (46) <G3 (42) Age, gender, smoking, PFS
pT1 (61) G3 (65) stage, size, grade, RFS
pTis (11) multifocality, concurrent
CIS, EORTC risk group
for progression and
recurrence, postoperative
bladder instillation
Ozcan (28)a 2015 Retrospective single center 286 (256/30) 60.7  9.42 (29-83) pTis (19) G2 (96) Age, gender, LVI, stage, CSS
pT0 (32) G3 (190) histological type, CIS, PSM,
pT1 (49) grade, hydronephrosis,
pT2 (81) WBC
Clinical Genitourinary Cancer December 2016

pT3 (73)

Michele Marchioni et al
pT4 (51)
Viers (29)b 2014 Retrospective single center 899 (723/176) 69 (IQR, 62-76) pT 1 (392) NA Age, gender, BMI, ECOG-PS, OS
pT2 (157) hydronephrosis, BCG CSS
pT3 (288) therapy, stage, lymph RFS
pT4 (59) node count, lymph node Death due to bladder
density, size, LVI, PSM, cancer
adjuvant therapy All cause mortality
Zhang (30)b 2015 Retrospective multicentre 124 (100/24) 65 (30-78) pT1 (15) Low (5) Age, gender, BMI, smoking, OS
pT2 (50) High (119) comorbidities, ECOG-PS,
pT3 (40) CT, RT, concomitant CIS,
pT4 (19) stage, grade
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NLR Clinical Use in Urothelial Cancer

Clinical Genitourinary Cancer December 2016

Table 1 Continued

Outcome
Author (Study) Year Study Design Patients (M/F) Age (years) T Stage (No.) Grade (No.) Variables Measured
Metastatic and
Advanced Urothelial
Cancer
Bambury (31)b 2015 Retrospective single center 129 (97/32) 66 (45-85) NA NA Age, gender, ECOG-PS, PFS
visceral metastases, liver OS
metastases, primary
invasive tumour site, line
of therapy, starting dose
of pemetrexed, time from
prior CT, RECIST-
measurable disease, prior
platinum exposure, prior
taxane exposure
Morizane (32)b 2012 Retrospective single center 30 (23/7) 72 (52-83) NA NA Age, gender, previous CSS
therapy, primary urothelial ORR
tumor site. site of metastasis
or recurrence
or invasion
Rossi (33)b 2015 Retrospective multicentre 292 (227/65) 69 (34-89) NA NA Age, gender, ECOG-PS, OS
HGB, site, metastatic site, PFS
first-line CT
Santoni (34)b 2015 Retrospective multicentre 298 (233/65) 69 (47-87) NA NA Age, gender, ECOG-PS, OS
HGB, site, visceral PFS
metastases, first-line CT COS
CPFS
Taguchi (35)b 2015 Retrospective multicentre 185 (148/37) 68 (IQR, 62-74.5) cT2 (61) NA Gender, age, BMI, ECOG-PS, CSS
cT3 (124) site, stage, adjuvant OS
CT, stage, WBC, HGB,
albumin, LDH, alkaline
phosphatase, CRP, eGFR,
first-line CT

Abbreviations: ASA ¼ American Society of Anesthesiologists; BMI ¼ body mass index; CCI ¼ Charlson comorbidity index; CIS ¼ carcinoma in situ; COS ¼ conditional overall survival; CPFS ¼ conditional progression-free survival; CRP C-reactive protein; CSM ¼ cancer-specific
mortality; CSS ¼ cancer-specific survival; CT ¼ chemotherapy; ECOG-PS ¼ Eastern Cooperative Oncology Group performance status; eGFR ¼ estimated glomerular filtration rate; EORTC ¼ European Organization for Research and Treatment of Cancer; HGB ¼ hemoglobin;
IQR ¼ interquartile range; LDH ¼ lactate dehydrogenase; LN ¼ lymph node; LVI ¼ lymphovascular invasion; MFS ¼ metastasis-free survival; MPV ¼ mean platelet volume; NAC ¼ neoadjuvant chemotherapy; ORR ¼ overall response rate; OS ¼ overall survival; PFS ¼
progression-free survival; PLR ¼ platelet/lymphocyte ratio; PLT ¼ platelet; PSM ¼ positive surgical margins; RDW ¼ red blood cell distribution width; RECIST ¼ Response Evaluation Criteria In Solid Tumors; RFS ¼ recurrence-free survival; RT ¼ radiotherapy; TURB-T ¼
transurethral resection of bladder tumor; URS ¼ ureterorenoscopy; WBC ¼ white blood cell.
a
Average or mean  SD (range).
b
Values are presented as median (range).
 Table 2 NLR Values, Main Outcomes, and Conclusions

NLR Cut-Off CSS OS RFS

Author (Study) NLR Value Follow-Up (mo) HR (95% CI) HR (95%CI) HR (95% CI) Conclusions
Upper Tract Urothelial Cancer
(UTUC)
Azuma (13)a 2.0 2.5 60.9 (1.9-187.3) Univariate analysis: NA Univariate analysis: Preoperative NLR could be an
(0.88-12.1) 6.14 (3.52-11.2) 4.48 (2.64-7.80) independent predictive marker for
(IQR, 1.72-3.79) P ¼ .0001 P < .0001 RFS and CSS in patients with UTUC
Multivariate analysis: Multivariate analysis:
3.06 (1.44-6.83) 2.11 (1.02-4.46)
P ¼ .0035 P ¼ .045
Cheng (14)a NA 2.7 36 Univariate analysis: Univariate analysis: NA In our univariate analysis, both
2.231 (1.161-4.284) 2.168 (1.262-3.725) absolute WBC count and
P ¼ .016 P ¼ .005 NLR were significantly correlated
Multivariate analysis: Multivariate analysis: with OS and CSS.
1.362 (0.652-2.847) 1.611 (0.890-2.916) However, only a high WBC count
P ¼ .411 P ¼ .115 was an independent
prognostic factor in the multivariate
model.
Elevated RDW and WBC count
are useful markers for predicting
survival of UTUC
patients.
Dalpiaz (15)b 4.56  3.39 2.7 45 (0-199) Univariate analysis: Univariate analysis: NA The assessment of the NLR appears
(1.11-22.0) 3.114 (1.471-6.594) 3.073 (1.665-5.672) to be reliable
P ¼ .003 P < .001 and widely available in clinical
Multivariate analysis: Multivariate analysis: practice with a high ability to predict
2.718 (1.246-5.928) 2.480 (1.308-4.702) survival rates in patients with UTUC
P ¼ .012 P ¼ .005
Hashimoto (16)c 2.84  1.35 NA NA NA NA Univariate analysis: Preoperative neutrophil count, such
Significant as clinical tumour stage, is
P ¼ .026 an independent predictor of RFS in
patients with nonmetastatic
UTUC.
Clinical Genitourinary Cancer December 2016

Kim (17)a NA 5 57.2 (6.8-158.3) Univariate analysis: NA Univariate analysis: NLR is not significantly associated

Michele Marchioni et al
1.179 (0.511-2.718) 1.209 (0.525-2.784) with CSS and RFS at univariate
P ¼ .700 P ¼ .656 analysis. However dNLR may predict
CSS and RFS.
Luo (18)b NA 3 40.7  23.8 Not specified NA NA For localised UTUC, pathological
P < .001 (P < .05) stage and preoperative
NLR independently predict systemic
recurrence and
cancer-specific death after RNU.
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NLR Clinical Use in Urothelial Cancer

Table 2 Continued
Clinical Genitourinary Cancer December 2016

NLR Cut-Off CSS OS RFS

Author (Study) NLR Value Follow-Up (mo) HR (95% CI) HR (95%CI) HR (95% CI) Conclusions
a
Sung (19) 2.04 2.5 40.2 (IQR: 33.0-66.1) At 3 years, time-dependent At 3 years, time-dependent area NA The combination of preoperative ESR
(IQR: 1.52-2.78) area under ROC curves: under ROC curves: and NLR might be a new prediction
0.612 (0.553-0.668) 0.619 (0.560-0.675) tool in
At 5 years, time-dependent At 5 years, time-dependent area patients with UTUC after radical
area under ROC curves: under ROC curves: nephroureterectomy.
0.638 (0.569-0.703) 0.633 (0.564-0.698)
Tanaka (20)a NA 3 28 (IQR, 14-57) Univariate analysis: NA Univariate analysis: Pre-NLR was significantly associated
2.07 (1.45-2.94) 1.75 (1.30-2.36) with worse pathologic findings,
P < .001 P < .001 and it was an independent risk
Multivariate analysis: Multivariate analysis: factor of disease recurrence and
1.47 (1.03-2.11) 1.38 (1.02-1.87) cancer-specific mortality
P ¼ .036 P ¼ .037 in UTUC patients treated with RNU.
Urothelial bladder cancer (UBC)
Demirtaş (21)b 4.43  4.11 2.5 pN0 NA There was no significant difference NA Lymph node density and preoperative
37.22  35.92 between patients with an NLR below NLR were not found to be independent
pN1-3 or above 2.5 in terms of overall predictors of prognosis.
27.75  31.50 survival (P ¼ .702)
Gondo (22)b 3.46  0.18 2.5 34.4  2.1 (2.1-127.9) Multivariate analysis NA NA NLR was an independent prognostic
1.946 (1.035-3.663) P ¼ factor.
.0387
Hermanns (23)a NA 3 58.4 (IQR, 21.3-94.5) Univariate analysis: Univariate analysis: Univariate analysis: Patients with an NLR 3.0 had
1.88 (1.52-2.33) 1.80 (1.48-2.20) 1.53 (1.23-1.89) significantly worse survival outcomes
P < .001 P < .001 P < .001 Neutrophil-to-lymphocyte ratio is an
Multivariate analysis: Multivariate analysis: Multivariate analysis: inexpensive prognostic biomarker for
1.88 (1.39-2.54) 1.67 (1.17-2.39) 1.49 (1.12-2) patients undergoing RC for BC.
P < .001 P ¼ .005 P ¼ .007
Kang (24)a Preoperative 2 38 Multivariate analysis Multivariate analysis (Preoperative): NA Postoperative NLR during the early
2.11 (1.55-2.99) (Preoperative): 1.13 (1.04-1.22) recovery time demonstrated
Postoperative 1.16 (1.06-1.28) P ¼ .003 prognostic significance for
1.95 (1.35-2.89) P ¼ .005 Multivariate analysis bladder cancer patients undergoing
Multivariate analysis (Postoperative): RC with PLND.
(Postoperative): 1.22 (1.14-1.31)
1.23 (1.12-1.35) P < .001
P ¼ .001
Krane (25)b 4.0  2.8 2.5 NA Multivariate analysis: Univariate analysis: NA Elevated NLR before radical
RR, 2.68 (1.01-8.59) RR, 2.25 (1.08-5.29) cystectomy have
P significant Multivariate analysis: worse overall survival than patients
RR, 2.49 (1.14-6.09) without markers of systemic
P significant inflammation. NLR is associated with
extravesical
disease.
 Table 2 Continued

NLR Cut-Off CSS OS RFS

Author (Study) NLR Value Follow-Up (mo) HR (95% CI) HR (95%CI) HR (95% CI) Conclusions
a
Ku (26) NA 5 37.7 (0.1-176.2) Univariate analysis: Univariate analysis: NA Cellular components of SIR have
2.272 (1.265-4.080) 2.328 (1.414-3.833) better prognostic values compared
P < .05 P < .05 with acute-phase protein in patients
Multivariate analysis: Multivariate analysis: undergoing radical cystectomy for
2.024 (1.086-3.774) 2.285 (1.351-3.867) bladder cancer.
P < .05 P < .05
Mano (27)a 2.85 (IQR, 2-3.9) Recurrence: 2.43 40 (IQR, 23-51) NA NA Multivariate analysis: NLR was a significant predictor of
Progression: 2.41 1.75 (1.05-2.92) disease progression and recurrence.
P ¼ .032
Ozcan (28)a NA 2.5 28 (0-144) Univariate analysis: NA NA Inexpensive, reproducible, and readily
1.798 (1.260-2.567) available peripheral blood count
P ¼ .001 components of white blood cell
Multivariate analysis: count and NLR were independent
1.965 (1.042-3.586) prognostic factors.
P ¼ .022
Viers (29)a NA 2.7 10.9 years (IQR, 8.3-13.9) 5 years (%): 5 years (%): NLR (as continuous) Elevated preoperative NLR is
High NLR 57% High NLR 44% HR, 1.04 associated with locally advanced
Low NLR 70% Low NLR 61% (95% CI, 1.01-1.08) tumor stage among patients with BC
HR, 1.57 HR, 1.69 P ¼ .02 undergoing RC.
P < .001 P < .001
Zhang (30)a 2.1 (0.6-6.2) 2.1 NA NA NLR was not significantly associated NA Our results show that preoperative
with oncological outcomes. LMR is a better prognostic factor in
P ¼ .709 BC patients undergoing RC, compared
with NLR and PLR.
Metastatic and advanced
urothelial cancer
Bambury (31)c NA 2.5 NA NA Univariate analysis: NA The data also suggest a role for NLR
3 1.04 (1.02-2.06) in the prognostication of advanced
P < .01 platinum-resistant UC, which may
Multivariate analysis: be relevant when constructing
Clinical Genitourinary Cancer December 2016

1.03 (1.01-1.05) prognostic models in future studies.

Michele Marchioni et al
P < .01
Morizane (32)b 3.64  3.63 3 NA Univariate analysis: NA NA Elevated pretreatment serum CRP
P ¼ .063 levels indicate a poor prognosis for
patients undergoing GC therapy for
advanced UC.
Rossi (33)a 3.9 3 40.2 (0.5-100.4) NA Univariate analysis: NA An increased NLR persistent during
1.74 (1.32-2.29) first-line chemotherapy is an
Multivariate analysis: independent predictive factor for
1.53 patients with advanced urothelial
P ¼ .0101 cancer.
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 NLR Clinical Use in Urothelial Cancer

years showed an increase in their COS

studies are needed to better clarify the

and CPFS over time. However, further

poor independent prognostic factor for

articles were selected by title and abstract. In the end, 23 articles

cispaltin or carboplatin; IQR ¼ interquartile ratio; LMR ¼ lymphocyte-monocyte ratio; NA ¼ not available; NLR ¼ neutrophil-lymphocyte ratio; OS ¼ overall survival; PLND ¼ pelvic lymph node dissection; PLR ¼ platelet-lymphocyte ratio; RC ¼ radical cystectomy; RDW ¼ red
Abbreviations: BC ¼ Bladder cancer; COS ¼ conditional overall survival; CRP ¼ C-reactive protein; CSS ¼ cancer-specific survival; DFP ¼ disease-free progression; dNLR ¼ derived neutrophil lymphocyte ratio; ESR ¼ erythrocyte sedimentation rate; GC ¼ gemcitabine-
Patients with NLR <3 and age <70

prognostic relevance of these factors

Pre-treatment NLR elevation was a

metastatic UC undergoing salvage

fulfilled the inclusion criteria.13-35 The oldest papers date from
2012.22,32 Table 1 shows the baseline characteristics of the selected

on life expectancy.
Conclusions

chemotherapy.
studies and examined populations. All scrutinized studies were
retrospective, and among them, only 5 were multicenter.20,30,33-35
A total of 6240 patients were included: 4797 males and 1443 fe-
males. In all the selected studies, there were more men than women
in the examined populations, except in 2 studies.14,18 The patients’
ages ranged between 29 and 89 years. Eight studies included pa-
tients affected by UTUC (for a total of 2204 patients), 10 studies
HR (95% CI)

were focused on UBC (3102 patients), and 5 studies regarded

metastatic and advanced UC (934 patients) (Table 1). Only 5
RFS

NA

NA

studies examined smoking status (324 patients).14,18,23,27,30 Tumor

blood cell; RFS ¼ recurrence-free survival; RNU ¼ radical nephroureterectomy; SIR ¼ systemic inflammatory response; UC ¼ urothelial cancer; UTUC ¼ upper tract urothelial cancer; WBC ¼ white blood cell.
size was examined as a continuous variable in 2 studies19,29 and in 2
other works as a dichotomous variable22,27 with 3 cm as the cut-off
differences for OS at any time point.
Patients stratified according to NLR
>3 vs. <3 showed no significant

value. In 8 studies, the materials and methods sections did not

specify the exclusion criteria.13,15,16,22,25,30,33,35 On the other hand,
1.488 (1.018-2.177)
Multivariate analysis:

the rest of the analyzed studies considered hematologic diseases,

HR (95%CI)

P ¼ .0400

infection or inflammatory conditions, abnormal urinalysis results,

OS

and nontransitional cell cancer as the main exclusion criteria. The

authors’ choice of the inclusion and exclusion criteria varied
considerably among different studies, and a standard could not be
reached.
In 6 studies, the patient population features significantly differ in
the Charlson Comorbility Index (CCI),23 body mass index
1.481 (1.012-2.171)
Multivariate analysis:

(BMI),17 gender,27,29 age,20,24,29 and serum hemoglobin (HGB),23

HR (95% CI)

P ¼ .0433

when reported according to NLR cut-off values.

CSS

NA

Finally, a critical grade of variability is present in all the studies in

terms of scientific design, patient selection, sample size, and
methods of reporting oncologic outcomes.

NLR and Oncologic Outcomes

13 (IQR, 7-25.5)
Follow-Up (mo)

In this review, CSS, OS, and RFS were evaluated as the main
oncologic outcomes.
NA

In 16 studies, the association between high NLR and worse CSS

was evaluated.13-15,17-20,22-26,28,29,32,35 Among these, in 14 studies,
Univariate analysis and multivariate analysis significant only for NLR analyzed as a continuous variable.

a high NLR correlated with a worse CSS.13-15,18-20,22-26,28,29,35

However, this association was not confirmed by a multivariate
analysis in 1 study.14 Additionally, OS was significantly associated
NLR Cut-Off

with NLR in 11 of 14 studies.14,15,19,21,23-26,29-31,33-35 Moreover, a

Value

high NLR was significantly associated with poorer RFS in 6 studies

3

out of 7.13,16,17,20,23,27,29 Among these, the association was not

In all selected studies, P was considered significant for values < .05.

confirmed by multivariate analysis in 1 study.16 (Table 2).

Among different urothelial cancer types, NLR was correlated
3 (IQR, 2.01-5.36)

with main oncologic outcomes in 87.5%, 80%, and 60% of

NLR
NA

included studies on UTUC, UBC, and metastatic and advanced

urothelial cancer, respectively (Table 3). The NLR cut-off values in
UTUC, UBC, and metastatic and advanced disease sub-groups
ranged from 2.5 to 5, from 2 to 5, and from 2.5 to 3, respectively.

Discussion
Table 2 Continued

The key findings of this review are summarized in the summary

Author (Study)

of evidence table (Table 3). Evidence evaluating the main oncologic

Mean  SD (range).
Taguchi (35)a
Santoni (34)

outcomes according to NLR values in patients affected by UC was

Median (range).

limited. Interestingly, our analysis highlighted a growing interest in

the role of NLR as a prognostic factor in UC in the last 3 years. This
wide interest is justified by the lack of UC biomarkers available as
b
a

482 - Clinical Genitourinary Cancer December 2016


Table 3 Summary of Evidence
Oncological No. of Studies Evaluating
Disease Outcomes
UTUC CSS
OS
RFS
Urothelial bladder CSS
cancer
OS
RFS
Metastatic and locally CSS
advanced
OS
RFS
Table 3 schematically shows the number of studies that find a correlation with main outcomes.
Abbreviations: NLR ¼ Neutrophil to lymphocyte ratio; OO ¼ oncological outcomes.
evidenced by the World Health Organization/International
Consultation on Urological Diseases Consensus, which concluded
that, at this stage, the added value of serum/urinary molecular
markers for the diagnosis of urothelial tumors has not yet been
identified.36 Recently, several studies suggested that high NLR
might represent an independent prognostic factor in UC for a worse
oncologic outcome; nevertheless, its clinical value remains unclear.
The wide majority of examined studies defined a correlation be-
tween high NLR and worse oncologic outcomes in term of CSS,
OS, and RFS. Unfortunately, a clear definition of the cut-off values
remains to be determined; nevertheless, a value of  2 seems to be
appropriate to define a “high NRL.” Even if a cut-off is useful for its
immediate clinical application, as demonstrated by Viers, NLR
could be also analyzed as a continuous variable, showing statistically
significant association with locally advanced disease.29 The main
hypothesis that justifies these findings is based on the involvement
of the inflammation in promoting cancer progression and metas-
tasis, favoring different cancerogenesis processes. Indeed, inflam-
matory mediators may increase vascular permeability, enhancing
lymphatic and blood vessels infiltration, adhesion to endothelium,
and stromal invasion at metastatic sites.37 Thus, a high NLR value
reflects an augmented inflammatory reaction, which in turn, cor-
relates with decreased tumor-specific immunity.37 Moreover,
widespread conditions such as smoker status, diabetes, hyperten-
sion, or chronic disease could be related with a general inflammatory
status, which might affect the NLR value.38,39 Increasing evidence
suggests a cooperative activity between innate and adaptive immune
response; in particular, between polymorphonuclear neutrophils and
T-lymphocytes in different physiologic and pathologic conditions,
including defense against tumors.40 Neutrophilia and lymphocyto-
penia were also reported to be poor prognostic markers in some
malignancies.13 NLR reflects the balance between innate (neutro-
phils) and adaptive (lymphocytes) immune responses. Elevated
NLR is associated with an increased concentration of inflammatory
cytokines, which may damage cellular DNA.38 Different
inflammation-based prognostic scores were developed for the pre-
diction of disease outcomes, such as the Glasgow prognostic score,
which evaluates CRP and albumin levels; it is considered to be an
Michele Marchioni et al
No. of Studies Finding % of Studies Finding
NLR/OO Correlation NLR/OO Correlation NLR/OO Correlation
7[13-15,17-20] 6[13-15,18-20] 86%
3[14,15,19] 3[14,15,19] 100%
4[13,16,17,20] 3[13,16,20] 75%
7[19-26,28,29] 7[19-26,28,29] 100%
7[21,23-26,29,30] 5[23-26,29] 71%
3[23,27,29] 3[23,27,29] 100%
2[32,35] 1[35] 50%
4[31,33-35] 3[31,33,35] 75%
e e e
independent predictor for survival in many cancers.41 Moreover,
Dalpiaz introduced a new derived index (the derived neutrophil-
lymphocyte ratio [dNLR]). They found that patients with high
pretreatment dNLR had higher cancer-specific and overall mortality
after surgery compared with patients who had low pretreatment
dNLR in a large European cohort of patients affected by UTUC.42
Interestingly, different authors tried to use NLR in association
with other parameters in order to create nomogram and prognostic
groups that were able to enhance the predicting power of NLR,
either by adding some biomarker (erythrocyte sedimentation rate)
or using dNLR.17,19
It is evident that the correct evaluation of the NLR prognostic
role cannot be left aside from a rigorous methodology during the
selection phase of study design to avoid different kinds of biases.
However, as pointed out in our analysis, 8 of the analyzed studies
included data of consecutive patients or did not specify exclusion
criteria in the materials and methods sections.13,15,16,22,25,30,33,35
Thus, the present study is an attempt to summarize and discuss
the current work in the field, although it has several limitations
mainly related to the overall quality of the studies examined. First,
all the included studies were retrospective, limiting the robustness of
a meta-analytic approach. Second, NLR could be affected by
different conditions, and this possibility was taken into account only
in a small portion of the examined studies. Third, a wide variability
in reporting oncologic outcomes is present, along with a certain
grade of variability that is present in terms of scientific design,
sample size, and follow-up duration. Fourth, the sample size is often
not sufficiently numerous to reach substantial results in terms of
oncologic outcome.
Conclusion
NLR is an economical, easily reproducible, and widely available
marker, and its use, in association with other tools such as the
nomogram, could be helpful in the clinical decision-making process.
Nevertheless, the current data are not sufficient to assess a cut-off
value for the general population or for a specific condition such as
UC. These observations clarify the impelling necessity to develop
further prospective studies based on rigorous methods and design.
Clinical Genitourinary Cancer December 2016 - 483
 NLR Clinical Use in Urothelial Cancer
Acknowledgment
The authors thank Kimberlee Ann Manzi for professionally
reviewing the linguistic style of the manuscript and Dr. Luca Cin-
dolo for his supervision of the manuscript.
Disclosure
The authors have stated that they have no conflicts of interest.
References
1. Rouprêt M, Babjuk M, Compérat E, et al. European Association of Urology
Guidelines on upper urinary tract urothelial cell carcinoma: 2015 update. Eur Urol
2015; 68:868-79.
2. Redrow GP, Matin SF. Upper tract urothelial carcinoma: epidemiology, high risk
populations, and detection. Minerva Urol Nefrol 2016. [Epub ahead of print].
3. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflam-
mation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis
2009; 30:1073-81.
4. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420:860-7.
5. Song A, Eo W, Lee S. Comparison of selected inflammation-based prognostic
markers in relapsed or refractory metastatic colorectal cancer patients. World J
Gastroenterol 2015; 21:12410-20.
6. Yang JJ, Hu ZG, Shi WX, Deng T, He SQ, Yuan SG. Prognostic significance of
neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis. World J
Gastroenterol 2015; 21:2807-15.
7. Cho H, Hur HW, Kim SW, et al. Pre-treatment neutrophil to lymphocyte ratio is
elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer
Immunol Immunother 2009; 58:15-23.
8. Aliustaoglu M, Bilici A, Ustaalioglu BB, et al. The effect of peripheral blood values
on prognosis of patients with locally advanced gastric cancer before treatment. Med
Oncol 2010; 27:1060-5.
9. Li MX, Liu XM, Zhang XF, et al. Prognostic role of neutrophil-to-lymphocyte
ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer
2014; 134:2403-13.
10. Azab B, Jaglall N, Atallah JP, et al. Neutrophil-lymphocyte ratio as a predictor of
adverse outcomes of acute pancreatitis. Pancreatology 2011; 11:445-52.
11. Park JJ, Jang HJ, Oh IY, et al. Prognostic value of neutrophil to lymphocyte ratio
in patients presenting with ST-elevation myocardial infarction undergoing primary
percutaneous coronary intervention. Am J Cardiol 2013; 111:636-42.
12. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med
2009; 6:e1000097.
13. Azuma T, Matayoshi Y, Odani K, et al. Preoperative neutrophil-lymphocyte ratio
as an independent prognostic marker for patients with upper urinary tract uro-
thelial carcinoma. Clin Genitourin Cancer 2013; 11:337-41.
14. Cheng YC, Huang CN, Wu WJ, et al. The prognostic significance of
inflammation-associated blood cell markers in patients with upper tract urothelial
carcinoma. Ann Surg Oncol 2016; 23:343-51.
15. Dalpiaz O, Ehrlich GC, Mannweiler S, et al. Validation of pretreatment neu-
trophilelymphocyte ratio as a prognostic factor in a European cohort of patients
with upper tract urothelial carcinoma. BJU Int 2014; 114:334-9.
16. Hashimoto T, Ohno Y, Nakashima J, Gondo T, Ohori M, Tachibana M. Clinical
significance of preoperative peripheral blood neutrophil count in patients with
non-metastatic upper urinary tract carcinoma. World J Urol 2013; 31:953-8.
17. Kim M, Moon KC, Choi WS, et al. Prognostic value of systemic inflammatory
responses in patients with upper urinary tract urothelial carcinoma. World J Urol
2015; 33:1439-57.
18. Luo HL, Chen YT, Chuang YC, et al. Subclassification of upper urinary tract
urothelial carcinoma by the neutrophil-to-lymphocyte ratio (NLR) improves pre-
diction of oncological outcome. BJU Int 2014; 113:E144-9.
19. Sung HH, Gyun Jeon H, Jeong BC, et al. Clinical significance of prognosis using
the neutrophilelymphocyte ratio and erythrocyte sedimentation rate in patients
undergoing radical nephroureterectomy for upper urinary tract urothelial carci-
noma. BJU Int 2015; 115:587-94.
20. Tanaka N, Kikuchi E, Kanao K, et al. A multi-institutional validation of the prog-
nostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carci-
noma treated with radical nephroureterectomy. Ann Surg Oncol 2014; 21:4041-8.
484 - Clinical Genitourinary Cancer December 2016
21. Demirtaş A, Sabur V, Akınsal EC, et al. Can neutrophil-lymphocyte ratio and
lymph node density be used as prognostic factors in patients undergoing radical
cystectomy? Sci World J 2013; 2013:703579.
22. Gondo T, Nakashima J, Ohno Y, et al. Prognostic value of neutrophil-to-lymphocyte
ratio and establishment of novel preoperative risk stratification model in bladder
cancer patients treated with radical cystectomy. Urology 2012; 79:1085-91.
23. Hermanns T, Bhindi B, Wei Y, et al. Pre-treatment neutrophil-to-lymphocyte
ratio as predictor of adverse outcomes in patients undergoing radical cystectomy
for urothelial carcinoma of the bladder. Br J Cancer 2014; 111:444-51.
24. Kang M, Jeong CW, Kwak C, Kim HH, Ku JH. The prognostic significance of
the early postoperative neutrophil-to-lymphocyte ratio in patients with urothelial
carcinoma of the bladder undergoing radical cystectomy. Ann Surg Oncol 2016; 23:
335-42.
25. Krane LS, Richards KA, Kader AK, Davis R, Balaji KC, Hemal AK. Preoperative
neutrophil/lymphocyte ratio predicts overall survival and extravesical disease in
patients undergoing radical cystectomy. J Endourol 2013; 27:1046-50.
26. Ku JH, Kang M, Kim HS, Jeong CW, Kwak C, Kim HH. The prognostic value of
pretreatment of systemic inflammatory responses in patients with urothelial car-
cinoma undergoing radical cystectomy. Br J Cancer 2015; 112:461-7.
27. Mano R, Baniel J, Shoshany O, et al. Neutrophil-to-lymphocyte ratio predicts
progression and recurrence of nonemuscle-invasive bladder cancer. Urol Oncol
Semin Orig Investig 2015; 33:67e1-7.
28. Ozcan C, Telli O, Ozturk E, et al. The prognostic significance of preoperative
leukocytosis and neutrophil-to-lymphocyte ratio in patients who underwent radical
cystectomy for bladder cancer. Can Urol Assoc J 2015; 9:E789-94.
29. Viers BR, Boorjian SA, Frank I, et al. Pretreatment neutrophil-to-lymphocyte ratio
is associated with advanced pathologic tumor stage and increased cancer-specific
mortality among patients with urothelial carcinoma of the bladder undergoing
radical cystectomy. Eur Urol 2014; 66:1157-64.
30. Zhang GM, Zhu Y, Luo L, et al. Preoperative lymphocyte-monocyte and platelet-
lymphocyte ratios as predictors of overall survival in patients with bladder cancer
undergoing radical cystectomy. Tumour Biol 2015; 36:8537-43.
31. Bambury RM, Benjamin DJ, Chaim JL, et al. The safety and efficacy of single-
agent pemetrexed in platinum-resistant advanced urothelial carcinoma: a large
single-institution experience. Oncologist 2015; 20:508-15.
32. Morizane S, Iwamoto H, Yao A, Isoyama T, Sejima T, Takenaka A. Serum C-
reactive protein level is a significant prognostic indicator in patients with advanced
urothelial cancer treated with gemcitabine-cisplatin or carboplatin - preliminary
results. Cent Eur J Urol 2012; 65:62-6.
33. Rossi L, Santoni M, Crabb SJ, et al. High neutrophil-to-lymphocyte ratio
persistent during first-line chemotherapy predicts poor clinical outcome in patients
with advanced urothelial cancer. Ann Surg Oncol 2014; 22:1377-84.
34. Santoni M, Crabb SJ, Conti A, et al. Conditional survival of patients treated with
first-line chemotherapy for metastatic urothelial cancer. Clin Genitourin Cancer
2015; 13:244-9.
35. Taguchi S, Nakagawa T, Matsumoto A, et al. Pretreatment neutrophil-to-
lymphocyte ratio as an independent predictor of survival in patients with
metastatic urothelial carcinoma: a multi-institutional study. Int J Urol 2015; 22:
638-43.
36. Schmitz-Dräger BJ, Droller M, Lokeshwar VB, et al. Molecular markers for
bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD
consensus. Urol Int 2015; 94:1-24.
37. Formica V, Luccchetti J, Cunningham D, et al. Systemic inflammation, as
measured by the neutrophil/lymphocyte ratio, may have differential prognostic
impact before and during treatment with fluorouracil, irinotecan and bevacizumab
in metastatic colorectal cancer patients. Med Oncol 2014; 31:166.
38. Azab B, Camacho-Rivera M, Taioli E. Average values and racial differences of
neutrophil lymphocyte ratio among a nationally representative sample of United
States subjects. PLoS One 2014; 9:e112361.
39. Kılıçaslan B, Dursun H, Kaymak S, et al. The relationship between neutrophil to
lymphocyte ratio and blood pressure variability in hypertensive and normotensive
subjecs. Turk Kardiyol Dern Ars 2015; 43:18-24.
40. Müller I, Munder M, Kropf P, Hänsch GM. Polymorphonuclear neutrophils and
T lymphocytes: strange bedfellows or brothers in arms? Trends Immunol 2009; 30:
522-30.
41. McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a
decade of experience in patients with cancer. Cancer Treat Rev 2013; 39:534-40.
42. Dalpiaz O, Pichler M, Mannweiler S, et al. Validation of the pretreatment
derived neutrophilelymphocyte ratio as a prognostic factor in a European
cohort of patients with upper tract urothelial carcinoma. Br J Cancer 2014;
110:2531-6.