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BMC Cancer

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Diagnostic and prognostic value of CEA, CA19–9, AFP and CA125 for early gastric cancer

  • Fan Feng1,
  • Yangzi Tian2,
  • Guanghui Xu1,
  • Zhen Liu1,
  • Shushang Liu1,
  • Gaozan Zheng1,
  • Man Guo1,
  • Xiao Lian1,
  • Daiming Fan1 and
  • Hongwei Zhang1Email author
Contributed equally
BMC Cancer201717:737

https://doi.org/10.1186/s12885-017-3738-y

Received: 1 August 2016

Accepted: 30 October 2017

Published: 9 November 2017

Abstract

Background

The diagnostic and prognostic significance of carcinoembryonic antigen (CEA), carbohydrate associated antigen 19–9 (CA19–9), alpha-fetoprotein (AFP) and cancer antigen 125 (CA125) in early gastric cancer have not been investigated yet. Thus, the present study aimed to explore the diagnostic and prognostic significance of the four tumor markers for early gastric cancer.

Methods

From September 2008 to March 2015, 587 early gastric cancer patients were given radical gastrectomy in our center. The clinicopathological characteristics were recorded. The association between levels of CEA and CA19–9 and clinicopathological characteristics and prognosis of patients were analyzed.

Results

There were 444 men (75.6%) and 143 women (24.4%). The median age was 57 years (ranged 21–85). The 1-, 3- and 5-year overall survival rate was 99.1%, 96.8% and 93.1%, respectively. The positive rate of CEA, CA19–9, AFP and CA125 was 4.3%, 4.8%, 1.5% and 1.9%, respectively. The positive rate of all markers combined was 10.4%. The associations between the clinicopathological features and levels of CEA and CA19–9 were analyzed. No significant association was found between CEA level and clinicopathological features. However, elevated CA19–9 level was correlated with female gender and presence of lymph node metastasis. Age > 60 years old, presence of lymph node metastasis and elevation of CEA level were independent risk factors for poor prognosis of early gastric cancer.

Conclusions

The positive rates of CEA, CA19–9, APF and CA125 were relatively low for early gastric cancer. Elevation of CA19–9 level was associated with female gender and presence of lymph node metastasis. Elevation of CEA level was an independent risk factor for the poor prognosis of early gastric cancer.

Keywords

Early gastric cancerDiagnosisPrognosisTumor marker

Background

Gastric cancer is the fourth commonest malignancy and the second leading cause of tumor related death all over the world [1]. Early gastric cancer is a lesion only invading mucosa or submucosa, with or without lymph node metastasis (LNM) [2]. Early diagnosis of gastric cancer is critical for optimal treatment. The ratio of early gastric cancer at diagnosis is increasing with advanced techniques and screening programs [3]. As detection of serum tumor markers are more convenient than other approaches, they are widely applied in early diagnosis of gastric cancer [4]. Unfortunately, the optimal serum biomarker for the detection of early gastric cancer is still under investigation [5].

The prognosis of early gastric cancer is favorable after radical gastrectomy, with a 5-year overall survival rate exceed 97% [6]. A variety of factors have been recognized as prognostic factors for early gastric cancer, including tumor size, differentiation status, tumor depth, LNM and vessel involvement [7]. In addition, tumor markers including CEA [8], CA19–9 [9], and AFP [10] were demonstrated to be prognostic factors for gastric cancer. However, prognostic significance of these markers for early gastric cancer have not been investigated yet.

Given this situation, the present study aims to explore the diagnostic and prognostic significance of CEA, CA19–9, AFP and CA125 for early gastric cancer.

Methods

This study was carried out in the Xijing Hospital of Digestive Diseases, the Fourth Military Medical University. From September 2008 to March 2015, 587 early gastric cancer patients with radical gastrectomy were enrolled in our present study. This study was approved by the Ethics Committee of Xijing Hospital, and written informed consent was obtained from all patients before surgery.

All patients were treated with proximal, distal or total D2 gastrectomy. The procedure was based on the Japanese Gastric Cancer Treatment Guidelines [11]. Tumor depth and LNM were defined by pathologists in the department of pathology according to the TNM classification.

Preoperative data including gender, age, tumor location, serum CEA, CA19–9, AFP and CA125 levels were recorded. Tumor size, differentiation status, tumor depth and LNM were collected based on pathology reports. Patients were followed up till November 2016 every 3 months.

The tumor markers were detected within 7 days before surgery. The cut off value of CEA, CA19–9, AFP and CA125 levels were 5 ng/ml, 27 U/ml, 8.1 ng/ml, 35 U/ml. The positive rates of tumor markers were defined as number of cases with elevated markers divided by total number of cases. The positive rates of combined markers were defined as number of cases with elevation in any of the markers divided by total number of cases.

Data were analyzed using SPSS 22.0 for Windows (SPSS Inc., Chicago, IL, USA). Discrete variables were analyzed by Fisher’s exact test or Chi-square test. Significant prognostic factors for early gastric cancer patients identified by univariate analysis were further assessed with multivariate analysis using the Cox’s proportional hazards regression model. Survival curves for overall survival were obtained using the Kaplan-Meier method. The P value less than 0.05 was considered to be statistically significant.

Results

The features of the entire cohort were summarized in Table 1. There were 444 men (75.6%) and 143 women (24.4%). The median age was 57 years (21–85 years). The median follow up time was 39 months (5–75 months). The total number of death during follow up was 25. The 1-, 3- and 5-year overall survival rate was 99.1%, 96.8% and 93.1%, respectively (Fig. 1).
Table 1

Clinicopathological characteristics of early gastric cancer patients

Characteristics

No. of patients

Percent

Gender

 Male

444

75.6

 Female

143

24.4

Age

  ≤ 60

368

62.7

  > 60

219

37.3

Tumor location

 Upper third

102

17.4

 Middle third

100

17.0

 Lower third

385

65.6

Tumor size (cm)

  ≤ 2

365

62.2

  > 2

222

37.8

Pathological type

 Well differentiated

186

31.7

 Moderately differentiated

163

27.8

 Poorly differentiated

220

37.5

 Signet ring cell or Mucinous

18

3.0

Tumor depth

 T1a

255

43.4

 T1b

332

56.6

Lymph node metastasis

 N0

495

84.3

 N1

55

9.4

 N2

29

4.9

 N3

8

1.4

Fig. 1

Overall survival of early gastric cancer patients

The positive rates of the four markers were summarized in Table 2. The positive rate of CEA, CA19–9, AFP and CA125 level were 4.3%, 4.8%, 1.5% and 1.9%, respectively. The highest positive rate was 8.2% for combination of two markers (CA19–9 and CEA), 9.4% for combination of three markers (CA19–9, CEA and AFP or CA19–9, CEA and CA125), and 10.4% for combination of all four markers.
Table 2

Positive rates of single and combined tumor markers in early gastric cancer patients

Tumor marker

 

CA19–9

AFP

CA125

CEA

25(4.3%)

48(8.2%)

31(5.3%)

35(6.0%)

CA19–9

28(4.8%)

 

37(6.3%)

33(5.6%)

AFP

9(1.5%)

  

20(3.4%)

CA125

11(1.9%)

   

CEA + CA19–9

  

55(9.4%)

55(9.4%)

CEA + AFP

   

41(7.0%)

CA19–9 + AFP

   

44(7.5%)

CEA + CA19–9 + AFP

   

61(10.4%)

Considering the extremely low positive rates of AFP and CA125, we only analyzed the correlation between level of CEA and CA19–9 and clinicopathological features. No association was found between CEA level and clinicopathological features (Table 3). However, elevation of CA19–9 level was correlated with female gender and presence of LNM (Table 4).
Table 3

Comparison of clinicopathological characteristics between two groups stratified by CEA level

Characteristics

CEA(−)

CEA(+)

P

Gender

 Male

422

22

0.161

 Female

140

3

 

Age

  ≤ 60

351

17

0.675

  > 60

211

8

 

Tumor location

 Upper third

99

3

0.744

 Middle third

95

5

 

 Lower third

368

17

 

Tumor size (cm)

  ≤ 2

346

19

0.205

  > 2

216

6

 

Pathological type

 Well differentiated

180

6

0.537

 Moderately differentiated

153

10

 

 Poorly differentiated

212

8

 

 Signet ring cell or Mucinous

17

1

 

Tumor depth

 T1a

245

9

0.539

 T1b

317

16

 

Lymph node metastasis

 N0

474

21

0.698

 N1

53

2

 

 N2

28

1

 

 N3

7

1

 
Table 4

Comparison of clinicopathological characteristics between two groups stratified by CA 19–9 level

Characteristics

CA19–9(−)

CA19–9(+)

P

Gender

 Male

428

16

0.025

 Female

131

12

 

Age

  ≤ 60

351

17

0.843

  > 60

208

11

 

Tumor location

 Upper third

95

7

0.543

 Middle third

96

4

 

 Lower third

368

17

 

Tumor size (cm)

  ≤ 2

345

20

0.327

  > 2

214

8

 

Pathological type

 Well differentiated

178

8

0.936

 Moderately differentiated

156

7

 

 Poorly differentiated

208

12

 

 Signet ring cell or Mucinous

17

1

 

Tumor depth

 T1a

243

12

1.000

 T1b

316

16

 

Lymph node metastasis

 N0

475

20

0.020

 N1

52

3

 

 N2

26

3

 

 N3

6

2

 
Prognostic factors for early gastric cancer patients were analyzed using univariate analysis (Table 5). The results showed that age, LNM and CEA level were prognostic factors for early gastric cancer. The variables used for adjustment in the multivariate analyses were age, LNM and CEA level. The results showed that age, LNM and CEA level were independent prognostic factors according to multivariate analysis (Table 6). The overall survival of early gastric cancer patients according to the levels of CEA and CA19–9 were shown in Figs. 2 and 3.
Table 5

Univariate analysis of prognostic factors for early gastric cancer

Prognostic factors

β

Hazard ratio (95% CI)

P value

Gender

0.105

1.110(0.443–2.783)

0.824

Age

1.195

3.304(1.425–7.661)

0.005

Tumor location

−0.283

0.754(0.478–1.189)

0.224

Tumor size

−0.687

0.503(0.201–1.260)

0.142

Pathological type

−0.388

0.679(0.431–1.067)

0.093

Tumor depth

0.736

2.088(0.831–5.241)

0.117

Lymph node metastasis

0.577

1.781(1.124–2.821)

0.014

CEA

1.404

4.070(1.208–13.713)

0.024

CA19–9

0.576

1.779(0.419–7.546)

0.435

AFP

−3.019

0.049(0.000–590,647.114)

0.717

CA125

0.740

2.095(0.283–15.490)

0.469

Table 6

Multivariate analysis of prognostic factors for early gastric cancer

Prognostic factors

β

Hazard ratio (95% CI)

P value

Age

1.379

3.971(1.671–9.435)

0.002

Lymph node metastasis

0.682

1.978(1.248–3.136)

0.004

CEA

1.284

3.611(1.065–12.245)

0.039

Fig. 2

Overall survival of early gastric cancer patients stratified by CEA level

Fig. 3

Overall survival of early gastric cancer patients stratified by CA19–9 level

Discussion

Serum tumor markers are widely applied in the diagnosis, treatment effect assessment and disease monitoring [12]. Up to date, a series of studies have explored the diagnostic and prognostic value of various serum tumor markers for gastric cancer [5]. However, no study has explored the diagnostic and prognostic value of serum tumor markers for early gastric cancer. Our present study found that the positive rates of serum CEA, CA19–9, APF and CA125 were relatively low for early gastric cancer. Elevation of CA19–9 level was correlated with female gender and presence of LNM. Elevation of CEA level was an independent risk factor for the poor prognosis of early gastric cancer.

The positive rates of the four markers for early gastric cancer varied widely. It was reported that the positive rate was 4.4%–15.4% for CEA [1315], 11.7% for CA19–9 [15], 2.5%–3.3% for AFP [16, 17] and 6.7% for CA125 [17]. In the present study, the positive rates of all four tumor markers were lower than previous reports. Even with the combination of four tumor markers, the positive rate was only 10.4%. This indicated that the diagnostic value of the four tumor markers was extremely low for early gastric cancer.

A strong correlation between elevated tumor markers and clinicopathological features has been reported previously. It was reported that serum CEA level was correlated with tumor depth, LNM [13] and liver metastasis [18]. Other studies have reported that CA19–9 level was correlated with tumor depth, LNM and tumor stage [19, 20]. However, the association between tumor markers and the clinicopathological features of early gastric cancer has not been investigated yet. In our present study, no association was found between CEA level and clinicopathological features. However, elevation of CA19–9 level was correlated with female gender and presence of LNM.

Early gastric cancer has a favorable outcome after radical gastrectomy. The preoperative tumor markers have been reported as valuable predictors for the prognosis of gastric cancer. A meta-analysis containing 14,651 gastric cancer patients demonstrated that serum CEA level was an independent prognostic factor for gastric cancer [8]. Another meta-analysis revealed that CEA protein and mRNA levels in peritoneal lavage were associated with peritoneal recurrence after radical gastrectomy [21]. A meta-analysis containing 11,408 gastric cancer patients showed that elevated serum CA19–9 level was correlated with poor prognosis [22]. Elevated AFP level was reported to be associated with liver metastasis and poor prognosis of gastric cancer [10, 23, 24]. Elevation of peritoneal lavage CA125 level was correlated with peritoneal dissemination and poor outcomes of gastric cancer [25]. However, the prognostic value of these tumor markers for early gastric cancer was unclear. In our study, considering the extremely low positive rate of AFP and CA125 level, only the prognostic significance of CEA and CA19–9 level were analyzed. The results showed that serum CEA level was an independent prognostic factor for early gastric cancer. However, serum CA19–9 level had no prognostic significance.

There are some limitations in our study. Firstly, we did not evaluate the predictive value of postoperative levels of serum tumor markers for recurrence patterns and prognosis of early gastric cancer. Secondly, the sample size was not large enough, and the positive rate of tumor markers was relatively low, which may result in bias during analysis. Thirdly, mortality was extremely low in early gastric cancer, which will influence the prognostic significance analysis of tumor markers.

Conclusions

The positive rates of CEA, CA19–9, APF and CA125 were relatively low for early gastric cancer. Elevation of CA19–9 level was associated with female gender and presence of lymph node metastasis. Elevation of CEA level was an independent risk factor for the poor prognosis of early gastric cancer.

Abbreviations

AFP: 

alpha-fetoprotein

CA125: 

cancer antigen 125

CA19–9: 

carbohydrate associated antigen 19–9

CEA: 

carcinoembryonic antigen

LNM: 

lymph node metastasis

Declarations

Acknowledgments

We wish to thank Xingbin Hu for his help with the revision of manuscript.

Funding

This study was supported in part by grants from the National Natural Scientific Foundation of China [NO. 31100643, 31,570,907, 81,572,306, 81,502,403, XJZT12Z03]. The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing of this manuscript.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

FF, TYZ and XGH conceived the study and drafted the manuscript. LZ, LSS and ZGZ collected the data and participated in drafting the manuscript. GM and LX performed statistical analysis. FDM designed the study and revised the manuscript. ZHW designed and supervised the study. All authors read and approved the final manuscript. All authors contributed to the writing of the manuscript and provided final approval of the manuscript. All authors have read and approved the final version of this manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Authors’ information

Not further applicable.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Xijing Hospital, and written informed consent was obtained from the patients in our center.

Consent for publication

Not applicable.

Competing interests

There are no financial or other relations that could lead to a conflict of interest. Prof. Daiming Fan, one of co-authors in the present study, is a member of the editorial board of this journal.

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Authors’ Affiliations

(1)
Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University
(2)
Department of Dermatology, Xijing Hospital, the Fourth Military Medical University

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© The Author(s). 2017

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