Download CA15-3 + CA125 + CEA + Prolactin

Estimation of CA 15-3 and CEA in combination is better than CA 125 alone in
the diagnosis of endometrial cancer
Dr Nithin Kumar
1
U,
Dr Sridhar M
2
G,
Dr
3
Habeebulla
1 Assistant Professor Department of Biochemistry, Yenepoya Medical college, Mangalore,
2 Professor ,Department of Biochemistry, JIPMER, Puducherry,
3 Professor ,Department of Obstetrics and Gynaecology, JIPMER, Puducherry
INTRODUCTION
Endometrial carcinoma is the most common gynecological malignancy and
its prevalence in India is increasing in last 5 year. According to GLOBOCAN
2012 statistics, approximately 12300 new cases are diagnosed yearly, of which
about 4700 women die from the disease each year in India (1). The overall 5year survival rate for all stages is 86% and for the disease confined to the
uterus is 96% (2,3). Most common presentation of endometrial cancer is
abnormal uterine bleeding. Nearly 3/4th of women present with early stage of
endometrial cancer (4).
As the survival rates are high if endometrial cancer is detected in early
stages, early diagnosis plays a role in reducing overall mortality. Endometrial
cancer is usually diagnosed from histopathological examination of endometrial
biopsy specimen or by endometrial cytology from an endometrial brush.
These methods have a lower sensitivity and high false negative rate in
detecting endometrial carcinoma (5). This warrants the use of non-invasive
serum markers to detect endometrial carcinoma.
Earlier studies have estimated serum concentrations of Cancer Antigen -125
(CA 125), Cancer Antigen 15-3 (CA 15 – 3), Prolactin, and Carcino Embryonic
Antigen (CEA) in endometrial carcinoma. However there are no studies
indicating usage of these tumor markers as screening or diagnostic tool.
The present study is undertaken to estimate and compare the
concentrations of serum prolactin, CA 125, CA 15-3, and CEA in patients with
endometrial carcinoma and abnormal uterine bleeding and to investigate
whether the above parameters be used individually or in combination to
diagnose endometrial cancer. Our study is designed to develop a panel of
tumor markers and investigate the predictive power of serum prolactin, CA 125, CA 15-3, and CEA in diagnosing endometrial carcinoma.
MATERIALS AND METHODS
A descriptive study was conducted in Department of Biochemistry in
collaboration with the Department of Obstetrics and Gynaecology, JIPMER,
Puducherry, India during reference period of January 2011 to April 2012. The
study was approved by JIPMER institute ethics sub-committee.
The study subjects were enrolled in the study based on inclusion and
exclusion criteria. All perimenopausal women with endometrial carcinoma
diagnosed by histopathological examination were taken into group 1.
Similarly weight matched perimenopausal women abnormal uterine bleeding
other than endometrial carcinoma were considered into group 2. All
endometrial cancer patients on treatment and those who are on hormone
replacement therapy were excluded from the study. Patients with abdominal
tuberculosis were also excluded as elevated CA 125 levels are associated with
this condition(6). Thirty eight patients with endometrial carcinoma were
included in Group 1, whereas forty weight matched patients with abnormal
uterine bleeding other than endometrial cancers were recruited into group 2.
The details about age, height and weight of every participant were
recorded to calculate the Body Mass Index (BMI). 5 ml of venous blood sample
was collected from each patient by standard phlebotomy procedure. Serum
was separated and stored at -80°C for assays of various parameters as per
protocol. Serum concentrations of CA125, CEA and Prolactin were measured
by a two-site sandwich immunoassay using direct chemiluminometric
technology (ADVIA Centaur® CP Immunoassay System, Siemens,
Australia)(7,8). Whereas CA 15-3 was assayed by using ELISA kit (Syntron
Bioresearch, California)(9).
The reference ranges for serum CA-125,
Prolactin, and CEA are less than 35 U/mL, 1.9–25 ng/mL and 0 - 3µg/L
respectively. The reference range for CA 15-3 was <33 U/mL.
The statistical analysis was carried out by using Statistical Package for
Social Sciences (SPSS, Version 20.0).
RESULTS
There were no statistically
significant
differences
in
demographic characteristics like
age, height, weight and BMI
between both the study groups as
represented in adjacent table.
Endometrial Carcinoma (n = 38)
Parameters
21.97 (12.53 – 48.51)
CA 15-3 (U/mL)
CA 125 (U/mL)
19.85 (7.2-47.78)
CEA (µg/L)
2.30 (1.58-5.03)
Prolactin (ng/mL)
8.36 (6.2-14.3)
Abnormal uterine bleeding (n=40)
P value
18.75 (9.38 – 23.89)
0.048
10.95
0.015
(6.73-16.97)
2.00 (1.45-2.40)
0.033
7.02 (4.93-10.02)
0.042are given in brackets.
Values are expressed as median . Interquartile ranges
We carried out correlation analysis between/ among the different
parameters in study group consisting of endometrial carcinoma cases. No
significant correlation was observed between CA 125, CA 15-3, CEA, and
Prolactin. Receiver operating characteristic curves were plotted for serum
levels of CA125, CA 15 -3, CEA and Prolactin to obtain optimal cut off values
to distinguish between endometrial cancer and abnormal uterine bleeding.
Parameter
CA15-3
CA125
CEA
PRL
AUC
0.630
0.660
0.640
0.634
Cut off value
27.55U/mL
17.8U/mL
3.6µg/L
11.27ng/mL
Sensitivity
44.74%
52.63%
34.21%
36.84%
Specificity
82.50%
80.00%
95.00%
87.5%
PPV
70.8%
71.4%
86.7%
73.7%
NPV
61.1%
64%
60.3%
59.3%
All tumor markers in our study had a very good specificity, but very less
sensitivity at the cut off when taken individually. So combination of tumor
markers were tried to create different panels, to increase sensitivity and
specificity for panel of tumor markers. Result obtained are shown in next
Models
AUC
Sensitivity Specificity PPV
NPV
table.
CA15- 3 + CEA
0.7322
65.8
77.5
86.2
70.5
CA15-3 +CA125
0.6678
68.4
67.5
66.7
69.2
CA15-3 + PRL
0.6671
63.2
72.5
68.6
67.4
CA125 + CEA
0.6737
63.2
75.0
70.5
68.2
CA125 + PRL
0.6803
68.4
70.0
68.4
70.0
CEA + PRL
0.727
52.6
82.5
74.1
64.7
CA15-3 + CA125 + CEA
0.725
78.9
62.5
66.7
75.75
CA15-3 + CA125 + Prolactin
0.6974
81.6
60.0
66.0
77.42
CA125 + CEA + Prolactin
0.7276
73.7
65
66.7
72.22
CA 15-3 + CEA + Prolactin
0.729
76.3
67.5
69.0
75
CA15-3 + CA125 + CEA + Prolactin
0.7526
86.8
55.0
64.7
81.48
DISCUSSION
In our study, CA 15-3 levels are significantly increased in carcinoma patients in
comparison with patients with uterine bleeding . Scambia et al and Panici et
al have reported an increase in the levels of CA 15-3 in carcinoma cases when
compared with endometrial hyperplasia patients (10,11) which might be
because of increased shedding of cancer antigens to the blood stream.
In our study serum concentrations of CA 125 are higher in endometrial
carcinoma patients when compared with abnormal uterine bleeding patients.
These findings are in accordance with previous studies which attributed
elevated CA 125 levels to the enhanced synthetic activity within the
neoplastic endometrial cells(12–14).
Previous study by Kanat-Pektas et al did not observe any difference in CEA
levels between endometrial carcinoma and healthy controls(12). In current
study CEA levels are significantly higher in endometrial carcinoma cases which
may be due to loss of polarity of cancer cells leading to redistribution of CEA
around the cell surface (15).
We observed significantly high serum levels of prolactin in cancer patients
when compared to abnormal uterine bleeding group. The higher levels of
prolactin may be explained by excessive prolactin release from the
endometrial tumor cells (17).
When taken in combination, only a panel consisting of CA 15-3 and CEA
showed the highest AUC than all other markers taken in different possible
combinations.
CONCLUSION
Endometrial
Abnormal uterine
carcinoma (n=38)
bleeding (n=40)
Age(years)
49.8±7.2
48.3±4.5
NS
Height(cm)
151.3±5.5
152.7±4.5
NS
Weight(kg)
60.2±11.5
59.4±12.6
NS
BMI(kg/m2)
26.4±5.7
25.4±5.1
NS
Variables
Among tumor markers, serum levels of CA15 3, CA125, CEA and prolactin
were significantly high in patients with endometrial carcinoma when
compared to subjects with abnormal uterine bleeding as shown in table.
p value
We found that serum concentrations of CA 125, CA 15-3, CEA, and Prolactin
were significantly higher in endometrial cancer. In addition we observed that
combination of CA 15- 3 and CEA has better diagnostic utility than any other
markers individually or combined in patients presenting with dysfunctional
uterine bleeding. The major limitations of the study are small sample size and
non-inclusion of healthy control group. Further evaluative studies has to be
done in high number of sample to use these makers as diagnostic tool.
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