the role of white cell count and c

8/18/2019 The Role of White Cell Count and c

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THE ROLE OF WHITE CELL COUNT AND C-REACTIVE PROTEIN

IN THE DIAGNOSIS OF ACUTE APPENDICITIS

Khan MN, Davie E, Irsha K De!ar"#en" $% Genera& S'r(er), Wisha* Genera& H$s!i"a&, Wisha*, Lanar+shire UK

a.+(r$'n/ Despite recent advances in diagnostic medicine, the diagnosis of appendicitis isstill doubtful in a number of cases. Majority of the clinicians rely on their clinical examinationstrengthened by the laboratory tests. This study was carried out to find out the specificity andsensitivity of white cell count (W! and "#eactive $rotein (#$! in diagnosingappendicitis in patients presenting with right iliac fossa pain. Me"h$s/ % total of &' patientswere included in this study that presented in the hospital with acute right iliac fossa pain andlater on operated and had appendicectomy. The histopathology data was collected to find out

the fre)uency of negative appendicectomy. %ccording to the histopathology reports these patients were grouped into three sub"groups as normal appendix, inflamed appendix or perforated*gangrenous appendix. % record was +ept of the W and #$ levels of these patients on admission. Res'&"s/ % total of &' patients were included in this study and out of them - had a normal appendix giving an over all negative appendicectomy rate of /.0.1ut of these were male and &2 were female, male to female ratio being 3&.. The age

range was &"- with a median age of &/. %mong the &&& patients who had appendicitis, 2had a ruptured *perforated appendix and &2 had an inflamed appendix. 1ver all the W waselevated in 4' patients and #$ was elevated in 24 cases. The cut off value for white cellcount was x 52 * 6. The reactive protein levels were calculated by immunoturbidimetrictest and the cut off value was ta+en as .-mg*dl. The sensitivity and specificity of W in thisstudy was 40 and 2&. 0 and that for #$ was -'.20 and 4.- 0. C$n.&'si$n3 7oth the

inflammatory mar+ers i.e. W and "reactive protein can be helpful in the diagnosis, whenmeasured together as this increases their positive predictive value.Ke) *$rs/ appendicitis, white cell count, reactive protein

INTRODUCTION

%cute appendicitis is still one of the commonest surgical emergencies. The diagnosis is primarily clinical. & %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. 8owever these sign 9 symptoms are not very specific for appendicitis and can mimic any other acute abdominal condition. The picture is more confused by the variable position of the appendix./ Despite advances in diagnostic modalities the diagnosis is still doubtful in 5"/5 0 of cases.' %nd the definite diagnosis of appendicitis still remains a clinical decision. , augmented by appropriatetests. % high degree of diagnostic accuracy is re)uired to reduce the incidence of negative appendicectomieswhich still remains around &5 0.2 1ne study has shown an incidence of '50 in women of reproductive age

group.- %cute appendicitis is a disease of young adults.4 :t is rare below years of age but people are vulnerableto it in extremes of their age and complication rate is higher in those groups. :t is more common in males ascompared to females. :t used to be called as the disease of developed countries with an association of high protein inta+e, but the incidence is also increasing in developing countries. % study reported it to be around

.*555 for males and .'*555 for females.

%part from a careful history and clinical examination, total white cell count has remained an important

factor in the definite diagnosis of appendicitis. ;arious studies have shown that this can be very non"specific attimes.5 #ecently interest has grown in other inflammatory mar+ers which could be helpful in diagnosingappendicitis. #$ is one of them. This study was conducted to chec+ the sensitivity and specificity of the whitecell count and #$ in patients presenting with right iliac fossa pain.

MATERIAL AND METHODS

This study was carried out at Wishaw


2/39

" perforated*gangrenous appendixTheir blood results were reviewed and a note of W and #$ levels was made. The sensitivity and

specificity of these tests were calculated according to the following formulas,

=ensitivity > True $ositives* True $ositives ? @alse Aegatives=pecificity > True Aegative* True Aegative ? @alse $ositiveThe cut off value for white cell count was x52*6. This value was selected arbitrarily as it

corresponds to the elevated W. The reactive protein levels were calculated by immunoturbidimetric testand the cut off value was ta+en as .-mg*dl. This cut off value was ta+en in light of the previous research whichshowed it to be highly accurate.

RESULTS

% total of &' patients were included in this study and out of them - had a normal appendix giving an over allnegative appendicectomy rate of /.0. 1ut of these were male and &2 were female, male to female ratio being 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 &"- with a median age of &/. %mong the &&& patients who hadappendicitis, 2 had a ruptured *perforated appendix and &2 had an inflamed appendix. 1ver all the W waselevated in 4' patients and #$ was elevated in 24 cases. The sensitivity and specificity of W in this study

was 4 0 and 2&. 0 and that for #$ was -'.2 and 4.- 0. The positive predictive values for W and #$were &0 and 20 respectively (pB5.55!.

Ta0&e-1/ Ana&)sis $% *hi"e .e&& .$'n" #eas're#en"s in !a"ien"s *i"h RIF !ain

-

&2

2

White ell ount

#aised/ 2 4

White ell ount

Aormal& 5 5-

patients with normal appendix patients with inflammed appendix

patients with perforated*gangrenous appendix

=ensitivity > 4.0, =pecificity > 2&.0$ositive predictive value > &0

Degree of freedom 3 &, hi =)uare > /'.&$ B 5.55 , hence the distribution is significant

DISCUSSION

Majority of the patients with acute appendicitis present with right sided lower abdominal pain and nausea andvomiting, but these symptoms are very non"specific. :n fact any acute abdominal condition can mimicappendicitis and hence the list of differential diagnosis is long and hence removal of a normal appendix is notunusual.

Ta0&e-2/ Ana&)sis $% CRP #eas're#en"s in !a"ien"s *i"h RIF !ain

-

&2

2

#$ #aised 2 4 4-

#$ Aormal /' 5 patients with normal appendix

patients with inflammed appendix

patients with perforated*gangrenous appendix=ensitivity > -'.20, =pecificity > 4.-0

$ositive predictive value > 20

Degree of freedom > &, hi =)uare > 2-.

$ B 5.55 , hence distribution is significant.

% high degree of diagnostic accuracy is re)uired to reduce the incidence of negative appendicectomies

which still remain around &5 0. 1ne study has shown the diagnostic accuracy of acute appendicitis of 250 inwomen of reproductive age group.& The implications can be two folds. @irstly although appendicectomy isconsidered to be a safe operation it still has got associated complications, most noticeable among them arewound infection, intra abdominal abscess, adhesions and bowel obstruction and pulmonary complications from

general anaesthesia.

=econdly, the group of patients who have persistent symptoms after the operation areunsatisfied with the health care they received and are a burden on the hospital resources.


3/39

To improve the diagnostic accuracy surgeons have relied on a good history and sound clinicalexamination augmented by laboratory investigations ranging from simple blood tests loo+ing at the white cellcount, to modern sophisticated investigations including computerised tomography, ultrasonography, peritoneal

aspirations, barium enema and laparoscopy./"2 7ut all these investigations have their demerits. They areinvasive, time consuming, operator dependent and not very freely available everywhere. %mong all theseloo+ing at the W has been very favourite test for the surgeons in deciding for probability of appendicitis

although studies have shown it to have a low specificity.-

The )uestion of specificity and sensitivity of thesetests remains open.

To improve the sensitivity and specificity surgeons have tried se)uential leu+ocyte counts and

neutrophil3 lymphocytic ratio.4" #ecently attention has been focussed on other inflammatory mar+ers whichcan be raised in appendicitis, #$ ("reactive protein! being one of them. #$ was identified in 5 and isregarded as the acute phase protein. :t has been studied as a screening device for inflammation , a mar+er for disease activity and as a diagnostic adjunct. &5 =everal studies have addressed the accuracy of #$ in diagnosingappendicitis and it is agreed that its level increases in appendicitis and this increase is related to the severity of appendiceal inflammation. 8owever #$ 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 #$ both are sensitive in diagnosing acute inflammation but they are not very specific. ombining the two tests together the specificity and positive predictive valueincreases. The measurement of #$ is useful in the diagnosis of acute appendicitis. :n this study we have -

patients in group :, where the appendix was found normal. :n & of these patients both values were in the normalrange. The accuracy of these tests increases with the increasing severity of inflammation. :n group ::: where the

appendix was found to be perforated or gangrenous, only - patients out of 4- had normal values of either #$or W. :n both groups :: and ::: no patients were found with #$ or W with in normal range. We wouldrecommend that if in a patient presenting with right iliac fossa pain, both #$ and W are normal thediagnosis of appendicitis is very unli+ely.

REFERENCES

. $al C, Chan %. %ppendicitis3 a continuing challenge. $a+ Med %ssoc 4E/4(-!34"&.&. %bbassi %, =hah F. %cute appendicitis in children. =urg $a+istan 4E&3&4"5

. Davenport M. %cute abdominal pain in children. 7M 2E&(-5&!3/4"'5

/. Delic , =av+ovic %, :sa+ovic G. ;ariations in the position and point of origin of vermiform appendix. Med %rch &55&E'2(!3'"4.

'. %nderson # , 8ugander % ,


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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

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 neutrophil–lymphocyte 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, andChina. 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

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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

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 inflammatoryresponse 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].

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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 neutrophil–lymphocyte 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.

2. ethod

This systematic review of published literature was undertaken according to a pre-defined protocol. The primary

outcome of interest was the relationship between the neutrophil–lymphocyte 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), theExcerpta Medica database (EMBASE), theCochrane Database of

Systematic Reviews (CDSR) for articles reporting the prognostic value of the NLR with regard to cancer outcome

(June 2005–October 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.

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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.

!. "tudies of the pro#nostic $alue of the %&'( 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 n

HR ( p-

value)

Thresh

old Comments

Azab et

al. [16

New

!or"

#$SA%

&reast '16 (.)*

#+,.,,,

1%

-'.'' levated NLR was associated with

the elderl/0 larger tuours0 and

ore advanced stage

2roctor

[11

3lasgow

#$4%

5arious )*7 1.7

#+,.,,1%

-* levated NLR #-*% was associated

with reduced * /ear 8S and 9:S

2roctor

[1

3lasgow

#$4%

5arious 1;01

1)

1.*;

#+,.,,1%

-( NLR and dNLR were associated with

reduced 8S and 9:S independent

of age0 se< and deprivation. NLR

superior to dNLR

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

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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.

). "tudies of the pro#nostic $alue of the %&' 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.

Study Centre

Tumour

site n

HR ( p-

value)

Thresh

old Comments

9ing et

al. [1)

3uangdo

ng#=hina%

=olorectal 1(1 (.))

#,.,,'%

-( levated NLR associated with

reduced 9:S and an independentprognostic factor and not

associated with

clinicopathological

characteristics

4won et

al. [17

&usan

#4orea%

=olorectal ;,, #Non>

signi?ca

nt%

-* levated NLR associated with

lower 8S on univariate anal/sis

onl/. NLR not associated with

clinicopathological factors or

stage of disease

Neal et

al. [;,

Leicester

#$4%

=olorectal ;,; ;.,*

#,.,,1%

-* NLR associated with post

operative orbidit/ and 8S on

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univariate anal/sis

@alsh et

al. [)

Suol"

#$4%

=olorectal ;', #+,.,,1% -* NLR - * associated with 8S and

=S survival on univariate anal/sis

Leitch et

al. [;1

3lasgow

#$4%

=olorectal ;'' #Non>

signi?ca

nt%

-* NLR associated with other

easures of s/steic

inBaation but not prognostic

in priar/ operable disease

Callappa

et al. [;;

Darrow

#$4%

=olorectal ;7 1.)1

#,.,;)%

-* levated NLR independentl/

associated with survival

Dalazun

et al. [;'

Leeds

#$4%

=olorectal ((, ;.;6

#+,.,,1%

-* levated NLR0 age and nuber of

etastases were independent

prognostic factors

3oez et

al. [;(

Leeds

#$4%

=olorectal *,1 1.'

#,.,';%


recurrence

Dung et

al. [;*

Eao>!uan

#Eaiwan%

=olorectal 1,(

,

1.;7

#,.,1;%

-* NLR associated with signi?cantl/

worse 8S #* /ears%. NLR

associated with advancing age

#-6*%0 E(b cancer0 elevated =A

and tuour

obstructionFperforation. NLR not

associated with histological

subt/pe0 tuour size0 tuour

grade

=hiang et

al. [;6

Lin"ou

#Eaiwan%

=olorectal ''

1

1.'1

#,.,1'%

-' levated NLR was associated

with clinicopathological factors

associated and with outcoe

$bu"ata

et al. [;

Eo"/o

#Gapan%

3astric 1* *.)

#+,.,,1%

-* NLR independentl/ prognostic

and associated with E>stage0

tuour size0 presence of l/ph

nodes0 and pathological stage

Aizawa etal. [;)

4ashiwa#Gapan%

3astric ;6; ;.;1#,.,1;%

-'.; NLR was an independentprognostic factor. NLR increased

in a E>stage dependent anner

Gung et

al. [;7

3wangHu

#4orea%

3astric ;7' 1.6*

#,.,17%

-; levated NLR signi?cantl/

associated with 8S and 9:S in

later stage gastric cancer.

levated NLR associated with

advanced E>stage0 and larger

tuour size

Rashid et

al. [',

9erb/

#$4%

8esophag

eal

;7( I -'.* NLR not associated with tuour

factors or with disease


11/39

recurrence or survival

@ang et

al. ['1

3uangzh

ou

#=hina%

3astric ';( ;.';

#,.,1(%

-* 32S ore prognostic than NLR

Cohri et

al. [';

Esu

#Gapan%

3astric '* ;.)

#+,.,,,

1%

-;.; NLR independentl/ associated

with prognosis together with

tuour size0 advanced E>stage in

relativel/ earl/ stage gastric

cancer

Shiada

et al. [''

Eo"/o

#Gapan%

3astric 1,;

)

1.)*

#,.,,'%

-( NLR was an independent

prognostic factor and increased

in a t>stage dependent anner

3arcea etal. ['(

Leicester#$4%

2ancreas ( I -* NLR signi?cantl/ associated withrecurrence0 and was ore

prognostic than coponents

alone

&hatti et

al. ['*

9erb/

#$4%

2ancreas )( 1.)

#,.,;'%

-( NLR reported an independent

prognostic factor for survival and

not associated with tuour

characteristics

Sith et

al. ['6

Liverpool

#$4%

2ancreas 11, I =ontinuou

s

No relationship between NLR and

survival

@ang et

al. ['

3uangzh

ou

#=hina%

2ancreas 1 ;.*(

#,.,,6%

-* NLR independentl/ associated

with 8S

3oez et

al. [')

Leeds

#$4%

=holangio>

carcinoa

; 1.)

#,.,,)%


poorer 9:S0 and associated with

larger tuours0 intrahepatic

satellite lesions0 icrovascular

invasion and l/ph node

involveent

4inoshita

et al. ['7

Eo"/o

#Gapan%

Liver 1*, I -* Along with 32S and 32S0 NLR

was associated with reduced 8S.

NLR not independentl/

associated with 8S

Cotour

a et al.

[1'

:u"uo"a

#Gapan%

Liver 1*) 6.;(

#,.,,,;%

-( Jncreasing NLR associated with

D== recurrence. Associated with

other ar"ers of s/steic

inBaation

Sa"ai et

al. [(,

Aoori

#Gapan%

Lung ;' #Non>

signi?ca

=ontinuou

s

NLR had no signi?cant

relationship with recurrence or


12/39

nt% survival

Sarraf et

al. [(1

London

#$4%

Lung 1) 1.1

#,.,,(%

-* NLR associated with E>stage and

was an independent predictor of

outcoe

Eoita et

al. [(;

Ci/aza"i

#Gapan%

Lung ;)( #


13/39

colorectal cancer. The relationship between the neutrophil–lymphocyte 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 associationbetween 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 disease-

free 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.


14/39

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 disease-

free survival in one study and was reported as an independent prognostic factor together with advancing stage

and increasing age, (HR=8.42 [95% CI: 1.09–64.84], 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: 1.14–15.82], p=0.031).

In conclusion, the last decade has seen the accumulation of good evidence supporting associations between the

neutrophil–lymphocyte 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


15/39

*. "tudies of the pro#nostic $alue of the %&' in patients with operable cancer who recei$ed

neoad+u$ant 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 neoadHuvant therap/.

Stud

y Centre

Tumour

site n

HR ( p-

value)

Thresh

old Comments

@ang

[*,

3uangdon

g #=hina%

D== 1,

1

;.6*

#+,.,,1%

-' levated NLR independentl/

associated with poor 9:S

Dalazun

[*1

New !or"

#$SA%

Liver 1*

,

17.77

#,.,,*%


increased ris" of recurrence and

death

&ertuzz

o [*;

&ologna

#Jtal/%

Liver ;1

7

17.1(

#+,.,,1%


lower 8S. levated NLR and C5J

negativel/ aected 9:S. levated

NLR and C5J were independentprognostic factors

Sato

[*'

Shizuo"a

#Gapan%

8esophag

eal

)' ;.)'

#,.,('%

-;.; NLR associated with pathological

response to neoadHuvant

cheotherap/

Ci/ata

[*(

8sa"a

#Gapan%

8esophag

eal

1*

;

#Non>

signi?can

t%

-( levated NLR associated with

survival but not independentl/

prognostic

Sharaiha [**

New !or"#$SA%

8esophageal

''7

;.;6#+,.,,1%

-* levated NLR associated withworse 9:S and 8S independent of

tuour t/pe


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



16/39

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.

,. "tudies of the pro#nostic $alue of the %&' in patients recei$in# chemoradiotherapy

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 NLR0 in cancer patients receiving

cheoFradiotherap/.

Jump to Section



17/39

Study Centre

Tumou

r site n

HR

( p-

valu

e)

Thresh

old Comments

=arruther

s et al.

[*6

3lasgow

#$4%

Rectal 11

*

(.1

#,.,,;%

-* levated NLR - * associated with

decreased 8S0 and 9:S

=hua et

al. [*

S/dne/

#Australia

%

Appendice

al

1

(

#,.,1% -* Low NLR associated with iproved

9:S and 8S. NLR0 =R2 and 2LR all

predicted 8S and 9:S on univariate

anal/sis

4ishi et

al. [*)

Ee and post>treatent NLR

independentl/ associated with 1>0

'>0 *>/ear survival

=edres et

al. [*7

&arcelona

#Spain%

Lung 1

1

1.*

#,.,1*%

-* Association with E and N stage0 but

no association between NLR and

nuber of etastatic sites0

perforance status0 t/pe of

cheotherap/0 use of

glucocorticoids. levated NLR

independentl/ associated with poor

8S and 9:S. 2atients with elevated

NLR that noralised following

treatent had better survival

4ao et al.

[6,

=oncord

#Australia

%

Lung 1

'

;.

#+,.,,

1%

-* NLR treatent

associated with shorter 8S and 9:S

Aliustaogl

u et al.

[6(

Jstanbul

#Eur"e/%

3astric 16

)

#,.,,1% -;.*6 levated NLR was associated with

8S

An et al. 3uangdo 2ancreatic 7* (.(7 -* levated pre>treatent NLR


18/39

[6* ng

#=hina%

#,.,1'% associated with poor 8S and an

independent predictor of 8S in

patients receiving cheotherap/

4eizan

et al. [66

&altiore

#$SA%

Renal 1'

'

#+,.,,

1%

-' NLR associated with 8S and 9:S

=hua et

al. [6

S/dne/

#Australia

%

5arious 6) ;

#,.,1%

-* =obined 32SFNLR score predicted

8S. NLR that noralised after three

doses of cheotherap/ associated

with iproved 8S


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 post-

treatment was associated with improved overall survival.


19/39

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.

. "tudies of the pro#nostic $alue of the %&' 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 NLR0 in cancer patients with

inoperable cancer.

Study Centre

Tumou

r site n

HR

( p-

value

)

Thresh

old Comments

4ane"o

et al.

[6)

Eo"/o

#Gapan%

=olorecta

l

*, (.'7

#,.,,1'

%

-* NLR independentl/ associated with

8S. levated NLR and

h/poalbuinaeia associated with

poor 8S and 9:S

=hua et

al. [6

S/dne/

#Australia%

=olorecta

l

'(

7

1.6

#,.,1%

-* NLR independent predictor of 8S.

LowFNoral NLR associated with

iproved clinical bene?t and

response to treatent

CcNall/

et al.

[67

8hio

#$SA%

D== 1,

'

#,.,;1% -* NLR independentl/ associated with

8S

Duanget al.

3uangzho D== 1( #,.,(1% -'.' levated NLR independentl/associated with poor survival in

Jump to Section



20/39

[, u #=hina% * patients with unresectable D==

Geong et

al. [1

Seoul

#4orea%

3astric 1,

(

#,.,'% -' levated NLR and 32S were

independent prognostic factors

@ang et

al. [;

9alian

#=hina%

5ariet/ (7

1.'*

#,.,1(%

-' levated NLR associated with

survival. NLR associated with E>

stage0 tuour t/pe


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.

/. 'elationships between clinicopatholo#ical factors and %&'

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

Jump to Section


21/39

increased tumour stage, tumour type, increasing age, and female gender, but not lymph node metastasis or high

CEA or alkaline phosphatise concentrations.

0. iscussion

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

Jump to Section


22/39

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.


23/39

onflict of interest

There is no conflict of interest to declare.

'e$iewers

Akiyoshi Kinoshita, MD, Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, 4-11-

1 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.

'eferences

1. CancerStats. http://www.cancerresearchuk.org. 2005–2009.

;. Hanahan, D. and Weinberg, R.A.The hallmarks of cancer.Cell. 2000; 100: 57–70

o View in Article

o | Abstract

o | Full Text

o | Full Text PDF

o | PubMed

o | Scopus (14582)

'. Hanahan, D. and Weinberg, R.A.Hallmarks of cancer: the next generation.Cell. 2011; 144: 646–674

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