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G Y N E CO L O G I C O N CO L O G Y

The diagnostic and prognostic value of serum YKL-40in endometrial cancer

Jiang-tao Fan Xiao-hui Si Yan Liao

Ping Shen

Received: 14 January 2012 / Accepted: 23 August 2012 / Published online: 4 September 2012

Springer-Verlag 2012

Abstract

Purpose To evaluate the diagnostic and prognostic valueof serum YKL-40 in endometrial cancer (EC).

Methods Serum YKL-40 levels were detected and com-

pared in 34 of the 50 cases with EC before surgery, in 22 of

the 34 with EC after surgery, in 30 cases with uterine

myoma, and in 30 healthy women as normal controls.

Receiver operating characteristics (ROC) curves were

adopted for diagnosis and calculation of area under each

ROC curve in EC. The progression-free survival (PFS) and

overall survival (OS) between YKL-40 positive and neg-

ative patients were compared in the follow-up.

Results The mean pre-operative serum YKL-40 values

were significantly higher than that in the uterine myoma

cases and in the healthy women (P = 0.000). The mean

post-operative serum YKL-40 in the 22 EC cases was

significantly lower than pre-operative serum YKL-40 lev-

els in these cases (P = 0.000). There were critical differ-

ences between the area under ROC curve for YKL-40 and

CA125 (P = 0.053). The PFS and OS for the YKL-40-

positive patients were significantly shorter than those for

the YKL-40-negative patients.

Conclusion Preliminary investigations have shown that

serum YKL-40 level may have a definite clinical value in

the diagnosis and prognosis of EC.

Keywords YKL-40 Endometrial cancer

Tumor marker Diagnosis Prognosis

Introduction

Endometrial cancer (EC) is the fourth most common cancer

in women [1]. The morbidity and the mortality is

increasing even though there has been a great progress in

early diagnosis and treatment of EC [2,3]. There are many

factors influencing the prognosis of EC, which are mainly

associated with the FIGO stage, histology type, and the

myometrial invasion and lymphovascular invasion.

Women with papillary serous or clear cell histology are at

high-risk for distant spread and recurrence of the disease,

even in early-stage and absence of myometrial invasion [4].

Serum CA125 has been considered to be valuable both in

diagnosis and prognosis of EC. CA125 has been reported to

be elevated in 1940 % of EC patients [5]. Up to now,

there is no defined prognostic cut-off value for CA125

level in EC [6]. It is important to find a new valuable serum

tumor marker for EC in improving early diagnostic rate and

decreasing mortality.

YKL-40, also known as human cartilage-glycoprotein

39 or Chitinase 3-like 1, is a member of mammalian

chitinase-like proteins and a highly conserved protein

[7]. The gene for YKL-40 (CHI3L1) is located on

chromosome 1q31-1q32 [8]. This protein does not have

the chitinase activity because of the mutation of a glu-

tamic acid to leucine in the chitinase-3-like catalytic

domain [9]. Several lines of evidence support that YKL-

40 is expressed by some types of malignant cells, such

as, breast, lung, ovary, uterine, and kidney tumor cells.

YKL-40 is also expressed by benign tumor cells, such as,

myelocytemetamyelocyte of normal bone marrow [10],

and macrophages during late stages of differentiation

[11], and differentiated vascular smooth muscle cells

[12]. The exact function of YKL-40 is yet to be

determined.

J. Fan (&) X. Si Y. Liao P. Shen

Department of Gynecology, The First Affiliated Hospital,

Guangxi Medical University, Nanning 530021, China

e-mail: papillomavirus69715@yahoo.com.cn

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Arch Gynecol Obstet (2013) 287:111115

DOI 10.1007/s00404-012-2546-5

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Recent studies showed that serum YKL-40 may be a

useful marker with diagnostic and prognostic value in

cancer. Elevations of serum YKL-40 are correlated with

the clinical outcome of gastric cancer [13], glioblastoma

[14], breast cancer [15], and small cell lung cancer [16].

Plasma YKL-40 level is related to the prognosis of ovarian

cancer and its elevation is associated with a shorter survival

[17].In this study, we investigated the diagnostic and prog-

nostic value of serum YKL-40 in EC. Our aim is to eval-

uate the possibility of serum YKL-40 as a tumor marker

in EC.

Materials and methods

Clinical data

All blood samples were collected from the patients hospi-

talized in the gynecologic department of the First AffiliatedHospital, GuangXi Medical University, China. Patients

undergoing gynecologic surgery in our hospital had their

tumor specimens and serum samples banked under the

Medical Ethics Committee of GuangXi Medical Univer-

sity, approved tissue, acquisition protocol after signing

informed consent. Fifty patients with EC identified by

histology, between March 2007 and April 2010 were col-

lected in this study. Patients with a prior history of other

malignancy, hepatitis or arthritis were excluded from the

study. Patients after surgery were followed-up till tumor

relapse or patient death. Clinical follow-up of patients in

this study ended at 31st December 2011.Thirty-four out of

50 (68 %) patients available with complete clinical and

follow-up data were recruited into the study finally. Blood

samples were collected and stored before and 7 days after

surgery. Blood samples from 30 cases with uterine myoma

and 30 cases healthy women were collected simultaneously

as controls. The median age of EC group, myoma group

and healthy group were 55 years (range 3365 years),

43 years (range 3648 years), and 38 years (range

2953 years), respectively. Twenty-three EC patients had

tumors with endometrioid adenocarcinoma, 10 patients

with serous adenocarcinoma, and 1 patient with clear cell

adenocarcinoma. Ten of the ECs were histological grade 1,

13 patients were grade 2, and 11 patients were grade 3.

Nineteen of 34 patients had FIGO stage I, 6 patients in

stage II, 7 patients in stage III, and 2 in stage IV.

Blood collection and serum separation

All blood samples were collected from patients with EC

and uterine myoma 57 days before surgery. The blood

samples from patients and healthy women were allowed to

clot at room temperature for at least 30 min and then

centrifuged for 10 min at 3,000 rpm. The serum aliquots

were stored at -20 C until tested.

Serum YKL-40 and CA125 assay

Serum YKL-40 levels were determined in duplicate for all

serum samples using the commercially available YKL-40ELISA Kit from Metra Biosystems (San Diego, USA)

according to the manufacturers protocol.

Serum CA125 testing was performed in the clinical

laboratory center of the First Affiliated hospital, Guangxi

Medical University. A chemiluminescent enzyme immu-

noassay on the Architect Analyzer (Abbott Laboratories,

Chicago, IL) was used. The sensitivity was 5 IU/ml. The

inter- and intra- assay coefficients of variation were 7.5 and

5.3 %, respectively. We consider 35 IU/ml as the upper

limit of normality for CA125.

Statistical analysis

SPSS statistical software (version 15.0, SPSS Inc., Chi-

cago, IL) was used for analysis. Differences were com-

pared by one-way ANOVA test or Chi-square test

(McNemars test). Time to events variables, such as overall

survival (OS) and progression-free survival (PFS), were

estimated using the KaplanMeier method. The log-rank

test was used to examine the significance of the relation-

ship between log-marker values and clinical outcomes.

Receiver operating characteristics curves (ROC) were

constructed for YKL-40 and CA125 serum concentrations

as diagnostics for cancer, by plotting sensitivity versus

1-specifity, and the area under each ROC curve was cal-

culated. A P value of\0.05 was considered significant.

Results

Serum YKL-40 level in each group

The mean serum value of YKL-40 in EC group (pre-

operative), myoma group, and healthy women was

158.49 80.39, 62.9 25.88, and 52.8 26.90 lg/L,

respectively. The levels in EC group (pre-operative) were

significantly higher than that of myoma group and healthy

women (P\ 0.001). There was no significant difference

between myoma group and healthy group (P = 0.997).

Serum YKL-40 in EC group with different clinical

pathologic features

Table1showed the serum YKL-40 values in EC group with

different clinical pathologic features. The pre-operative

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serum YKL-40 value significantly correlated with FIGO

stage, histological grade, and the metastasis of retroperito-

neal lymph node (P\0.01).

The diagnostic value of serum YKL-40 for EC

At the value of 106.6 lg/L which was defined as the nor-

mal value based on the mean value, plus two standard

deviation obtained from healthy women, serum YKL-40

has a sensitivity of 73.5 % (25/34), a specificity of 81.6 %

(49/60), a positive predictive value of 69.4 %, a negative

predictive value of 84.4 %, and a false negative rate of

26.5 % (9/34) for the diagnosis of EC. The area under the

curve for the ROC curve assessing serum YKL-40 and

CA125 as a diagnostic tool for EC was 0.807 and 0.667,

respectively. There were critical differences between YKL-

40 and CA125 (P = 0.053).

The serum level of serum YKL-40 and CA125

in early-stage of EC

In the early-stage of EC(FIGO stage I and II) patients, 16

(64.0 %) of 25 had elevated serum YKL-40 values com-

pared with 8 (32.0 %) of 25 with elevated CA125

(P = 0.008) (Table 2).

The pre-and post-operative serum YKL-40 values

There was significant difference between serum YKL-40

values before and 7 days after surgery for 22 EC patients,

which is 165.12 96.9 and 120.91 92.77 lg/L,

respectively (P\ 0.001).

The relationship between serum YKL-40 level

and the prognosis of EC patients

Thirty-four EC patients were followed-up and the PFS

and OS were recorded. At the end of follow-up, at the

value of 106.6 lg/L, there were 11 death or relapsed casesin YKL-40 positive patients and the median PFS and OS

were 18 and 21 m, respectively. In the YKL-40 negative

EC patients, there was one death patient and the median

PFS and OS were not observed during follow-up. Sig-

nificantly poorer survival was found for EC patients with

serum YKL-40 levels C106.6 lg/L compared with

patients with serum YKL-40 levels \106.6 lg/L

(P\0.01). KaplanMeier survival curves were shown in

Figs.1 and 2.

Table 1 Serum YKL-40 of EC patients with different clinical path-

ologic features

Factor N YKL-40

(lg/L)

P value

Age (years) [0.05

\60 12 162.1 37.4

C60 22 149.6

42.4

FIGO stage \0.01

III 25 124.2 57.3

IIIIV 9 303.8 60.3

Histological type [0.05

Endometrioid adenocarcinoma 23 147.3 50.4

Papillary serous/clear cell

adenocarcinoma

11 161.5 45.1

Histological grade \0.01

Grade 12 23 123.4 59.2

Grade 3 11 272.6 71.3

Myometrial invasion [0.05

\1/2 20 127.3 54.1C1/2 14 151.7 45.1

Lymph node \0.01

? 12 280.4 53.7

- 22 130.2 46.1

Washing cytology [0.05

? 7 159.8 58.5

- 27 148.9 63.1

Table 2 The positive rate of serum YKL-40 and CA125 in early-

stage EC

YKL-40 CA125 Total

?

? 8 8 16

0 9 9

Total 8 17 25

30.0020.0010.000.00

survial months

1.0

0.8

0.6

0.4

0.2

0.0

C

umS

urvival

YKL-40=106.6

group

Fig. 1 Comparison of PFS between YKL-40 positive and negative in

EC patients

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Discussion

YKL-40 is a kind of glycoprotein found by Johansen et al.

[18]. Up to now, the function of YKL-40 in the develop-

ment of cancer is not known. But it has been suggested that

YKL-40 may play a role in extracellular matrix degrada-

tion or angiogenesis [19]. Some in vivo researches showed

that YKL-40 was secreted by activated neutrophil granu-

locytes and macrophages, and was secreted increasingly in

the inflammatory conditions. This suggested that YKL-40

may have a role in tissue remodeling, contributing to

cancer growth and metastasis. The limitation of serumCA125 and CA15-3 in diagnosis of EC mentioned above,

especially the poor sensitivity and specificity for diagnosis

of early-stage disease, narrowed the clinical application of

these markers. Some studies are now assessing the feasi-

bility of serum YKL-40 to be a diagnostic indicator. In our

study, pre-operative serum YKL-40 levels in EC patients

were significantly higher than that in myoma and healthy

women, while there was no statistical difference between

myoma patients and healthy women. At the level of

106.6 lg/L, serum YKL-40 has a sensitivity of 73.5 % and

a specificity of 81.6 % for diagnosis of EC, which is higher

than that of CA125 (55.8 and 76.7 %). There was criticaldifference (P = 0.053) between the area under ROC

curves of serum YKL-40 and CA125 for diagnosis of EC.

This may associate with the small sample cases.

In our study, we compared the diagnostic value of YKL-

40 and CA125 in early-stage disease. At the level of

106.6 lg/L, 64.0 % (16/25) of the early-stage EC patients

had an elevated serum YKL-40, compared with 32.0 %

(8/25) of early-stage EC patients with CA125 [35 U/L

(P = 0.008). Serum YKL-40 has advantages over CA125

for diagnosis of early-stage EC, contributing to early

management of disease.

The study showed that serum YKL-40 level is related to

the stage of tumor [20]. In our study, serum YKL-40 levels

were elevated in 64.0 % of early-stage EC patients and in

all (9/9) advanced EC patients, indicating that serum

YKL-40 levels were associated with stage. Other similar

study, however, found the opposite results [21]. Largescale studies are still wanted to obtain the convincing

conclusions.

Many studies showed that serum YKL-40 was an

important factor to predict the prognosis of disease

[22, 23]. Our primary investigation found that the serum

YKL-40 levels 7 days after surgery were significantly

lower than that of pre-operation, indicating the concentra-

tions of YKL-40 decreased after the tumor burden was

removed. The changes of serum YKL-40 before and after

surgery reflected the regression of tumor cells and indi-

cated that serum YKL-40 may be useful for the monitoring

of cancer patients. The follow-up result of our study foundthat the median PFS and OS of YKL-40 positive patients

were 18 and 21 m, respectively, compared with signifi-

cantly longer PFS and OS ([30 m) of YKL-40 negative

patients, also indicating serum YKL-40 may be one of the

prognostic factor for EC. The possible mechanism of YKL-40

to affect the prognosis of disease may be: YKL-40 is a

proliferation factor of fibroblasts which play a major role in

cancer development, spread, differentiation, and regres-

sion, then can affect the prognosis of cancer indirectly.

To sum up, because the post-operative therapies can

result in improved clinical outcome for the high-risk EC

patients, it is very important to identify and select the

patients with high-risk features who would benefit from

these post-operative therapies. Serum YKL-40 may play a

role in stratifying EC patients with high-risk factors. Fur-

thermore, studies of serum YKL-40 are warranted to better

assess the ability of this marker for monitoring EC patients

after surgery.

Conflict of interest We declare that we have no conflict of interest.

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