THE ROLE OF WHITE CELL COUNT AND C-REACTIVE PROTEIN

IN THE DIAGNOSIS OF ACUTE APPENDICITIS

Khan MN, Davie E, Irshad K
Department of General Surgery, Wishaw General Hospital, Wishaw, Lanarkshire. UK

Background: Despite recent advances in diagnostic medicine, the diagnosis of appendicitis is

still doubtful in a number of cases. Majority of the clinicians rely on their clinical examination
strengthened by the laboratory tests. This study was carried out to find out the specificity and
sensitivity of white cell count (WCC) and C-Reactive Protein (CRP) in diagnosing
appendicitis in patients presenting with right iliac fossa pain. Methods: A total of 259 patients
were included in this study that presented in the hospital with acute right iliac fossa pain and
later on operated and had appendicectomy. The histopathology data was collected to find out
the frequency of negative appendicectomy. According to the histopathology reports these
patients were grouped into three sub-groups as normal appendix, inflamed appendix or
perforated/gangrenous appendix. A record was kept of the WCC and CRP levels of these
patients on admission. Results: A total of 259 patients were included in this study and out of
them 37 had a normal appendix giving an over all negative appendicectomy rate of 14.3%.
Out of these 11 were male and 26 were female, male to female ratio being 1:2.3. The age
range was 12-73 with a median age of 24. Among the 222 patients who had appendicitis, 96
had a ruptured /perforated appendix and 126 had an inflamed appendix. Over all the WCC was
elevated in 185 patients and CRP was elevated in 168 cases. The cut off value for white cell
count was 11 x 106 / L. The C reactive protein levels were calculated by immunoturbidimetric
test and the cut off value was taken as 1.7mg/dl. The sensitivity and specificity of WCC in this
study was 83% and 62.1 % and that for CRP was 75.6% and 83.7 %. Conclusion: Both the
inflammatory markers i.e. WCC and C-reactive protein can be helpful in the diagnosis, when
measured together as this increases their positive predictive value.
Key words: appendicitis, white cell count, C reactive protein

INTRODUCTION
Acute appendicitis is still one of the commonest surgical emergencies. 1 The diagnosis is primarily clinical. 2 A
typical patient is one presenting with right lower abdominal pain, nausea and vomiting and has got tenderness
and guarding in right iliac fossa on examination. However these sign & symptoms are not very specific for
appendicitis and can mimic any other acute abdominal condition. 3 The picture is more confused by the variable
position of the appendix.4 Despite advances in diagnostic modalities the diagnosis is still doubtful in 30-40 % of
cases.5 And the definite diagnosis of appendicitis still remains a clinical decision. , augmented by appropriate
tests. A high degree of diagnostic accuracy is required to reduce the incidence of negative appendicectomies
which still remains around 20 %.6 One study has shown an incidence of 50% in women of reproductive age
group.7 Acute appendicitis is a disease of young adults.8 It is rare below 3 years of age but people are vulnerable
to it in extremes of their age and complication rate is higher in those groups. It is more common in males as
compared to females. It used to be called as the disease of developed countries with an association of high
protein intake, but the incidence is also increasing in developing countries. A study reported it to be around
1.9/1000 for males and 1.5/1000 for females.9
Apart from a careful history and clinical examination, total white cell count has remained an important
factor in the definite diagnosis of appendicitis. Various studies have shown that this can be very non-specific at
times.10 Recently interest has grown in other inflammatory markers which could be helpful in diagnosing
appendicitis. CRP is one of them. This study was conducted to check the sensitivity and specificity of the white
cell count and CRP in patients presenting with right iliac fossa pain.

MATERIAL AND METHODS

This study was carried out at Wishaw General Hospital, which is a modern district general hospital in the west
of Scotland, serving a population of 160,000. This study included all the patients admitted with right iliac fossa
pain and then had appendicectomy between September 2001-2002. The records of all such patients were
accessed from the pathology department with the histopathology results. This was used to get the incidence of
negative appendicectomy and then on these features patients were divided into 3 groups as
1- normal appendix
2- inflamed appendix

3-

perforated/gangrenous appendix
Their blood results were reviewed and a note of WCC and CRP levels was made. The sensitivity and
specificity of these tests were calculated according to the following formulas,
Sensitivity = True Positives/ True Positives + False Negatives
Specificity = True Negative/ True Negative + False Positive
The cut off value for white cell count was 11x10 6/L. This value was selected arbitrarily as it
corresponds to the elevated WCC. The C reactive protein levels were calculated by immunoturbidimetric test
and the cut off value was taken as 1.7mg/dl. This cut off value was taken in light of the previous research which
showed it to be highly accurate.11

RESULTS
A total of 259 patients were included in this study and out of them 37 had a normal appendix giving an over all
negative appendicectomy rate of 14.3%. Out of these 11 were male and 26 were female, male to female ratio
being 1:2.3, again highlighting the fact that the diagnosis of appendicitis is straightforward in men but could be
just a guess in females. The age range was 12-73 with a median age of 24. Among the 222 patients who had
appendicitis, 96 had a ruptured /perforated appendix and 126 had an inflamed appendix. Over all the WCC was
elevated in 185 patients and CRP was elevated in 168 cases. The sensitivity and specificity of WCC in this study
was 83 % and 62.1 % and that for CRP was 75.6 and 83.7 %. The positive predictive values for WCC and CRP
were 92% and 96% respectively (p<0.001).
Table-1: Analysis of white cell count measurements in patients with RIF pain

White Cell Count

Raised
White Cell Count
Normal

Group I
n = 37

Group II
n = 126

Group III
n = 96

14

96

89

23

30

07

Group I = patients with normal appendix

Group II = patients with inflammed appendix
Group III = patients with perforated/gangrenous appendix
Sensitivity = 83.3%, Specificity = 62.1%
Positive predictive value = 92%
Degree of freedom : 2, Chi Square = 45.23
P < 0.001 , hence the distribution is significant

DISCUSSION
Majority of the patients with acute appendicitis present with right sided lower abdominal pain and nausea and
vomiting, but these symptoms are very non-specific. In fact any acute abdominal condition can mimic
appendicitis and hence the list of differential diagnosis is long and hence removal of a normal appendix is not
unusual.
Table-2: Analysis of CRP measurements in patients with RIF pain

CRP Raised
CRP Normal

Group I
N = 37
6
31

Group II
N = 126
81
45

Group III
N = 96
87
09

Group I = patients with normal appendix

Group II = patients with inflammed appendix
Group III = patients with perforated/gangrenous appendix
Sensitivity = 75.6%, Specificity = 83.7%
Positive predictive value = 96%
Degree of freedom = 2, Chi Square = 67.99
P < 0.001 , hence distribution is significant.

A high degree of diagnostic accuracy is required to reduce the incidence of negative appendicectomies
which still remain around 20 %. One study has shown the diagnostic accuracy of acute appendicitis of 60% in
women of reproductive age group. 12 The implications can be two folds. Firstly although appendicectomy is
considered to be a safe operation it still has got associated complications, most noticeable among them are
wound infection, intra abdominal abscess, adhesions and bowel obstruction and pulmonary complications from
general anaesthesia.13 Secondly, the group of patients who have persistent symptoms after the operation are
unsatisfied with the health care they received and are a burden on the hospital resources.

To improve the diagnostic accuracy surgeons have relied on a good history and sound clinical
examination augmented by laboratory investigations ranging from simple blood tests looking at the white cell
count, to modern sophisticated investigations including computerised tomography, ultrasonography, peritoneal
aspirations, barium enema and laparoscopy.14-16 But all these investigations have their demerits. They are
invasive, time consuming, operator dependent and not very freely available everywhere. Among all these
looking at the WCC has been very favourite test for the surgeons in deciding for probability of appendicitis
although studies have shown it to have a low specificity.17 The question of specificity and sensitivity of these
tests remains open.
To improve the sensitivity and specificity surgeons have tried sequential leukocyte counts and
neutrophil: lymphocytic ratio.18-19 Recently attention has been focussed on other inflammatory markers which
can be raised in appendicitis, CRP (C-reactive protein) being one of them. CRP was identified in 1930 and is
regarded as the acute phase protein. It has been studied as a screening device for inflammation , a marker for
disease activity and as a diagnostic adjunct. 20 Several studies have addressed the accuracy of CRP in diagnosing
appendicitis and it is agreed that its level increases in appendicitis and this increase is related to the severity of
appendiceal inflammation.11 However CRP levels may be elevated in patients with complications from
pneumonia, pelvic inflammatory disease, and urinary tract infections.
This study showed that white cell count and CRP both are sensitive in diagnosing acute inflammation
but they are not very specific. Combining the two tests together the specificity and positive predictive value
increases. The measurement of CRP is useful in the diagnosis of acute appendicitis. In this study we have 37
patients in group I, where the appendix was found normal. In 23 of these patients both values were in the normal
range. The accuracy of these tests increases with the increasing severity of inflammation. In group III where the
appendix was found to be perforated or gangrenous, only 7 patients out of 87 had normal values of either CRP
or WCC. In both groups II and III no patients were found with CRP or WCC with in normal range. We would
recommend that if in a patient presenting with right iliac fossa pain, both CRP and WCC are normal the
diagnosis of appendicitis is very unlikely.

REFERENCES
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Pal K, Khan A. Appendicitis: a continuing challenge. J Pak Med Assoc 1998;48(7):189-92.

Abbassi A, Shah Y. Acute appendicitis in children. J Surg Pakistan 1998;2:28-30
Davenport M. Acute abdominal pain in children. BMJ 1996;312(7029):498-501
Delic J, Savkovic A, Isakovic E. Variations in the position and point of origin of vermiform appendix. Med Arch 2002;56(1):5-8.
Anderson R , Hugander A , Ghazi S , Ravan H , Offenbartl S, Nystron P et al. Diagnostic value of disease history, clinical presentation
and inflammatory parameters of appendicitis. World J Surg 1999;23(2):133-40.
Eryilmaz R, Sahin M, Amlimoglu O, Bas G, Ozkan O. The value of C reactive protein and leukocyte count in preventing negative
appendicectomies. Ulus Travma Derg 2001;7(3):142-5.
Andeson R, Lambe M, Reinhold B. Fertility pattern after appendectomy: Historical Cohort study BMJ 1999;18:963-7.
Peltokallio P, Tykka H. Evaluation of the age distribution and mortality of acute appendicitis. Arch Surg 1981;116: 153-6.
Ellis W. Acute Appendicitis: In Hamilton Baileys Emergency Surgery. 12th ed. Oxford. Butterworth Heinemann, 1995;411-23.
Khalid K, Ahmed N, Farooq, Anjum I, Sial G. Acute Appendicitis-laboratory dependence can be misleading: audit of 211 cases. J Coll
Physicians Surg Pak 2001;11(7):434-7.
Rodriguez S, Martin P, Seco I, Garcia C, Naranjo A. C reactive protein and leukocyte count in the diagnosis of acute appendicitis in
children. Dis Colon Rectum 1999;42(10):1325-9.
Gronroos J, Gronroos P. A fertile aged woman with right lower abdominal pain but unelevated leukocyte count and C reactive protein.
Acute appendicitis is very unlikely. Langenbecks Arch Surg 1990; 384(5):437-40.
Malik K, Khan A, Waheed A. Evaluation of Alvarado Score in the diagnosis of Acute Appendicitis. J Coll Physicians Surg Pak
2000;10:392-4.
Eriksson S, Josephson T, Styrud J. A high degree of accuracy is possible in the diagnosis of appendicitis. Laboratory tests,
ultrasonography and computerized tomography are of great value. Lakartidningen 1999;96(25):3058-61.
Zeidan B, Wasser T, Nicholas G. Ultrasonography in the diagnosis of appendicitis. J R Coll Surg Edinb 1997;42(1):24-6.
Caldwell M, Watson R. Peritoneal aspiration cytology as a diagnostic aid in acute appendicitis. Br J Surg 1994;81:276-8.
Coleman C, Thompson J, Bennion R, Schmit P. White Blood Cell count is a poor predictor of severity of disease in diagnosis of
appendicitis. Am Surg 1998;64(10):983-5.
Thomson M, Underwood M, Dookeran K, Lloyd D, Bell P. Role of sequential leukocyte count and CRP measurements in acute
appendicitis. Br J Surg 1992; 79(8):822-4.
Goodman D, Goodman C, Monk J. Use of neutrophil: lymphocyte ratio in the diagnosis of appendicitis. Am Surg 1995;61(3):257-9.
Clyne B, Olshaker J. The C Reactive Protein. J Emerg Med 1999;17(6):1019-25.

Address for Correspondence:

M.N Khan, Specialist Registrar, General Surgery, Luton & Dunstable Hospital, Luton. 16 Calnwood Road,
Luton, England, LU4 0ET. Phone No.0044-7944551416, 0044-1582491122bleep 501,
Email:najmussaqib_pk@hotmail.com

The systemic inflammation-based neutrophil

lymphocyte ratio: Experience in patients with cancer
Graeme J.K. Guthrie
,

Kellie A. Charles
,

Campbell S.D. Roxburgh

,

Paul G. Horgan
,

Donald C. McMillan
,

Stephen J. Clarke
Jump to Section

Abstract
There is increasing and consistent evidence that cancer-associated inflammation is a key determinant of outcome
in patients with cancer. Various markers of inflammation have been examined over the past decade in an attempt
to refine stratification of patients to treatment and predict survival. One routinely available marker of the systemic
inflammatory response is the neutrophillymphocyte ratio (NLR), which is derived from the absolute neutrophil
and absolute lymphocyte counts of a full blood count. To date, over 60 studies (>37,000 patients) have examined
the clinical utility of the NLR to predict patient outcomes in a variety of cancers. The present systematic review
examines and comments on the clinical utility of the NLR. The NLR had independent prognostic value in (a)
unselected cohorts (1 study of >12,000 patients), (b) operable disease (20 studies, >4000 patients), (c) patients
receiving neoadjuvant treatment and resection (5 studies, >1000 patients), (d) patients receiving
chemo/radiotherapy (12 studies, >2000 patients) and (e) patients with inoperable disease (6 studies, >1200
patients). These studies originated from ten different countries, in particular UK, Japan, and China. Further,
correlative studies (15 studies, >8500 patients) have shown that NLR is elevated in patients with more advanced
or aggressive disease evidenced by increased tumour stage, nodal stage, number of metastatic lesions and as
such these patients may represent a particularly high-risk patient population. Further studies investigating the

tumour and host-derived factors regulating the systemic inflammatory response, in particular the NLR, may
identify novel treatment strategies for patients with cancer.

Keywords:
Cancer, Tumour-stage, Neutrophil lymphocyte ratio, Survival
Jump to Section

1. Introduction
Cancer is the leading cause of disease worldwide with 12.7million new cancer cases diagnosed worldwide in
2008 [1]. More than one in three people will develop some form of cancer in their lifetime and it remains the
leading cause of death with 7.6million cancer deaths worldwide recorded in 2008 [1], far exceeding deaths from
other diseases such as heart disease and stroke [1]. Despite intense research activity outcomes from malignancy
remain poor for the most common cancers.
In recent years there have been significant advances in cancer treatment. However, the appropriate stratification
of cancer patients and subsequent allocation to surgical, oncological and palliative treatments remains a
challenge. Until recently, the prediction of outcome has relied almost exclusively on accurate staging of the
tumour. Indeed, many studies have attempted to refine TNM staging using tumour-associated criteria.
It is now widely recognised that outcomes in patients with cancer are not determined by tumour characteristics
alone, and that patient-related factors are also key to outcome. In the last decade, it has become increasingly
apparent that cancer-associated inflammation is a key determinant of disease progression and survival in most
cancers [[2], [3]]. In particular, the host response in the form of systemic inflammation has been shown to
independently predict outcome. The basis of this is not altogether clear, however a marked systemic inflammatory
response is associated with important patient-related factors such as nutritional, functional and immunological
decline.
In recent years many studies have investigated the most commonly used measures of the systemic inflammatory
response and their potential use in stratifying cancer patients.
For example, there is good evidence that markers of the acute phase response, particularly C-reactive protein
and albumin, are both sensitive and reliable markers of systemic inflammation in cancer patients [4]. Indeed, the
last decade has seen the evolution of a prognostic scoring system, the Glasgow Prognostic Score (GPS) based
on the combination of these acute phase proteins that provides objective, reliable prognostic information for both
operable and inoperable cancers [5]. Indeed, this scoring system has been validated in a variety of clinical
scenarios and is now recognised to have prognostic value, independent of tumour-based factors [5].

It is also well established that the systemic inflammatory response is associated with alterations in circulating
white blood cells, specifically the presence of neutrophilia with a relative lymphocytopaenia [[6], [7]]. In addition,
haematological tests are carried out routinely for cancer patients in a variety of clinical scenarios, and as such
represent an easily measurable objective parameter able to express the severity of the systemic inflammatory
response in patients with cancer. Indeed, Walsh et al., investigated the prognostic value of the neutrophil
lymphocyte ratio (NLR), in their centre, because C-reactive protein concentrations were not routinely performed
as part of pre-treatment assessment [8].
In recent years, and in a similar way to the GPS [5], many research groups have investigated the value of the
haematological components of the systemic inflammatory response specifically for use in predicting outcome,
and have reported that the individual components of the differential white cell count, specifically the neutrophil
and lymphocyte counts, may have clinical utility in predicting survival [9]. Indeed, the combination of these
haematological components of the systemic inflammatory response, as the neutrophillymphocyte ratio (NLR),
has been reported to have prognostic value in a variety of cancers [[4], [10]].
Therefore the aim of the present review was to provide a concise overview of the NLR studies in patients with
cancer and comment on the current and future clinical utility of this simple objective systemic inflammation-based
score.
Jump to Section

2. Method
This systematic review of published literature was undertaken according to a pre-defined protocol. The primary
outcome of interest was the relationship between the neutrophillymphocyte ratio and cancer outcome (overall
survival/cancer-specific survival/disease recurrence or response to treatment). The secondary outcomes of
interest were the associations between the NLR and other clinical, pathological or inflammatory characteristics.
A literature search, using appropriate free text and medical subject heading (MeSH) terms, was made of the US
National Library of Medicine (MEDLINE), the Excerpta Medica database (EMBASE), the Cochrane Database of
Systematic Reviews (CDSR) for articles reporting the prognostic value of the NLR with regard to cancer outcome
(June 2005October 2012).
On completion of the online search, the titles and abstracts were examined before full text was obtained for
studies with potential relevance. Of these, studies which had examined the prognostic value of NLR in solid organ
malignant disease were included while review articles, studies relating to duplicate data sets, studies not available
in English language and those published in abstract form only were excluded. The bibliographies of all included
articles were subsequently hand-searched to identify any additional studies of interest. Studies were selected
after review by the authors.

Study heterogeneity precluded a meaningful meta-analysis and the results are presented in descriptive form only.
For each group of studies a weighted average hazard ratio for an incremental increase in the NLR was calculated
by multiplying the hazard ratio reported in the study by the number of patients in the study. The product of this
multiplication was added to the products of other studies in the group and the total was divided by the total
number of all the patients in the group studies.
Jump to Section

3. Studies of the prognostic value of the NLR, in unselected cohorts of patients with cancer
Three studies, comprising data on 21,193 patients reported the prognostic value of the NLR in unselected cohorts
of patients with cancer (Table 1, Refs. [[11], [16], [17]]). Two studies specifically assessed the prognostic value of
the NLR, while one compared the NLR with other well recognised markers of the systemic inflammatory response
in cancer, notably C-reactive protein, albumin, and platelets and their combinations in the prognostic scores
mGPS and platelet-lymphocyte ratio (PLR). Two studies examined markers of systemic inflammation across all
tumour types while the remaining one investigated its prognostic value in breast cancer. NLR was associated with
disease-free and overall survival in two studies and was reported as an independent predictor of survival along
with the derived NLR (dNLR) in one study. Despite being relatively similar, the threshold chosen to define an
elevated NLR differed across all three studies, ranging from >3.33 to >5, and therefore calculation of a weighted
average hazard ratio for an incremental change in NLR was not appropriate.

Table 1Studies of the prognostic value of the NLR in unselected cohorts of

patients with cancer.

Stud
y

Centr
e

Tumou
r site

HR (pvalue)

Thresh
old

Azab et
al. [16]

New
York
(USA)

Breast

316

4.85
(<0.000
1)

>3.33

Elevated NLR was associated with

the elderly, larger tumours, and
more advanced stage

Proctor
[11]

Glasgow
(UK)

Various

8759

1.97
(<0.001)

>5

Elevated NLR (>5) was associated

with reduced 5year OS and DFS

Proctor
[17]

Glasgow
(UK)

Various

12,1
18

1.52
(<0.001)

>4

NLR and dNLR were associated with

reduced OS and DFS independent
of age, sex and deprivation. NLR
superior to dNLR

DFS, disease-free survival; OS, overall survival.

Comments

In conclusion, there is evidence that the NLR has prognostic value in a variety of tumour types. Although the NLR
is associated with survival, other markers of the systemic inflammatory response, notably the GPS/mGPS, may
be superior predictors of survival. Indeed, a recent large cohort study (Glasgow Inflammation Outcome Study)
reported that the mGPS had superior prognostic value over the NLR in differentiating good from poor prognostic
groups in a variety of tumour types [11].
More recently, the components of a number of systemic inflammation-based scores (neutrophils, lymphocytes,
platelets, C-reactive protein and albumin) have been compared in a large unselected cohort of patients with
cancer. Of these components, only neutrophils, platelets, C-reactive protein and albumin were shown on
mutivariate survival analysis to have independent prognostic value [12]. These results may explain the reported
superiority of the GPS over the NLR.
Jump to Section

4. Studies of the prognostic value of the NLR in patients with operable cancer
Thirty-four studies, comprising data on 12,426 patients have investigated the prognostic value of the neutrophil
lymphocyte ratio in patients with a variety of solid organ malignancies including colorectal, gastric, oesophageal,
pancreatic, liver, urological and gynaecological cancers (Table 2, Refs. [[8], [18], [19], [20], [21],
[22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [4
4],[45], [46], [47], [48], [49]]). Interestingly, the threshold that defined an elevated NLR differed across these thirty
four studies with >5 being the most commonly used threshold (n=16 studies).

Table 2Studies of the prognostic value of the NLR in patients with operable
cancer.

Tumour
site

Guangdo
ng
(China)

Colorectal

141

4.88
(0.003)

>4

Elevated NLR associated with

reduced DFS and an independent
prognostic factor and not
associated with
clinicopathological
characteristics

Kwon et
al. [19]

Busan
(Korea)

Colorectal

200

(Nonsignifica
nt)

>5

Elevated NLR associated with

lower OS on univariate analysis
only. NLR not associated with
clinicopathological factors or
stage of disease

Neal et
al. [20]

Leicester
(UK)

Colorectal

202

2.05
(0.001)

>5

NLR associated with post

operative morbidity and OS on

Study

Centre

Ding et
al. [18]

HR (p- Thresh
value) old

Comments

univariate analysis
Walsh et
al. [8]

Suffolk
(UK)

Colorectal

230

(<0.001)

>5

NLR>5 associated with OS and

CS survival on univariate analysis

Leitch et
al. [21]

Glasgow
(UK)

Colorectal

233

(Nonsignifica
nt)

>5

NLR associated with other

measures of systemic
inflammation but not prognostic
in primary operable disease

Mallappa
et al. [22]

Harrow
(UK)

Colorectal

297

1.81
(0.028)

>5

Elevated NLR independently

associated with survival

Halazun
et al. [23]

Leeds
(UK)

Colorectal

440

2.26
(<0.001)

>5

Elevated NLR, age and number of

metastases were independent
prognostic factors

Gomez et
al. [24]

Leeds
(UK)

Colorectal

501

1.3
(0.032)

>5

Elevated NLR associated with

recurrence

Hung et
al. [25]

Tao-Yuan
(Taiwan)

Colorectal

104
0

1.29
(0.012)

>5

NLR associated with significantly

worse OS (5years). NLR
associated with advancing age
(>65), T4b cancer, elevated CEA
and tumour
obstruction/perforation. NLR not
associated with histological
subtype, tumour size, tumour
grade

Chiang et
al. [26]

Linkou
(Taiwan)

Colorectal

373
1

1.31
(0.013)

>3

Elevated NLR was associated

with clinicopathological factors
associated and with outcome

Ubukata
et al. [27]

Tokyo
(Japan)

Gastric

157

5.78
(<0.001)

>5

NLR independently prognostic

and associated with T-stage,
tumour size, presence of lymph
nodes, and pathological stage

Aizawa et
al. [28]

Kashiwa
(Japan)

Gastric

262

2.21
(0.012)

>3.2

NLR was an independent

prognostic factor. NLR increased
in a T-stage dependent manner

Jung et
al. [29]

Gwangju
(Korea)

Gastric

293

1.65
(0.019)

>2

Elevated NLR significantly

associated with OS and DFS in
later stage gastric cancer.
Elevated NLR associated with
advanced T-stage, and larger
tumour size

Rashid et
al. [30]

Derby
(UK)

Oesophag
eal

294

>3.5

NLR not associated with tumour

factors or with disease

recurrence or survival
Wang et
al. [31]

Guangzh
ou
(China)

Gastric

324

2.32
(0.014)

>5

GPS more prognostic than NLR

Mohri et
al. [32]

Tsu
(Japan)

Gastric

357

2.78
(<0.000
1)

>2.2

NLR independently associated

with prognosis together with
tumour size, advanced T-stage in
relatively early stage gastric
cancer

Shimada
et al. [33]

Tokyo
(Japan)

Gastric

102
8

1.85
(0.003)

>4

NLR was an independent

prognostic factor and increased
in a t-stage dependent manner

Garcea et
al. [34]

Leicester
(UK)

Pancreas

74

>5

NLR significantly associated with

recurrence, and was more
prognostic than components
alone

Bhatti et
al. [35]

Derby
(UK)

Pancreas

84

1.78
(0.023)

>4

NLR reported an independent

prognostic factor for survival and
not associated with tumour
characteristics

Smith et
al. [36]

Liverpool
(UK)

Pancreas

110

Continuou
s

No relationship between NLR and

survival

Wang et
al. [37]

Guangzh
ou
(China)

Pancreas

177

2.54
(0.006)

>5

NLR independently associated

with OS

Gomez et
al. [38]

Leeds
(UK)

Cholangiocarcinoma

27

1.78
(0.008)

>5

Elevated NLR associated with

poorer DFS, and associated with
larger tumours, intrahepatic
satellite lesions, microvascular
invasion and lymph node
involvement

Kinoshita
et al. [39]

Tokyo
(Japan)

Liver

150

>5

Along with mGPS and GPS, NLR

was associated with reduced OS.
NLR not independently
associated with OS

Motomur
a et al.
[13]

Fukuoka
(Japan)

Liver

158

6.24
(0.0002)

>4

Increasing NLR associated with

HCC recurrence. Associated with
other markers of systemic
inflammation

Sakai et
al. [40]

Aomori
(Japan)

Lung

23

(Nonsignifica

Continuou
s

NLR had no significant

relationship with recurrence or

nt)

survival

Sarraf et
al. [41]

London
(UK)

Lung

178

1.1
(0.004)

>5

NLR associated with T-stage and

was an independent predictor of
outcome

Tomita et
al. [42]

Miyazaki
(Japan)

Lung

284

(<0.001)

>2.5

NLR predicted significantly worse

5year survival. NLR only
independent risk factor

Tomita et
al. [43]

Miyazaki
(Japan)

Lung

301

(<0.001)

>2.5

Combined use of NLR and CRP

reported as independent
prognostic factor

Hashimot
o et al.
[44]

Tokyo
(Japan)

Renal

84

(0.026)

Continuou
s

NLR associated with DFS

Gondo et
al. [45]

Tokyo
(Japan)

Bladder

189

1.95
(0.0387)

>2.5

NLR independent predictor of

prognosis

Ohno et
al. [46]

Tokyo
(Japan)

Renal

192

2.16
(0.0259)

>2.7

Pre-operative NLR associated

with CRP. T-stage and elevated
NLR were independent predictors
of recurrence with decreased
survival

Ohno et
al. [47]

Tokyo
(Japan)

Renal

250

3.12
(0.0007)

>2.7

Elevated NLR associated with

DFS and was independent
prognostic variable.

Cho et al.
[48]

Seoul
(Korea)

Ovary

192

8.4
(0.041)

>2.6

Elevated NLR, advancing stage,

and older age were independent
prognostic factors

Idowu et
al. [49]

Liverpool
(UK)

Sarcoma

223

5.13
(0.024)

>5

NLR independently associated

with OS and associated with
worse DFS

DFS, disease-free survival; OS, overall survival.

Ten studies comprising data on 7015 patients have investigated the prognostic value of the NLR in operable
colorectal cancer [[8], [18], [19], [20], [21], [22], [23], [24], [25], [26]], including in patients with resection of
colorectal liver metastases. These studies were from the UK (6), Taiwan (2), China (1) and Korea (1). The
neutrophillymphocyte ratio was consistently associated with overall and disease-free survival in studies of
operable colorectal cancer on univariate analysis, however, NLR was reported to have independent prognostic
value in only four studies in colorectal cancer. NLR was consistently associated with other markers of systemic
inflammation, in particular C-reactive protein and the modified Glasgow Prognostic Score (mGPS) in operable

colorectal cancer. The relationship between the neutrophillymphocyte ratio and pathological features in
colorectal cancer was inconsistent.
Only two studies reported a significant direct association between the NLR and T-stage while associations with
other tumoural factors including tumour size, differentiation and tumour location were reported in one study. With
regard to the threshold defining an elevated NLR, the most consistently used threshold was >5 (eight studies),
one study used a threshold of >4, and another study used a threshold of >3. Of the studies using the most
common threshold (>5), the weighted average hazard ratio for an incremental increase in the NLR was 1.4.
Seven studies, (six gastric and one oesophageal), comprising data on 2715 patients investigated the prognostic
value of the NLR in operable gastro-oesophageal cancer [[27], [28], [29], [30], [31], [32], [33]]. These studies were
from Japan (4), the UK (1), China (1) and Korea (1). The majority of studies reported that NLR was an
independent predictor of survival in operable gastro-oesophageal cancer. Four studies reported an association
between elevated NLR and tumour variables, in particular, NLR was reported to increase with T-stage. The
threshold used to define an elevated NLR was inconsistent with each study in oesophageal disease utilising a
different threshold, ranging from >2 to >5. Given the heterogeneity of thresholds used in this group of studies it
was not appropriate to calculate the weighted average hazard ratio for an incremental increase in the NLR.
There were four studies, comprising data on 445 patients investigating the prognostic value of the NLR in
pancreatic cancer [[34], [35], [36], [37]]. Three of these were from the UK and one was from China. Two studies
reported that NLR was an independent predictor of overall survival, however this was not the case for diseasefree survival. In addition, there were no reports of a significant association between clinicopathological variables
and NLR. Interestingly, the study by Wang and colleagues [33] reported that the NLR was significantly associated
with markers of functional decline, including poor performance status and weight loss. The threshold used to
define an elevated NLR was >5 in two studies, >4 in one study, and one study used continuous measurement of
the NLR in the analysis.
Of the two studies using the most commonly used threshold of >5 only one reported a hazard ratio and therefore
it was not appropriate to calculate the weighted average hazard ratio for an incremental increase in the NLR.
Three studies, comprising data on 335 patients investigated the prognostic value of the NLR in hepatocellular
carcinoma [[13], [39], [40]]. Two of these studies were from Japan, and one was from the UK. Two studies
reported the NLR to be associated with overall survival and one study by Gomez et al. [38] reported and elevated
NLR (>5) to be associated with development of satellite lesions, microvascular invasion, and nodal disease. As in
other studies of operative disease at least one group reported that the acute phase protein response appears to
have superior prognostic value. The threshold used to define an elevated NLR was >5 in two studies, and >4 in
one study. Of the two studies using the most commonly used threshold of >5 only one reported a hazard ratio and
therefore it was not appropriate to calculate the weighted average hazard ratio for an incremental increase in the
NLR.

Four studies, comprising data on 786 patients, three from Japan and one from the UK, reported the prognostic
value of the NLR in lung cancer patients undergoing resection [[40], [41], [42], [43]]. Three studies reported a
significant association between elevated NLR and survival. Elevated NLR was reported as an independent
prognostic variable in two of these studies. Interestingly, a study by Tomita and colleagues reported that a
combined score using C-reactive protein and NLR was an independent predictor of survival. However, in this
study they report that an elevated C-reactive protein was associated with longer survival, contrary to the
published literature on the prognostic value of C-reactive protein in many solid organ malignancies [4]. The
threshold used to define an elevated NLR was >2.5 in two studies, >5 in one study and as a continuous variable
in one study. Only one study used the most commonly used threshold of >5 and so calculation of the weighted
average hazard ratio was therefore not appropriate.
Four studies, comprising data on 715 patients reported the prognostic value of the NLR in urothelial malignancy
[[44], [45], [46], [47]]. All of these studies were from Japan. Three studies reported that elevated NLR was an
independent predictor of survival, with one study reporting an association with disease-free survival. No
associations with tumoural factors were reported. The threshold used to define an elevated NLR was >2.7 in two
studies, 2.5 in one study and as a continuous variable in one study. None of these studies used the most
common threshold of >5. Given the heterogeneity of the thresholds used calculation of the weighted average
hazard ratio was not appropriate.
One study, comprising data on 192 patients reported the prognostic value of the NLR in gynaecological
malignancy [48]. This study was from Korea. The pre-treatment NLR was associated with overall and diseasefree survival in one study and was reported as an independent prognostic factor together with advancing stage
and increasing age, (HR=8.42 [95% CI: 1.0964.84], p=0.041).
There was one study of the prognostic value of the NLR in patients with soft tissue sarcoma [49]. This study by
Idowu and colleagues reported an association between pre-operative NLR and disease-free survival. Along-with
tumour grade, NLR was associated with overall survival (HR=4.24 [95% CI: 1.1415.82], p=0.031).
In conclusion, the last decade has seen the accumulation of good evidence supporting associations between the
neutrophillymphocyte ratio and outcome in patients with operable disease, in particular gastrointestinal cancer.
However, while pre-operative NLR is associated with both disease-free and overall-survival in some studies there
is a lack of consistent evidence for its value as an independent predictor of survival, particularly in early stage and
less aggressive disease. Other markers of the systemic inflammatory response, in particular the mGPS, appear
to have stronger prognostic value in these patients.
Jump to Section

5. Studies of the prognostic value of the NLR in patients with operable cancer who received
neoadjuvant therapy
Six studies, comprising data on 1044 patients have reported the prognostic value of the NLR in patients who
received neo-adjuvant therapy and subsequently underwent cancer resection (Table 3, Refs. [[50], [51], [52],
[53], [54], [55]]).

Table 3Studies of the prognostic value of the NLR in patients with operable
cancer who received neoadjuvant therapy.

Stud
y

Centre

Wang
[50]

Guangdon
g (China)

Halazun
[51]

Tumour
site

HR (pvalue)

Thresh
old

HCC

10
1

2.65
(<0.001)

>3

Elevated NLR independently

associated with poor DFS

New York
(USA)

Liver

15
0

19.99
(0.005)

>5

Elevated NLR associated with

increased risk of recurrence and
death

Bertuzz
o [52]

Bologna
(Italy)

Liver

21
9

19.14
(<0.001)

>5

Elevated NLR associated with

lower OS. Elevated NLR and MVI
negatively affected DFS. Elevated
NLR and MVI were independent
prognostic factors

Sato
[53]

Shizuoka
(Japan)

Oesophag
eal

83

2.83
(0.043)

>2.2

NLR associated with pathological

response to neoadjuvant
chemotherapy

Miyata
[54]

Osaka
(Japan)

Oesophag
eal

15
2

(Nonsignifican
t)

>4

Elevated NLR associated with

survival but not independently
prognostic

Sharaih
a [55]

New York
(USA)

Oesophag
eal

33
9

2.26
(<0.001)

>5

Elevated NLR associated with

worse DFS and OS independent of
tumour type

Comments

DFS, disease-free survival; OS, overall survival.

Three of these studies, comprising data on 470 patients, were in hepatocellular carcinoma (HCC) [[50], [51],[52]].
One study was from the USA, one was from Italy, and one from Japan. Among these studies it was consistently
reported that elevated NLR was associated with increased risk of recurrence and risk of death. Although the
thresholds for an elevated NLR differed in one of these studies it was consistently reported that elevated NLR was

an independent predictor of both disease-free and overall survival in hepatocellular carcinoma. Interestingly, two
of these studies reported a significant relationship between NLR and microvascular invasion in HCC. The
threshold used to define an elevated NLR was >5 in two studies, and >3 in one study. The weighted average
hazard ratio for an incremental increase in the NLR in the two studies using the most commonly used threshold of
>5 was 19.49.
Three studies, comprising data on 574 patients, reported the prognostic value of NLR in patients with
oesophageal cancer [[53], [54], [55]]. Two studies were from Japan while one was from the USA. In patients
receiving neoadjuvant chemotherapy followed by resection it was reported that elevated NLR was associated with
survival. Interestingly, while the study by Sato and colleagues reported an independent association between the
NLR and pathological response to treatment, the study by Sharaiha and colleagues reported no association
between the NLR and response to treatment. However, both these studies reported an association between
elevated NLR and poor prognosis with Sharaiha and colleagues reporting elevated NLR as an independent
prognostic factor regardless of tumour type.
The threshold used to define an elevated NLR was >5 in one study, >4 in one study, and >2.2 in one study and
therefore it was not appropriate to calculate the weighted average hazard ratio for an incremental increase in the
NLR between these studies.
In conclusion, in patients receiving neoadjuvant chemotherapy followed by surgery it was consistently reported
that NLR predicts recurrence and overall survival. Interestingly, there was inconsistency with regard to the ability
of the NLR to predict pathological response to treatment in this group of patients.
Jump to Section

6. Studies of the prognostic value of the NLR in patients receiving chemo/radiotherapy

Twelve studies, comprising data on 2156 patients, reported the prognostic value of the NLR in patients with
cancer receiving chemotherapy, radiotherapy or a combination of both (Table 4, Refs. [[56], [57], [58], [59], [60],
[61], [62], [63], [64], [65], [66], [67]]). Three studies, comprising data on 579 patients, reported the prognostic
value of the NLR in patients with colorectal cancer receiving chemotherapy [[56], [57], [58]]. The NLR was
reported to have prognostic value independent of tumour stage for both overall and disease-free survival in all of
these studies. One study was from Australia, one was from the UK, and one further study was from the USA. The
threshold used to define an elevated NLR was >5 in two studies, and >2.6 in one study. The weighted average
hazard ratio for an incremental increase in the NLR in the two studies using the most commonly used threshold of
>5 was 2.75.

Table 4Studies of the prognostic value of the NLR, in cancer patients receiving
chemo/radiotherapy.

HR
(pvalu
e)

Rectal

11
5

4.1
(0.002)

>5

Elevated NLR>5 associated with

decreased OS, and DFS

Sydney
(Australia
)

Appendice
al

17
4

(0.01)

>5

Low NLR associated with improved

DFS and OS. NLR, CRP and PLR all
predicted OS and DFS on univariate
analysis

Kishi et
al. [58]

Texas
(USA)

CRC Liver
Metastase
s

29
0

2.22
(0.016)

>5

Pre- and post-treatment NLR

independently associated with 1-,
3-, 5-year survival

Cedres et
al. [59]

Barcelona
(Spain)

Lung

17
1

1.5
(0.015)

>5

Association with T and N stage, but

no association between NLR and
number of metastatic sites,
performance status, type of
chemotherapy, use of
glucocorticoids. Elevated NLR
independently associated with poor
OS and DFS. Patients with elevated
NLR that normalised following
treatment had better survival

Kao et al.
[60]

Concord
(Australia
)

Lung

17
3

2.7
(<0.00
1)

>5

NLR<5 associated with improved

survival in those undergoing 1st
line, 2nd and 3rd line
chemotherapy. Normalisation of
NLR after 1 cycle treatment
associated with prolonged survival

Yao et al.
[61]

Nanjing
(China)

Lung

18
2

1.81
(0.008)

>2.63

Elevated NLR associated with

poorer DFS and OS

Lee et al.
[62]

Goyang
(Korea)

Lung

19
9

1.05
(0.051)

>3.25

Pre- and post-treatment NLR

associated with disease progression
after 1st line treatment

Teramuka
i et al.
[63]

Kyoto
(Japan)

Lung

38
8

1.48
(0.013)

>4.74

Elevated NLR pre-treatment

associated with shorter OS and DFS

Aliustaogl
u et al.
[64]

Istanbul
(Turkey)

Gastric

16
8

(0.001)

>2.56

Elevated NLR was associated with

OS

An et al.

Guangdo

Pancreatic

95

4.49

>5

Elevated pre-treatment NLR

Study

Centre

Carruther
s et al.
[56]

Glasgow
(UK)

Chua et
al. [57]

Tumou
r site

Thresh
old

Comments

[65]

ng
(China)

(0.013)

associated with poor OS and an

independent predictor of OS in
patients receiving chemotherapy

Keizman
et al. [66]

Baltimore
(USA)

Renal

13
3

(<0.00
1)

>3

NLR associated with OS and DFS

Chua et
al. [67]

Sydney
(Australia
)

Various

68

2
(0.01)

>5

Combined GPS/NLR score predicted

OS. NLR that normalised after three
doses of chemotherapy associated
with improved OS

DFS, disease-free survival; OS, overall survival.

Five studies, comprising data on 1113 patients, reported the prognostic value of NLR in patients with thoracic
malignancy receiving chemotherapy [[59], [60], [61], [62], [63]]. These studies were from Japan (1), Australia (1),
Spain (1), Korea (1), and China (1). In this group the pre-treatment NLR was consistently reported to be of
prognostic value both for disease-free and overall survival. Further, the post-treatment NLR was also reported to
be prognostic in this group of patients, in particular the study by Lee and colleagues reported that post-treatment
NLR was independently prognostic for disease-free and overall survival. In addition, the NLR was consistently
associated with response to treatment and prediction of survival. Studies by Kao et al. and Cedres et al. both
reported that normalisation of the NLR following chemotherapy was predictive of improved survival while those
patients with a persistently elevated NLR post-therapy was associated with a worse overall survival.
The threshold used to define an elevated NLR was >5 in two studies, >4.744 in one study, >3.25 in one study,
and >2.63 in one study. The weighted average hazard ratio for an incremental increase in the NLR in the two
studies using the most commonly used threshold of >5 was 2.1.
There was one study reporting the prognostic value of the NLR in gastric cancer [64] (n=168), one in pancreatic
cancer [65] (n=95), one in renal cancer [66] (n=133), and one further study reporting the prognostic value of the
NLR in a variety of solid organ malignancies [67] (n=68). Interestingly the threshold used to determine an
elevated NLR varied across all studies, ranging from >2.56 to >5.
In the gastric cancer study by Aliustaoglu et al. [64] it was reported that an elevated NLR (>2.56) was associated
with overall survival but was not an independent predictor of survival. In the pancreatic study it was reported that
an elevated pre-treatment NLR (>5) was an independent predictor of overall survival (HR 4.489,p=0.013). In
renal cancer patients elevated NLR (>3) was also associated with overall and disease-free survival but was not
an independent predictors of survival. Interestingly, the study by Chua and colleagues reported the independent
prognostic value of the NLR (HR 2.0, p=0.010) and that a scoring system using both the NLR and the GPS was
a strong predictor of overall survival. Similar to other studies this study also reported that a normalised NLR posttreatment was associated with improved overall survival.

In conclusion, both the pre- and post-treatment NLR have been reported to be of prognostic value in patients with
more advanced cancer who receive chemotherapy. Pre-treatment NLR was associated with survival across a
variety of tumour types.
Interestingly, at least 3 studies reported that normalisation of the NLR post-treatment was associated with
improved survival. Further, a combined scoring system using the NLR and the GPS was reported to be a strong
predictor of overall survival.
Jump to Section

7. Studies of the prognostic value of the NLR in patients with inoperable cancer
Six studies, comprising data on 1248 patients reported the prognostic value of the NLR in patients with
inoperable cancer (Table 5, Refs. [[68], [69], [70], [71], [72]]). Two studies were in advanced colorectal cancer and
comprised data on 399 patients, one study was from Japan and another from Australia. Both studies reported an
association between elevated NLR and poorer survival in advanced colorectal cancer. In addition, both studies
reported an association with hypoalbuminaemia and that elevated NLR was an independent predictor of worse
survival. Both of these studies used the most commonly used threshold (>5) to determine an elevated NLR. Over
these two studies the weighted average hazard ratio for an incremental increase in the NLR was 1.9.

Table 5Studies of the prognostic value of the NLR, in cancer patients with
inoperable cancer.

HR
(pvalue
)

Study

Centre

Tumou
r site
n

Thresh
old

Kaneko
et al.
[68]

Tokyo
(Japan)

Colorecta
l

50

4.39
(0.0013
)

>5

NLR independently associated with

OS. Elevated NLR and
hypoalbuminaemia associated with
poor OS and DFS

Chua et
al. [67]

Sydney
(Australia)

Colorecta
l

34
9

1.6
(0.01)

>5

NLR independent predictor of OS.

Low/Normal NLR associated with
improved clinical benefit and
response to treatment

McNally
et al.
[69]

Ohio
(USA)

HCC

10
3

(0.021)

>5

NLR independently associated with

OS

Huang
et al.

Guangzho

HCC

14

(0.041)

>3.3

Elevated NLR independently

associated with poor survival in

Comments

[70]

u (China)

patients with unresectable HCC

Jeong et
al. [71]

Seoul
(Korea)

Gastric

10
4

(0.037)

>3

Elevated NLR and mGPS were

independent prognostic factors

Wang et
al. [72]

Dalian
(China)

Variety

49
7

1.35
(0.014)

>3

Elevated NLR associated with

survival. NLR associated with Tstage, tumour type

DFS, disease-free survival; OS, overall survival.

Two studies, comprising data on 248 patients, were in advanced hepatocellular cancer, one from the USA and
one from China. Both studies reported that elevated NLR was an independent predictor of survival in advanced
disease. However each study used a different threshold for determining an elevated NLR, >5 and >3.3,
respectively.
One study from Korea reported that an elevated NLR (>3) and mGPS were independent predictors of survival in
advanced gastric cancer.
A large study (n=497) from China reported the prognostic value of the NLR in patients with a variety of tumours
with bony metastases. They reported that elevated NLR together with tumour type was associated with worse
survival and was an independent prognostic factor in patients with bony metastases (HR 1.348, p=0.014).
In conclusion, in patients with advanced, inoperable disease the NLR reliably predicts poorer survival.
Jump to Section

8. Relationships between clinicopathological factors and NLR

Several of the studies identified in this review examined factors associated with an elevated NLR. In unselected
patients with breast cancer elevated NLR was associated with advancing age, larger tumours, and stage of
disease. Further, increasing tumour stage was also associated with elevated NLR in patients with operable
cancers, namely colorectal, gastro-oesophageal hepatocellular, lung. In addition, factors that represent more
aggressive tumour behaviour, such as increased tumour size, microvascular and lymphatic invasion, lymph node
involvement, number of metastatic lesions and elevated CEA concentrations, were associated with elevated NLR.
Conversely, a number of studies failed to report a relationship between NLR and tumour characteristics.
Only one study in patients receiving chemotherapy (either neoadjuvant or combined chemotherapy/radiotherapy)
has reported that NLR was associated with T-stage and nodal status but not with number of metastatic lesions,
performance status, type of chemotherapy or use of glucocorticoid medication Further, only a single study in
inoperable cancer examined factors associated with NLR and reported that NLR>3 was associated with

increased tumour stage, tumour type, increasing age, and female gender, but not lymph node metastasis or high
CEA or alkaline phosphatise concentrations.
Jump to Section

9. Discussion
The hypothesis that haematological markers of the systemic inflammatory response, in particular the neutrophil
lymphocyte ratio, reliably predict survival in patients with malignancy is one that has garnered a lot of interest in
the last decade. Many groups have investigated the prognostic value of the NLR in a variety of tumours and at
differing stages of disease.
It is clear that there are important associations between the NLR and other markers of the systemic inflammatory
response in patients with operable cancer, in particular with elevated C-reactive protein and hypoalbuminaemia.
While there is good evidence for the prognostic value of the combination of these acute phase proteins in the
mGPS (with its standard thresholds) in early stage disease, the prognostic value of the NLR in isolation is not so
robust in operable cancer, for example in colorectal cancer only four of eleven studies reported NLR as
independently prognostic with an weighted average hazard ratio of 1.4.
It appears that the NLR is more consistently independently prognostic in patients with upper gastrointestinal
malignancy, a group of solid organ malignancies that tend to present at a later stage with more advanced
features. In addition, the association between NLR and T-stage in these tumours appears to be more robust than
in earlier stage, less aggressive cancers. Similarly, the NLR is more consistently prognostic in more advanced
states such as those patients requiring chemotherapy or who have inoperable disease.
Thus, despite the heterogeneous groups of cancer patients within which these relationships have been examined,
a consistent finding in this review was that NLR may reflect a more advanced stage of disease with potentially
more aggressive tumour behaviour. The mechanism that links tumour and host biology remains unclear however,
recent studies have proposed potential mediators linking the tumour and host interaction.
Of particular interest is the emerging role of pro-inflammatory cytokines in the plasma of patients with elevated
NLR (>5) and the observation that these inflammatory cytokines may establish and perpetuate a tumour
microenvironment favouring aggressive tumour behaviour. Recently, a number of studies have undertaken
measurements of circulating cytokines together with the NLR [[13], [14]]. This data offers a unique insight into the
mechanisms underlying an elevated NLR, for example Motomura et al. showed that an elevated NLR was
associated with an increase in IL-17 [13] and an increase in the peritumoural infiltration of macrophages. Kantola
and co-workers reported that an elevated NLR was associated with elevated circulating concentrations of IL-1ra,
IL-6, IL-7, IL-8, IL-12, MCP-1, PDGFBB. Taken together, these elevated cytokine concentrations and increased
tumour macrophage infiltration would suggest that the NLR reflects, at least in part, the up-regulation of the

innate immune response. Despite the increasing evidence that pro-inflammatory cytokines play a significant role
in the tumour-host interaction that may influence tumour behaviour these links require further investigation.
With regard to those patients receiving chemotherapy the NLR was consistently reported to have prognostic
value, particularly in patients with lung cancer. In addition, NLR was consistently reported to predict response to
treatment. Further, it has been reported by at least two studies that normalisation of the NLR post-treatment was
significant with those patients not normalising their NLR having a worse prognosis.
These observations are important as the ability of clinicians to predict both response to treatment and value of
treatment after one cycle may help decide both which patients should commence treatment and those who have
responded after one cycle of treatment. This would have important clinical utility as it would potentially identify
those patients in whom aggressive chemotherapy may be futile.
The importance of such an ability to determine more accurately which patients should receive chemotherapy is
important for both quality of life and survival as reported in recent study by Temel et al. [15]. However, the
literature regarding post-treatment measurement of the NLR appears limited and inconsistent and therefore
further longitudinal studies of the prognostic value of the NLR are warranted.
Given these observations it is therefore reasonable to propose that this commonly measured haematological test
could be used as a biomarker in patients who require adjunctive treatment or who do not appear clinically to be
suitable for surgical intervention and would therefore be useful in the improved stratification of patients with
cancer.
While these observations may be of clinical importance, it is important to note that there was considerable
heterogeneity in the thresholds used to determine an elevated NLR across these studies. A threshold of >5 was
the most consistently used, however a variety of thresholds have been reported both in operable disease, in those
receiving chemotherapy, and in inoperable disease. The heterogeneity of the thresholds used makes a conclusion
regarding the clinical utility of the NLR somewhat difficult and further work utilising the most common threshold of
>5 should be considered in an attempt to refine whether this simple measure of the systemic inflammatory
response is reliable as a prognostic marker in the clinical setting.
Interestingly, recent work has proposed that the combination of measures of the systemic inflammatory response
may be a powerful predictor of outcome in cancer. At least one study in the current review has proposed the use
of a combined score using the NLR and markers of the acute phase response and reported that it has improved
value in patients with cancer. Further, a recent large prospective cohort study has reported the use of a combined
biomarker score that has prognostic value in patients with cancer.
Therefore, further studies are required to investigate the prognostic value of such a combined score using
established routinely measured prognostic markers of the systemic inflammatory response, namely C-reactive
protein, albumin, neutrophil and lymphocyte counts.

Jump to Section

Conflict of interest
There is no conflict of interest to declare.
Jump to Section

Reviewers
Akiyoshi Kinoshita, MD, Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, 4-111 Izumihon-cho, Komae-shi, Tokyo 201-8601, Japan.
Mitsuru Ishizuka, MD, Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi,
Mibu, Tochigi 321-0293, Japan.
Basem Azab, MD, Staten Island University Hospital, Department of Medicine, 475 Seaview Avenue, New York,
Staten Island 10305, United States.
Jump to Section

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