Diagnostic value of serum CA125,CA19-9 and CA15-3 in endometriosis: A meta-analysis

Abstract

Aim

To evaluate the diagnostic value of serum cancer antigen (CA)125, CA19-9 and CA15-3 concentrations in endometriosis.

Methods

Case–control studies evaluating CA125, CA19-9 and CA15-3 and endometriosis, published between January 2000 and November 2014 were retrieved from PubMed® and Google Scholar. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated. Subgroup analyses were carried out by ethnicity and disease stage (early, stage I/II; advanced, stage III/IV).

Results

The analysis included 12 case–control studies (963 cases, 855 controls). CA125 was associated with endometriosis in the overall population (SMD 0.82, 95% CI 0.72, 0.92), Caucasian subgroup (SMD 1.08, 95% CI 0.96, 1.19), and early (SMD 1.20, 95% CI 0.93, 1.48) or advanced disease (SMD 1.29, 95% CI 1.04, 1.55). CA19-9 was associated with endometriosis in the overall population (SMD 0.48, 95% CI 0.24, 0.72), Caucasian subgroup (SMD 0.31, 95% CI 0.07, 0.55), Asian subgroup (SMD 9.65, 95% CI 7.88, 11.42) and advanced disease (SMD 0.60, 95% CI 0.34, 0.87). CA15-3 was significantly associated with advanced disease (SMD 0.47, 95% CI 0.09, 0.84).

Conclusions

Serum CA125 and CA19-9 may represent useful biomarkers for the noninvasive diagnosis of endometriosis.

Keywords

CA125 CA19-9 CA15-3 endometriosis meta-analysis

Introduction

Endometriosis is a benign gynaecological disease that occurs in up to 10% of women of reproductive age (16–50 years old).¹ It can cause dyspareunia, dysmenorrhoea, menstrual irregularities, low back pain and infertility.^2,3 Although the most accurate diagnostic method is histological examination of laparascopically excised lesions, less-invasive auxiliary tests have been developed, including the use of biochemical markers.⁴

Elevated serum concentrations of cancer antigen [CA] 125, CA19-9, and CA15-3 are observed in some carcinomas,^5–7 and are considered oncofetal antigens, or serum tumour markers. Serum CA125 concentration was first used in the diagnosis of endometriosis in 1983,⁸ followed by several other biomarkers including CA19-9, CA15-3, copeptin, interleukin (IL)-6 and IL-8.^9–13

Published data regarding these biomarkers are inconsistent due to study limitations including small sample size, use of outdated assay techniques, and quantification of a limited number of biomarkers. The diagnostic value of serum CA125, CA19-9 and CA15-3 concentration in endometriosis therefore remains unclear. The aim of the present meta-analysis was to evaluate the association between serum CA125, CA19-9 and CA15-3 and endometriosis, by analysing data from studies using current assay techniques.

Materials and methods

Search strategy

A systematic search of PubMed® and Google Scholar was performed to identify studies published between January 2000 and November 2014 using the keywords “CA125”, “CA19”, “CA15” and “endometriosis”. Inclusion criteria were: (i) case–control studies published in peer reviewed journals; (ii) full text available; (iii) studies focusing on the relationship between serum CA125, CA19-9 or CA15-3 concentration and endometriosis; (iv) raw data available, including numbers of cases and controls and mean ± SD biomarker concentrations. All studies related to CA125, CA1-9 and CA15-3 were included, with no restriction on the number of biomarkers investigated in each study.

Data extraction

Data were reviewed and extracted independently by two reviewers (Y.M. and C.L.). Data retrieved included name of first author, year of publication, country of study, ethnicity, mean ± SD biomarker concentration, and numbers of cases and controls. All disagreements were resolved by consensus, with unresolved issues referred to a third author. In the case of duplicate articles, only the most comprehensive and/or the most recently published were included.

Statistical analyses

The mean differences of each included study were expressed as the standardized mean difference (SMD) and 95% confidence intervals (CI), with statistical significance defined as occurring when 95% CI did not include 0.0. Independent analyses were performed for each biomarker (CA125, CA19-9 and CA15-3). Subgroup analyses were carried out by ethnicity (Caucasian or Asian), clinical stage (early [stage I/II] or advanced [stage III/IV]). The I² statistic was calculated to evaluate the heterogeneity among trials. The Mantel–Haenszel fixed-effects model was applied in cases of low heterogeneity (I²< 50), and the random-effects model was applied for datasets showing obvious heterogeneity (I²> 50). Results were summarized using forest plots. Potential publication bias was assessed using Begg’s funnel plots and Egger’s linear regression test. Meta-analyses were performed using STATA® version 12.0 (STATA Corp. LP, College Station, TX, USA). All reported P-values were two sided.

Results

The search strategy identified 12 qualifying studies (963 cases and 855 controls; Figure 1, Table 1).^{9,11,12,14–22} All studies evaluated CA125, four studied CA19-9,^9,11,12,20 and two CA15-3.^9,12 A total of nine studies included Caucasian populations,^{9,11,12,14,16–18,21,22} and three included Asian populations.^15,19,20

Figure 1.

Flow diagram of identification and collection of eligible studies in a meta-analysis to evaluate the diagnostic value of serum cancer antigen (CA)125, CA19-9 and CA15-3 concentrations in endometriosis.

Table 1.

Characteristics of studies included in a meta-analysis of the diagnostic value of serum cancer antigen (CA) 125, CA19-9 and CA15-3 concentration in endometriosis.

Author, year	Country	Ethnicity	Cases		Controls
Author, year	Country	Ethnicity	n	Mean ± SD	n	Mean ± SD
CA-125
Wei, 2014²⁰	China	Asian	34	48.13 ± 3.58	30	13.7 ± 1.3
Tuten, 2014⁹	Turkey	Caucasian	50	77.4 ± 65.2	36	15.8 ± 7.0
Santulli, 2014²¹*	France	Caucasian	225	55.2 ± 68.7	279	22.5 ± 25.2
Santulli, 2014²¹*	France	Caucasian	99	60.8 ± 63.5	279	22.5 ± 25.2
Anastasi, 2013²²	Italy	Caucasian	57	46.1 ± 34.0	50	16.8 ± 8.6
Mohamed, 2013¹⁶	Egypt	Caucasian	30	36.4 ± 14.2	30	12.6 ± 6.1
Ramos, 2012¹⁸*	Brazil	Caucasian	44	52.0 ± 7.9	58	29.2 ± 5.7
Ramos, 2012¹⁸*	Brazil	Caucasian	44	42.2 ± 5.7	58	21.2 ± 2.8
Qi, 2011, 2011¹⁹	China	Asian	75	31.9 ± 15.8	55	30.6 ± 19.3
Kurdoglu, 2009¹¹	Turkey	Caucasian	101	62.2 ± 87.4	26	15.92 ± 9.1
Amaral, 2006¹⁷	Brazil	Caucasian	35	39.1 ± 45.8	17	10.5 ± 5.9
Kitawaki, 2005¹⁵	Japan	Asian	88	50.8 ± 68.6	161	84.8 ± 126.9
Matalliotakis, 2005¹²	U.S.	Caucasian	65	180.2 ± 82.4	43	93.2 ± 39.1
Kafali, 2004¹⁴	Turkey	Caucasian	16	35.8 ± 21.1	12	12.2 ± 4.8
CA-19.9
Wei, 2014²⁰	China	Asian	34	44.2 ± 4.2	30	13.9 ± 1.2
Tuten, 2014⁹	Turkey	Caucasian	50	29.4 ± 40.0	36	12.6 ± 16.1
Kurdoglu, 2009¹¹	Turkey	Caucasian	101	39.6 ± 54.7	26	9.8 ± 10.5
Matalliotakis, 2005¹²	U.S.	Caucasian	65	88.6 ± 67.2	43	95.9 ± 104.8
CA-15.3
Tuten, 2014⁹	Turkey	Caucasian	50	19.4 ± 11.7	36	14.3 ± 5.2
Matalliotakis, 2005¹²	U.S.	Caucasian	65	68.8 ± 66.4	43	65.6 ± 72.1

Two studies were reported in each of these citations.

There was statistically significant heterogeneity (I²> 90%) in all CA125 datasets (overall, Caucasian and Asian), therefore a random-effects model was used. Findings of the meta-analysis are given in Table 2, with forest plots shown in Figure 2. There were significant associations between serum CA125 concentration and endometriosis in the overall population (SMD 0.82, 95% CI 0.72, 0.92; Figure 2[a]) and the Caucasian subgroup (SMD 1.08, 95% CI 0.96, 1.19; Figure 2[b]) but not in the Asian subgroup (SMD − 0.06, 95% CI − 0.27, 0.15; Figure 2[c]). There was no evidence of publication bias in the overall or Caucasian groups (Table 2; Figure 3). It was not possible to determine publication bias in the Asian subgroup due to the small sample size (data not shown).

Table 2.

Findings of a meta-analysis of the diagnostic value of serum cancer antigen (CA) 125, CA19-9 and CA15-3 concentration in endometriosis, in the overall population and Caucasian and Asian subgroups.

Analysis Model	Analysis Method	Heterogeneity		SMD (95% CI)	Publication Bias
Analysis Model	Analysis Method	I² (%)	P-value		Begg	Egger
CA-125
Overall	Random	96.8	1.1 × 10⁻⁹	0.82 (0.72, 0.92)	0.127	0.218
Caucasian	Random	94.7	3.9 × 10⁻⁸	1.08 (0.96, 1.19)	0.062	0.011
Asian	Random	98.4	9.8 × 10⁻⁷	−0.06 (−0.27, 0.15)	–^a	–^a
CA-19.9
Overall	Random	97.3	2.0 × 10^-6	0.48 (0.24, 0.72)	0.296	0.095
Caucasian	Random	70.3	0.035	0.31 (0.07, 0.55)	–^a	–^a
Asian	–^a	–^a	–^a	9.65 (7.88, 11.42)	–^a	–^a
CA-15.3
Overall	Random	62.9	0.100	0.26 (−0.03, 0.55)	–^a	–^a

Not available due to small number of studies included.

SMD, standardized mean difference; 95% CI, 95% confidence intervals.

Figure 2.

Forest plots for the association between endometriosis and serum cancer antigen (CA) 125 concentration. (a) overall population; (b) Caucasian subgroup; (c) Asian subgroup.

Figure 3.

Begg’s funnel plots for the association between endometriosis and serum cancer antigen (CA) 125 concentration. (a) overall population; (b) Caucasian subgroup.

There was statistically significant heterogeneity (I²> 60%) in all CA19-9 and CA15-3 datasets, therefore a random-effects model was used. Results of the meta-analysis are shown in Table 2, with forest plots in Figure 4. CA19-9 was significantly associated with endometriosis in the overall population (SMD 0.48, 95% CI 0.24, 0.72; Figure 4[a]), Caucasian subgroup (SMD 0.31, 95% CI 0.07, 0.55; Figure 4[b]) and the Asian subgroup (SMD 9.65, 95% CI 7.88, 11.42 Figure 4[c]). Tests found no evidence for publication bias in the overall population, but were not performed in Caucasian and Asian subgroups due to the small sample size. There was no significant association between CA15-3 and endometriosis in the overall population (SMD 0.26, 95% CI − 0.03, 0.55 (Figure 4[d]). Neither ethnicity based subgroup analyses nor assessments of publication bias were conducted for CA15-3 due to small sample size.

Figure 4.

Forest plots for the association between endometriosis and serum cancer antigen (CA) 19-9 and CA15-3 concentration. (a) CA19-9, overall population; (b) CA19-9, Caucasian subgroup; (c) CA19-9, Asian subgroup; (d) CA15-3, overall population.

Data regarding the associations between biomarker concentration and endometriosis stage are given in Table 3, with forest plots shown in Figure 5. There was significant heterogeneity for stage III/IV in the CA125 and CA19-9 datasets and stage I/II in the CA15-3 dataset. Meta-analysis indicated that CA125 was associated with both early (I/II; SMD 1.20, 95% CI 0.93, 1.48; Figure 5[a]) and advanced stage disease (III/IV; SMD 1.29, 95% CI 1.04, 1.55; Figure 5[b]). Serum CA19-9 was significantly associated with stage III/IV disease (SMD 0.60, 95% CI 0.34, 0.87; Figure 5[d]) but not with stage I/II disease (Figure 5[c]). Similarly, CA15-3 (SMD 0.47, 95% CI 0.09, 0.84; Figure 5[f]) was significantly associated with stage III/IV disease but not with stage I/II disease (Figure 5[e]).

Figure 5.

Forest plots for the association between endometriosis stage and serum cancer antigen (CA) 125, CA19-9 and CA15-3 concentration. (a) CA125 in stage I/II disease; (b) CA125 in stage III/IV disease; (c) CA19-9 in stage I/II disease; (d) CA19-9 in stage III/IV disease; (e) CA15-3 in stage I/II disease; (f) CA15-3 in stage III/IV disease.

Table 3.

Findings of a meta-analysis of the diagnostic value of serum cancer antigen (CA) 125, CA19-9 and CA15-3 concentration in endometriosis, stratified by clinical stage.

Stage	Analysis Method	Heterogeneity		SMD (95% CI)
Stage	Analysis Method	I² (%)	P-value	SMD (95% CI)
CA-125
I/II	Fixed	13.9	0.326	1.20 (0.93, 1.48)
III/IV	Random	79.1	0.001	1.29 (1.04, 1.55)
CA-19.9
I/II	Fixed	10.2	0.342	0.15 (−0.12, 0.42)
III/IV	Random	70.4	0.018	0.61 (0.34, 0.87)
CA-15.3
I/II	Random	72.2	0.058	0.19 (−0.13, 0.52)
III/IV	Fixed	33.4	0.221	0.47 (0.09, 0.84)

SMD, standardized mean difference; 95% CI, 95% confidence intervals.

Discussion

The diagnosis of endometriosis can be delayed up to 8.5 years from the onset of symptoms.^23–25 Although laparoscopy is the gold-standard diagnostic method, ∼66% of women who undergo laparoscopy are found to be free of the disease. Taken together with the potential risks and cost associated with laparoscopy,²⁶ the development of a noninvasive diagnostic method would have a huge impact on patients’ health-related quality-of-life and reduce the number of unnecessary interventions.²⁷

The current meta-analysis found that the serum CA125 concentration was associated with endometriosis in Caucasian, Asian and overall populations, and with both early and advanced stage disease. This elevated serum CA125 might be due to the induction of inflammatory reactions that alter endothelial permeability, allowing CA125 to reach the circulation, or the higher CA125 concentration in ectopic rather than entopic endometrium.²⁸ Our meta-analysis confirmed the clinical value of CA125 as an auxiliary biological marker in endometriosis diagnosis.

Statistically significant associations between CA19-9 and endometriosis were observed in Caucasian, Asian and overall populations in the present analysis, in accordance with the findings of others.²⁹ In a finding consistent with others,^30,31 our results showed that CA19-9 was significantly associated with advanced stage (stage III and IV) endometriosis. CA19-9 may therefore be useful in the diagnosis of later-stage disease.

The present meta-analysis found that CA15-3 is not useful for the general diagnosis of endometriosis, but that it may be a valid biomarker of advanced disease. Our finding is in contrast to other research,⁹ which reported no significant increase in serum CA15-3 levels in patients with endometriosis.

In conclusion, endometriosis is significantly associated with elevated serum CA125 and CA19-9 concentrations, and CA19-9 is increased further in the more advanced stages of disease. Serum CA125 and CA19-9 may represent useful biomarkers for the noninvasive diagnosis of endometriosis.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This work was part of the programme of the Scientific and Technological Project of Technology Bureau of Zhengzhou, funded under the Technology Bureau of Zhengzhou (grant no. 141PPTGG445).

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