Pre-treatment diagnosis of endometrial cancer through a

combination of CA125 and multiplication of neutrophil

and monocyte
Bo Wook Kim
1
, Young Eun Jeon
1
, Hanbyoul Cho
1
, Eun Ji Nam
2
, Sang Wun Kim
2
,
Sunghoon Kim
2
, Young Tae Kim
2
and Jae-Hoon Kim
1
1
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, and
2
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University
College of Medicine, Seoul, Koreajog_1694 48..56
Abstract
Aim: This study aimed to investigate the clinical value of pre-treatment leukocyte differential counts and the
prediction of endometrial cancer using leukocyte markers.
Material and Methods: Medical records of 238 women with pathologically conrmed endometrial cancer
between March 2000 and June 2009 at two Korean hospitals were reviewed and compared to 596 healthy
people visiting the Health Promotion Center in Gangnam Severance Hospital. For all study subjects, leukocyte
differential counts and CA125 levels in serum obtained prior to operation were recorded. Multiplication of
neutrophil and monocyte (MNM) was determined by multiplying neutrophil and monocyte counts then
dividing by 10 000. Differences between endometrial cancer patients and healthy controls were compared. The
sensitivity and specicity for each marker as well as the combined use of CA125 and other leukocyte markers
were assessed using receiver operating characteristic curves.
Results: Mean white blood cell (WBC) counts were 6676 (64406913) cells/mL in endometrial cancer patients
compared to 5663 (55425784) cells/mL in healthy controls (P < 0.001). The area under curve (AUC) for CA125
was 0.689 with a sensitivity of 49.13%and specicity of 83.1%using an optimal cut-off value of 18.7 U/mL. The
AUC for MNM was 0.696 with a sensitivity of 62.9% and specicity of 69.1%. The combination of CA125 and
MNM showed a higher AUC of 0.760 than use of CA125 or MNM alone.
Conclusion: The combination of MNM and CA125 is a simple and cost-effective method for predicting
endometrial cancer.
Key words: CA 125, endometrial cancer, leukocyte, monocyte, neutrophil.
Introduction
Endometrial cancer is the fourth most common malig-
nancy in women and the most common in the female
genital tract in the USA. 7780 deaths resulting from
endometrial cancer were expected, while 42 160 women
were estimated to be newly diagnosed in 2009.
1
Vaginal bleeding commonly occurs in the early stage
of endometrial cancer. Because patients usually visit
medical institutions during this stage, an early diagno-
sis can be made in most cases. In some cases of endome-
trial cancer, however, asymptomatic metastasis is found
in the lymph node or intra-abdominal space, of which
prognosis is commonly poor. Regardless, in cases in
Received: March 23 2011.
Accepted: April 27 2011.
Reprint request to: Dr Jae-Hoon Kim, Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University
College of Medicine, 146-92 Dogok-Dong, Gangnam-Gu, Seoul 135-720, Korea. Email: jaehoonkim@yuhs.ac
doi:10.1111/j.1447-0756.2011.01694.x J. Obstet. Gynaecol. Res. Vol. 38, No. 1: 4856, January 2012
48 2011 The Authors
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
which the presence of endometrial cancer is suspected
due to the presence of bleeding, it is necessary to
perform a non-invasive test prior to invasive tests, such
as an endometrial biopsy.
In high-risk patients, such as breast cancer patients
taking tamoxifen, patients who are severely obese,
patients with diabetes mellitus or those with heredi-
tary non-polyposis colon cancer (HNPCC) syndrome,
a cost-effective screening test may be helpful for early
detection of endometrial cancer. Sonography and
endometrial biopsy are recommended for diagnosis of
endometrial cancer. To date, however, effective sero-
logical markers have not been introduced. Elevated
serum CA125 levels have been detected in 1020% of
patients with early-stage disease and approximately
25% of patients with asymptomatic recurrent dis-
ease.
2,3
Moreover, serum CA125 elevation greater than
35 U/mL is not sufciently accurate to stratify patient
risk and the prognostic cut-off value for CA125 levels
to guide other therapeutic plans is undened.
4,5
Other
biomarkers, including CA 199, M-CSF, insulin and
leptin have been studied, but they are less clinically
effective.
69
It is well established that in cases in which unop-
posed estrogen is persistently present, the endome-
trium can progress to endometrial cancer due to
excessive proliferation and resultant DNA damage.
Recently, inammation and elevated leukocyte count
have shown proven associations with various can-
cers of the lung, breast, ovary, colon and liver.
1015
Such cytokines associated with inammation as
COX-2, PGE2 and NF-kB have been reported at a
higher concentration in endometrial cancer.
16
Accord-
ing to a prospective study, white blood cell (WBC)
counts were relatively higher in the endometrial
cancer of postmenopausal women.
17
It can therefore
be inferred that the development of endometrial
cancer is associated with the inammatory and
immune responses. Recently, diagnostic and prognos-
tic tumor markers using leukocytes subsets have been
reported, with the neutrophil to lymphocyte ratio
(NLR) and multiplication of neutrophil and monocyte
counts (MNM) being recently introduced in various
cancers.
15,1820
The present study aimed to investigate the clinical
value of pre-treatment leukocyte differential counts
and its diagnostic and prognostic importance in
endometrial cancer. We hypothesized that leukocyte
count differences between endometrial cancer pati-
ents and healthy women could be found, and these
differences may be useful indices of diagnostic and
prognostic markers for endometrial cancer, especially
in combination with CA-125.
Material and Methods
Study population
The present study was carried out in accordance with
the ethical standards of the Helsinki Declaration and
was approved by the Institute of Review Boards
(IRBs # 3-2009-0161) of Severance and Gangnam Sev-
erance Hospitals. The study involved a retrospective
medical record review of 238 women with pathologi-
cally conrmed endometrial cancer between March
2000 and June 2009 at two Korean academic institu-
tions. All endometrial cancer patients were surgically
staged according to the International Federation of
Gynecology and Obstetrics (FIGO) staging system.
Recurrence status was determined using computed
tomography (CT), magnetic resonance imaging (MRI)
and positron emission tomography (PET). Healthy
controls consisted of 596 women visiting the Health
Promotion Center in Gangnam Severance Hospital
between June 2007 and June 2009 with no history of
cancer or gynecological disease. WBC counts and
CA125 level for healthy controls were collected from
retrospective medical records. There were no abnor-
malities in the laboratory examinations or gynecologi-
cal sonography, and participants with a history of
hematological abnormality were excluded.
Hematological analysis
For all study subjects, peripheral venous blood was
collected 3 days before operation for leukocyte differ-
ential counts and CA125 levels. While the interval of
endometrial biopsy to staging surgery was less than
2 weeks, WBC counts prior to endometrial biopsy
were selected because endometrial biopsy can affect
WBC count elevation. Leukocyte differential counts
were analyzed by the ADIVA 120/2120 Hematology
system (Bayer Health Care, Diagnostics Division,
Tarrytown, NY, USA), and CA125 levels were mea-
sured with CA125 II ECLIA (electrochemilumines-
cence immunoassay) on the Roche/Hitachi Modular
Analytics E170 (Roche Diagnostics, Tokyo, Japan).
Calculated leukocyte markers were NLR and MNM.
The NLR was dened as the absolute neutrophil
count divided by the absolute lymphocyte count.
19
The MNM was dened as the multiplication of neu-
trophil counts and monocyte counts then divided by
10 000.
18
Diagnosis of endometrial cancer
2011 The Authors 49
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
Statistical analysis
Data were summarized with number of patients,
mean SD and 95% condence intervals (CI) for the
mean. Comparisons of leukocyte counts between the
two study groups were analyzed using independent
t-test and ANOVA post hoc test. To evaluate the odds
ratios (OR) for development of endometrial cancer,
binary logistic regression was applied. For construction
of receiver operating characteristic (ROC) curves, a
predicted probability for development of endometrial
cancer was calculated for each patient using the logistic
regression formula. Sensitivity and specicity for each
marker were assessed using ROC curves, with the
resulting area under the curve (AUC) indicating
average sensitivity of a marker over the entire ROC
curve. All analyses were performed using SPSS version
12.0 (SPSS, Chicago, IL, USA). A P-value of <0.05 was
considered statistically signicant.
Results
Patient characteristics of 238 endometrial cancers are
shown in Table 1. The majority of patients had early-
stage, favorable histological cell type and risk factors.
Meanages of endometrial cancer patients andhealthy
controls were 52.1 years and 50.7 years, respectively,
with no signicant difference between the groups
(Table 2). Mean CA 125 of controls and endometrial
cancer patients were 14.1 and 42.0 U/mL (P < 0.001),
respectively. WBC counts were 6676 cells/mL in the
endometrial cancer group and 5663 cells/mL in healthy
controls (P < 0.001). Neutrophil, lymphocyte and
monocyte differential counts (4023, 2033 and 319 cells/
mL, respectively) were signicantly higher in endome-
trial cancer patients when compared to controls
(P < 0.001); however, eosinophil and basophil differen-
tial counts did not show signicant difference (P = 0.64
and P = 0.523, respectively). NLR and MNM signi-
cantly differed between the two groups (2.27 vs 1.91
[P = 0.012] and 134.6 vs 86.8 [P < 0.001], respectively).
Table 3 shows leukocyte differentials according to
pathological characteristics in endometrial cancer
patients. Neutrophil counts, MNM and CA125 were
increased in the advanced stage of cancer (P = 0.033,
0.016 and 0.041, respectively). Monocyte counts were
elevated in positive peritoneal cytology (P = 0.013).
Table 4 shows OR for the association of leukocyte
differentials, NLR, MNM, andCA125 with endometrial
cancer using binary logistic regression. WBC counts
including their subsets revealed increased OR in devel-
opment of endometrial cancer as leukocyte levels
increased. Elevated MNM and CA125 35 U/mL also
showed an increased OR.
Table 5 discloses the diagnostic sensitivity and speci-
city of CA 125, neutrophil, monocyte subsets, NLR,
MNM and marker combinations. The AUC of CA125
was 0.689 with a sensitivity of 49.1% and specicity of
83.1%. For monocyte, the AUC was 0.706 with 55.0%
sensitivity and 77.3% specicity. As single markers, the
AUC of monocyte was higher than CA125, neutrophil
and MNM. When markers were combined, CA125 and
monocyte presented the highest AUC of 0.785 with
64.5% sensitivity and 79.8% specicity. The combina-
tion of CA125 and MNM produced an AUC of 0.760
with 71.7% sensitivity and 69.6% specicity.
Figure 1 illustrates composite analysis of MNM and
CA125 levels in patients with endometrial cancer and
Table 1 Patient characteristics of 238 endometrial
cancers
Frequency %
Age 52.1
FIGO stage
I 192 80.7
II 17 7.1
III 21 8.8
IV 8 3.4
Total 238 100
Tumor grade
1 122 52.8
2 75 32.5
3 34 14.7
Total 231 100
Myometrial inltration
<50 200 84.0
>50 38 16.0
Total 238 100
Cervical stromal invasion
Negative 217 91.6
Positive 20 8.4
Total 237 100
LVSI
Negative 197 83.1
Positive 40 16.9
Total 237 100
Peritoneal cytology
Negative 207 93.2
Positive 15 6.8
Total 222 100
Histological type
Endometrioid 186 78.2
Non-endometrioid 52 21.8
Total 238 100
Mean value.
FIGO, International Federation of Gynecology and Obstetrics;
LVSI, lymphovascular space invasion.
B. W. Kim et al.
50 2011 The Authors
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
healthy controls. In endometrial cancer patients,
CA125 was not elevated in 186 (78.1%) of 238 patients.
Of these 186 patients who were false negative for
CA125, 116 (62.3%) showed a positive MNM cut-off
value of 100.1, which maximized the sum of sensitivity
and specicity.
Discussion
Routine screening methods for endometrial cancer are
not yet proven. Transvaginal sonography and endome-
trial biopsy are recommended to diagnose endome-
trial cancer in postmenopausal bleeding or high-risk
patients. Hematological marker has not been intro-
duced to diagnose endometrial cancer in such patients.
CA125 has limitation to diagnose because of sensitivity.
However, less invasive andcost-effective hematological
marker couldbe helpful todiagnose endometrial cancer
in such patients. In the current study, we observed that
neutrophil and monocyte counts were elevated in
endometrial cancer. The MNM, which was a combina-
tion of two parameters, showed a similar AUC of
CA125 alone. However, the combination of CA125
and MNM showed higher diagnostic accuracy than
single markers, CA125 or MNM. CA125 is insufcient
to diagnose endometrial cancer due to low sensitivity;
however, MNM was shown to complement CA125.
Transvaginal sonography for diagnosis of endome-
trial cancer in postmenopausal women produced
9096% sensitivity and 5461% specicity with a 5-mm
cut-off value.
2123
In the United Kingdom Collaborative
Trial of Ovarian Cancer Screening (UKCTOCS), trans-
vaginal sonography to predict endometrial cancer
showed 80.5% sensitivity and 85.7% in postmeno-
pausal women with a 5-mm cut-off value.
24
Although
this study included endometrial hyperplasia and was
not designed for endometrial cancer, it showed favor-
able sensitivity in postmenopausal women. Biological
marker in our study showed lower diagnostic power
than sonography as a single marker. However, biologi-
cal marker could complement the low positive predic-
tive value of sonography and be a useful marker for
detecting recurrence depending on markers.
Chronic inammation has been reported to have a
relationship with malignancy of epithelial origin.
25
Chronic inammation featuring elevated WBC is
associated with cancer development and progression
in bladder, cervical, gastric, intestinal, esophageal,
ovarian, prostate andthyroidcancers.
2630
Ingynecologi-
cal cancers, ovarian and cervical cancer have revealed
elevated whole blood cells counts, including elevated
neutrophil and monocyte counts.
15,18,31
Margolis et al.
reported that elevated WBC counts were observed in
endometrial cancer in postmenopausal women as well
as in breast, colorectal and lung cancer.
17
In the current
study, meanleukocyte counts, includingneutrophil and
monocyte counts, were more elevated in the endome-
trial cancer groupthaninhealthy controls, as they are in
other gynecological cancers.
In cases of colorectal, ovarian and cervical cancer,
NLR and MNM have been reported to be high,
15,18,19
as they were in our study. Although the mechanisms
by which neutrophil and monocyte counts increase
in cancer are not fully understood, tumor cells secrete
various cytokines and chemokines, and these cells
are eventually involved in the proliferation of leuko-
cytes, including neutrophils and monocytes. The toxic
granule of neutrophilic cytoplasm attacks the cancer
Table 2 Mean counts of leukocyte subsets, NLR, MNM and combination markers in the study subjects
Mean (95% CI) P-value
Control
(n = 596)
Endometrial cancer
(n = 238)
Age 50.7 (50.151.4) 52.1 (50.553.2) 0.06
CA125 14.1 (13.314.9) 42.0 (31.152.8) <0.001
WBC (cells/mL) 5663 (55425784) 6676 (64406913) <0.001
Neutrophil (cells/mL) 3300 (32033396) 4023 (38214226) <0.001
Lymphocyte (cells/mL) 1826 (17841867) 2033 (19472120) <0.001
Monocyte (cells/mL) 248 (242255) 319 (305333) <0.001
Eosinophil (cells/mL) 141 (131151) 133 (116150) 0.38
Basophil (cells/mL) 36 (3538) 36.1 (3239) 0.54
NLR 1.91 (1.841.98) 2.27 (20.12.50) <0.001
MNM 86.8 (82.691.0) 134.6 (124.0145.3) <0.001
Probability of a difference between mean leukocyte differential counts of endometrial cancer and control groups by independent t-test.
MNM, multiplication of monocyte and neutrophil counts then divided by 10 000; NLR, neutrophil to lymphocyte ratio; WBC, white blood
cells.
Diagnosis of endometrial cancer
2011 The Authors 51
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
cells, which is considered one of the immunological
defense mechanisms. However, neutrophilic releases
of vascular endothelial growth factor and IL-8 are con-
tributors to cancer related angiogenesis.
32
Normally,
monocytes are present in peripheral blood and differ-
entiate into dendritic cells or macrophages in tissue
by inuence of chemokines and cytokines in inam-
mation or tumor development. Tumor-associated
Table 3 Leukocyte differentials, NLR, MNM and CA125 according to pathological characteristics in the endometrial cancer
group
Mean (95% CI)
WBC Neutrophil Lymphocyte Monocyte NLR MNM CA125
All patients (n = 238) 6676 4023 2033 319 2.27 134.6 42.0
(64406913) (38214226) (19472120) (305333) (20.12.50) (124.0145.3) (31.152.8)
Stage
I-II (n = 208) 6596 3906 2062 314 2.19 127.4 35.9
(63636829) (37134099 ) (19682155) (300329) (1.952.43) (117.3137.4) (25.346.4)
III-IV (n = 30) 7238 4835 1851 350 2.86 183.6 83.7
(63248152) (40055665) (16432059) (305396) (2.213.52) (139.4227.8) (38.9128.5)
P-value 0.174 0.033 0.110 0.088 0.053 0.016 0.041
Grade
1 (n = 122) 6487 3850 2069 316 2.10 125.4 121
(61846789) (35984102) (19532185) (298334) (1.832.37) (113.3137.4) (23.651.7)
2 (n = 75) 6857 4113 2019 322 2.29 141.5 73
(64067307) (37404486) (18612176) (294351) (1.982.59) (118.6164.4) (27.076.2)
3 (n = 34) 7025 4448 1998 329 2.60 153.7 33
(63697682) (38605036) (17372259) (296362) (1.923.28) (125.0182.3) (20.862.6)
P-value 0.190 0.108 0.806 0.222 0.222 0.139 0.546
Myometrial inltration, %
<50 (n = 200) 6607 4007 2024 318 2.30 133.2 38.6
(63626853) (37934221) (19292118) (302333) (2.042.56) (122.0144.4) (27.549.8)
50 (n = 38) 7041 4108 2094 325 2.16 140.9 59.9
(63547729) (35494668) (18792309) (291359) (1.762.56) (110.7171.2) (24.295.6)
P-value 0.178 0.713 0.557 0.695 0.663 0.597 0.160
Cervical stromal invasion
No (n = 217) 6615 3944 2054 317 2.20 130.5 36.3
(63786853) (37464142) (19622145) (303331) (1.972.43) (120.0141.0) (26.346.4)
Yes (n = 20) 7217 4758 1825 335 3.07 173.1 78.0
(61998234) (37665750) (15642086) (275395) (1.944.20) (121.4224.9) (33.3122.7)
P-value 0.157 0.108 0.147 0.482 0.130 0.107 0.071
LVSI
No (n = 197) 6615 3931 2051 318 2.19 130.3 36.7
(63706860) (37284134) (19572146) (302333) (1.952.43) (119.3141.3) (25.348.0)
Yes (n = 40) 6997 4475 1972 323 2.69 154.4 68.1
(63067688) (38325118) (17542190) (289356) (2.023.36) (122.7186.0) (35.9100.2)
P-value 0.227 0.110 0.498 0.785 0.166 0.154 0.069
Peritoneal cytology
Negative (n = 207) 6691 4003 2054 314 2.25 131.2 36.0
(64466935) (37964210) (19612147) (299328) (2.012.50) (120.5142.0) (26.145.9)
Positive (n = 15) 7178 4837 1834 386 2.95 200.6 96.6
(58098546) (35576117) (15392129) (314458) (1.933.97) (130.2270.9) (14.9178.3)
P-value 0.322 0.189 0.223 0.013 0.15 0.055 0.136
Histological type
Endometrioid (n = 168) 6696 4012 2054 323 2.20 135.7 44.4
(64296963) (37894235) (19572151) (307339) (1.992.41) (123.6147.8) (30.957.9)
Non-endometrioid
(n = 52)
6608 4063 1967 303 2.56 129.9 33.5
(61247093) (36064520) (17782157) (277329) (1.843.28) (108.3151.5) (20.246.8)
P-value 0.760 0.836 0.413 0.235 0.340 0.654 0.413
Cells/mL.
LVSI, lymphovascular space invasion; MNM, multiplication of monocyte and neutrophil counts then divided by 10 000; NLR, neutrophil/
monocyte ratio; WBC, white blood cells.
B. W. Kim et al.
52 2011 The Authors
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
macrophages (TAM) derived from monocytes are a
substantial component of inammatory inltrates in
neoplastic tissues. TAM have two contrary roles in
tumor conditions. First, they kill neoplastic cells by
activation from IL-2, interferon and IL-12. Second,
TAM produce various potent angiogenic growth
factors, cytokines and proteases to potentiate tumor
progression.
2630
In colorectal, ovarian, gastric and pancreatic cancers,
increased neutrophil counts and decreased lymphocyte
Table 4 Odds ratios for the association of leukocyte differentials, NLR, MNM,
and CA125 with endometrial cancer
Range No. cases OR (95% CI) P-value
WBC
<4000 444 1.00 (reference)
40006000 278 2.67 (1.903.78) <0.001
>6000 112 5.22 (3.358.14) <0.001
Neutrophil

<4000 558 1.00 (reference)

40006000 231 2.13 (1.532.98) <0.001
<6000 45 5.82 (3.0910.99) <0.001
Lymphocyte
<2000 506 1.00 (reference)
20003000 286 1.57 (1.142.17) 0.006
>3000 42 4.29 (2.258.17) <0.001
Monocyte
<200 190 1.00 (reference)
200300 362 2.19 (1.333.62) <0.001
>300 282 6.30 (3.8410.33) <0.001
NLR
<2.0 526 1.00 (reference)
2.03.0 212 1.26 (0.881.78) 0.204
>3.0 96 1.70 (1.082.69) 0.022
MNM
<100 476 1.00 (reference)
100200 289 3.04 (2.184.25) <0.001
>200 69 7.37 (4.3012.62) <0.001
CA125
<35 U/mL 764 1.00 (reference)
>35 U/mL 66 8.28 (4.7014.60) <0.001
Cells/mL.
MNM, multiplication of monocyte and neutrophil counts then divided by 10 000; NLR,
neutrophil/monocyte ratio; OR, odds ratio; WBC, white blood cells.
Table 5 Diagnostic sensitivity and specicity of CA125, neutrophil, monocyte
subset, NLR, and MNM in endometrial cancer
AUC Sensitivity (%) Specicity (%) P-value
CA125 (18.7 U/mL) 0.689 49.1 83.1 <0.001
Neutrophil 0.641 79.4 23.7 <0.001
Monocyte 0.706 55 77.3 <0.001
NLR 0.539 51.2 59.1 0.076
MNM 0.696 62.9 69.1 <0.001
CA125 + MNM 0.76 71.7 69.6 <0.001
CA125 + Neutrophil 0.721 73.5 59.5 <0.001
CA125 + Monocyte 0.785 64.5 79.8 <0.001
CA125 + NLR 0.689 49.5 82 <0.001
Neutrophil + Monocyte 0.668 62.8 65.9 <0.001
AUC, area under curve; MNM, multiplication of monocyte and neutrophil counts then
divided by 10 000; NLR, neutrophil to lymphocyte ratio.
Diagnosis of endometrial cancer
2011 The Authors 53
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
counts have been reported. Consequently, the increased
NLR was related with poor prognosis.
15,19,20,33
In the
current study, however, NLR was less elevated than
MNM. Lymphocyte counts have a tendency to decrease
withdisease progerssion, resultinginlower levels inthe
advanced stage of cancer. However, the biological
behaviors of cancers may differ between anatomic sites.
87.8% of the endometrial cancers in the current study
were early stage. Further, it is difcult to analyze
the survival rate due to low recurrence and death
rate. Therefore, NLR may not be useful in early-stage
endometrial cancer. In the present study, we have
shown that MNM has greater diagnostic accuracy
than NLR.
Another mechanism of endometrial cancer develop-
ment is chronic inammation induced by hormonal
imbalance. In premenopausal women, the endome-
trium goes through the cycles of rapid growth, remod-
eling, differentiation and angiogenesis. Estrogen
inuences endometrial growth by growth factors and
cytokines, such as IL-1, IL-6 and TNF-a.
3436
Unopposed
estrogen where there is a lack of the protective proges-
terone triggers excessive mitosis and proliferation of
endomertrial cells, leading to DNA mutation. These
phenomena have beenwell describedinthe progression
to cancer development. During the menstrual cycle, the
endometrium is exposed to physiologically chronic
inammatory-like processes.
37
Exposure to excessive
estrogen leads to secretion of cytokines which are asso-
ciated with cancer progression. Obesity, a risk factor for
endometrial cancer, causes a chronic inammatory con-
dition due to elevation of serum levels of C-reactive
protein, IL-6, TNF-a, and leptin, which are known
markers of inammation.
38
Progesterone, the antagonist of estrogen, inhibits
cytokine-induced transcription of COX-2 and stimu-
lates prostaglandin dehydrogenase, an enzyme that
breaks down prostaglandins.
39,40
COX-2 protein levels
are elevated in patients with endometrial cancer cells.
By inhibiting COX-2, progesterone can interfere with
cell proliferation and the invasion ability of endome-
trial cancer, leading to apotosis.
41
Accordingly, PGE2
induced by COX-2 is elevated in malignant endome-
trial epithelial carcinomas.
16
Progesterone provides
anti-inammatory activity against these molecules.
While unoposed estrogen and insufcient progester-
one persistes, the endometrium undergoes inamma-
tory, proliferative and anti-apoptotic effects, which are
precursors of malignancy.
Although chronic endometritis has not been proven
to be associated with endometrial cancer, chronic
endometritis has been reported to be related with
endometrial hyperplasia in animals.
42,43
Endometrial
hyperplasia-pyometra complex is a common disease in
animals.
44
In human cases, chronic endometritis could
arise fromnon-hormonal use. Non-hormonal intrauter-
ine device (IUD) has a function to prevent sperm
reaching the ovum by local inammation. Most non-
hormonal IUD induce mild inammation that does not
pose a clinical problem and are accepted as effective
and safe. Although non-hormonal IUD has not been
proven to be associated with endometrial cancer, some
non-hormonal IUDusers develop chronic endometritis
and are suggested to be related with endometrial
hyperplasia, the precursor of endometrial cancer.
45
When abnormal prolonged bleeding from non-
hormonal use occurs, it is recommended that endome-
trial biopsy and removal is performed. It should be
investigated whether or not endometrial cancer devel-
ops from endometrial hyperplasia arising in chronic
endometritis.
The limitation of the present study is that leukocyte
markers are not specic to endometrial cancer. Inam-
mation arises from various conditions, such as infec-
tion, autoimmune disease and malignancy. More
400
300
200
100
0
1 10 35
CA125
M
M
M
100
Healthy control
Endometrial Cancer
600
Figure 1 Composite analysis of multiplication of neutro-
phil and monocyte counts (MNM) and CA125 levels in
patients with endometrial cancer () and healthy con-
trols (). Dotted line indicates cut-off value (35 U/mL)
of CA125 and solid line indicates optimal cut-off value
(100.1) of MNM that maximizes the sum of sensitivity
and specicity.
B. W. Kim et al.
54 2011 The Authors
Journal of Obstetrics and Gynaecology Research 2011 Japan Society of Obstetrics and Gynecology
advanced cases of endometrial cancer are required to
disclose correlations between leukocyte markers and
prognosis.
The present study demonstrates that the combination
of MNMand CA125 has signicantly higher diagnostic
accuracy than single use of CA125 in endometrial
cancer. A major advantage of using changes in leuko-
cyte differential counts is that these counts can be easily
obtained from nearly all patients by routine complete
blood counts (CBC) with no additional costs or testing.
Acknowledgments
This work was supported in part by the Basic Science
Research Program through the National Research
Foundation of Korea (NRF) funded by the Minis-
try of Education, Science and Technology (MEST)
(NRF-2008314-E00121), 311-2006-2-E00339 and 2010-
0011153; by a faculty research grant of the Yonsei
University College of Medicine for 2010(6-2010-0110);
and a grant funded by Sano-Aventis Korea and Cheil
Jedang (CJ).
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