Combined detection tumor markers for diagnosis and prognosis of gallbladder cancer

doi:10.3748/wjg.v20.i14.4085

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Evidence-Based Medicine

World J Gastroenterol. Apr 14, 2014; 20(14): 4085-4092
Published online Apr 14, 2014. doi: 10.3748/wjg.v20.i14.4085

Table 1 Surgical modalities and their relationship with tumor stage in the gallbladder cancer group

Surgical modality	TNM stage
Surgical modality	II	IIIA	IIIB	IVA	IVB
C + N	6	8	2
C + WR + N	1		6		4
C + S4aS5 + N		1	7		3
C + ELH + N					1
C + ERH + N				1
C + BD + N
C + WR + BD + N		1	6		2
C + S4As5 + BD + N			4		2
C + CH + BD + N			3		1
C + S4aS5 + other + N				1	1
C + S4aS5 + other + N			5
C + ERH + BD + other + N				1	1
HPD + N				1
Palliative resection				1	2
Simple drainage				1	3
Pure exploration					2

BD: Bile duct resection; C: Cholecystectomy; CH: Central hepatectomy; ELH: Extended left hepatectomy; ERH: Extended right hepatectomy; HPD: Hepato-pancreaticoduodenectomy; N: Lymphadenectomy; Other: Other organ tissue resection; S4aS5: Liver resection of segments IVa and V; WR: Wedge resection of the gallbladder fossae.

Table 2 Comparison of serum cancer antigen 199, cancer antigen 125, cancer antigen 242, and carcinoembryonic antigen levels

Group	n	MFI (CEA)	MFI (CA199)	MFI (CA125)	MFI (CA242)
Control group	78	3.93 ± 2.04	14.97 ± 8.91^b	10.48 ± 6.38^b	9.48 ± 3.43^b
Benign disease	78	3.83 ± 1.85	15.17 ± 7.82^c	12.99 ± 6.99^c	10.19 ± 3.08^c
GBC	78	9.36 ± 3.58	238.17 ± 346.36^b^c	55.34 ± 81.78^b^c	39.92 ± 45.9^b^c

Results are mean ± SD.

^bP < 0.01 vs control group;

^cP < 0.05 vs benign disease group. MFI: Mean fluorescence intensity; CA: Cancer antigen; CEA: Carcinoembryonic antigen; GBC: Gallbladder cancer.

Table 3 Positive rates of carcinoembryonic antigen, cancer antigen 125, cancer antigen 242, and cancer antigen 199 n (%)

	GBC(n = 78)	Benign gallbladder disease (n = 78)	Healthy controls(n = 78)
CEA Pc	9 (11.5)	1 (1.2)	2 (2.5)
CA242 Pc	50 (64.1)^b	2 (2.5)	1 (1.2)
CA125 Pc	35 (44.8)^b	2 (2.5)	2 (2.5)
CA199 Pc	56 (71.7)^b	4 (5.0)	3 (3.8)
Combination Pc	7 (8.9)	0 (0.0)	0 (0.0)

^bP < 0.01 vs benign gallbladder disease and healthy control group. Combination = Carcinoembryonic antigen (CEA) + cancer antigen CA242 + CA125 + CA199. Pc: Positive cases; GBC: Gallbladder cancer.

Table 4 Correlations between gallbladder cancer markers, tumor size, location, and staging

Group	n	MFI (CEA)	MFI (CA199)	MFI (CA125)	MFI (CA242)
Age (yr)
≥ 50	45	9.5 ± 4.3	239.1 ± 324.6	55.9 ± 86.6	39.9 ± 42.9
< 50	33	9.2 ± 2.7	236.9 ± 319.4	54.6 ± 78.9	39.9 ± 47.3
Sex
Male	30	9.3 ± 6.6	234.6 ± 356.9	54.8 ± 81.7	38.5 ± 47.1
Female	48	9.4 ± 3.8	240.4 ± 298.7	55.7 ± 89.5	40.8 ± 49.9
Tumor position
Neck	37	8.5 ± 3.9	262.2 ± 177.8^b	62.1 ± 47.0^b	42.5 ± 45.9^b
Body	23	5.2 ± 4.2	28.3 ± 20.7	56.9 ± 99.7	19.0 ± 21.6
Bottom	5	3.3 ± 2.6	27.6 ± 2.4^b	14.5 ± 6.5^b	8.5 ± 2.9^b
Cystic duct	13	21.5 ± 25.1	622 ± 196.9	49.0 ± 32.9	81.7 ± 56.7
Staging
II	7	3.2 ± 2.2	66.1 ± 6.3^a	17.7 ± 7.7^a	8.4 ± 3.3^a
IIIA	10	2.0 ± 0.9	89.5 ± 8.2	47.3 ± 38.2	10.2 ± 9.9
IIIB	33	6.9 ± 6.4	205.5 ± 33.9^a	59.6 ± 114.1^a	22 ± 22.6^a
IVA	6	3.5 ± 3.3	383.6 ± 55.5^a	58.1 ± 25.5^a	55.2 ± 25.3^a
IVB	22	19.9 ± 9.1	418.7 ± 316.5^a	64.1 ± 50.5^a	86.2 ± 56.9^a
Tumor size
> 5 cm	20	9.6 ± 2.2	768.1 ± 272.9^a	82.9 ± 21.9^a	81.8 ± 53.1^a
≤ 5 cm	58	9.3 ± 1.2	55.4 ± 68.7^a	45.8 ± 10.1^a	25.5 ± 32.9^a
Pathological type
Highly differentiated	8	3.0 ± 2.0	68.9 ± 5.9^a	16.7 ± 7.7^a	8.7 ± 3.1^a
Moderately differentiated	54	6.9 ± 5.9	142.3 ± 200.4	49.9 ± 9.9	33.8 ± 41.3
Poorly differentiated	11	3.5 ± 2.5	649.1 ± 209.1^a	84.0 ± 29.4^a	73.4 ± 58.9^a
Carcinoid	2	20.9 ± 14.6	766.3 ± 330.5^a	121.3 ± 45.2^a	62.7 ± 9.4^a
Squamous cell carcinoma	2	107.5 ± 69.1	334.4 ± 14.9^a	116.0 ± 103.1^a	108.5 ± 58.7^a
Signet ring cell carcinoma	1	31	1000^a	89.3^a	69.3^a

Results are mean ± SD.

^aP < 0.05,

^bP < 0.01 vs control group. MFI: Mean fluorescence intensity; CA: Cancer antigen; CEA: Carcinoembryonic antigen.

Table 5 Analyses of the sensitivity of tumor markers in different stages of gallbladder cancer n (%)

Clinical stages	Cases (n)	CEA	CA199	CA242	CA125
II	7	1 (14.2)	3 (42.8)^a	4 (57.1)^a^c	2 (28.5)^a
IIIA	10	1 (10)	5 (50)	6 (60)	3 (30)
IIIB	33	2 (6)	18 (54.5)	20 (60.6)	14 (42.4)
IVA	6	2 (33.3)	4 (66.6)	4 (66.6)	3 (50)
IVB	22	3 (13.6)	16 (72.7)	16 (72.7)	13 (59)

^aP < 0.05 vs sensitivity of stage IVA, B;

^cP < 0.05 vs sensitivity of CA125 and CA199. CA: Cancer antigen; CEA: Carcinoembryonic antigen.

Table 6 Evaluation of diagnostic value of a single tumor marker in 78 gallbladder cancer cases

Diagnostic value	n	Sensitivity	Specificity	Positive likelihood ratio	Negative likelihood ratio
CEA	9	11.5%	97.4%	4.42	0.91
CA199	56	71.7%	96.1%	18.4	0.29
CA242	50	64.1%	98.7%	49.5	0.36
CA125	35	44.8%	96.2%	11.79	0.57

Sensitivity = true positive/patients × 100%; Specificity = true negative/normal × 100%; Positive likelihood ratio = sensitivity/(1 - specificity); Negative likelihood ratio = (1 - sensitivity)/specificity. CA: Cancer antigen; CEA: Carcinoembryonic antigen.

Table 7 Analyses of different combinations of markers in gallbladder cancer diagnosis

Group	n	1 item (+)	2 item (+)	3 item (+)	4 item (+)
Normal	78	4 (5.1)	3 (3.8)	0 (0)	0 (0)
Gallbladder cancer (GBC)	78	71 (91.0)	67 (85.9)	54 (69.2)	7 (8.9)
Positive likelihood rate		17.8%	22.6%	100%	100%

Table 8 Correlations between carcinoembryonic antigen, cancer antigen 125, cancer antigen 242, and cancer antigen 199 expression and lymph node metastasis

Indicators	No LN metastasis(n = 25)	Adjacent LN metastasis (n = 36)	Distal LN metastasis (n = 17)
CEA, μg/L	7.5 ± 3.4	9.5 ± 5.9	9.8 ± 3.6
CA199, U/mL	122.2 ± 117.2	237.4 ± 189.5^b	491.2 ± 222.5^a^b
CA242, U/mL	9.5 ± 2.9	38.5 ± 15.7^b	58.7 ± 29.6^a^b
CA125 U/mL	13.5 ± 16.5	43.6 ± 37.9^b	61.8 ± 67.8^a^b

Results are mean ± SD.

^aP < 0.05,

^bP < 0.01 vs patients without lymph node (LN) metastasis. CA: Cancer antigen; CEA: Carcinoembryonic antigen.

Table 9 Carcinoembryonic antigen, cancer antigen 125, cancer antigen 242, and cancer antigen 199 expressions during follow-up

Groups	n	CEA	CA199	CA242	CA125
Non-recurrence group	22	7.34 ± 2.14	78.65 ± 86.43^d	12.41 ± 1.25^d	11.96 ± 2.37^d
Recurrence group	8	9.34 ± 3.04	219.74 ± 321.63^b	34.54 ± 8.38^b	53.88 ± 8.2^b

Results are mean ± SD.

^bP < 0.01 vs non-recurrence group;

^dP < 0.01 vs gallbladder cancer (GBC) group. CA: Cancer antigen; CEA: Carcinoembryonic antigen.

Table 10 Results of Cox proportional hazards model for multivariate regression analysis

Prognostic factor	Parameter estimate	Waldχ²	P value	HR	95%CI
CEA	-0.043	0.498	0.48	0.957	0.849-1.080
CA199	0.005	12.076	0.001	1.005	1.002-1.009
CA242	-0.007	0.386	0.535	0.993	0.972-1.015
CA125	0.003	0.714	0.398	1.003	0.996-1.009
Surgical modality	0.569	2.450	0.118	1.766	0.866-3.599
LN metastasis	1.191	3.276	0.07	3.291	0.906-11.957
Position (neck)	-1.578	6.358	0.012	0.206	0.061-0.704
Age	-0.010	0.073	0.787	0.990	0.922-1.063
Sex	0.796	2.508	0.113	2.216	0.828-5.932

Multivariate survival analysis using the Cox proportional hazards model for independent prognostic factors of gallbladder cancer (GBC). P < 0.05 was considered statistically significant. CA: Cancer antigen; CEA: Carcinoembryonic antigen; LN: Lymph node.

Citation: Wang YF, Feng FL, Zhao XH, Ye ZX, Zeng HP, Li Z, Jiang XQ, Peng ZH. Combined detection tumor markers for diagnosis and prognosis of gallbladder cancer. World J Gastroenterol 2014; 20(14): 4085-4092
URL: https://www.wjgnet.com/1007-9327/full/v20/i14/4085.htm
DOI: https://dx.doi.org/10.3748/wjg.v20.i14.4085