Assessment of tumor markers CA 19-9, CEA, CA 125, and CA 242 for the early diagnosis and prognosis prediction of gallbladder cancer

doi:10.4240/wjgs.v14.i11.1272

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World Journal of Gastrointestinal Surgery

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

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World J Gastrointest Surg. Nov 27, 2022; 14(11): 1272-1284
Published online Nov 27, 2022. doi: 10.4240/wjgs.v14.i11.1272

Table 1 Demographic characteristics

Parameters	GBC, n = 80	Benign GB disease, n = 120	Total, n = 200	P value
Age, yr (n = 200)	57.0 (50.2-66.5)	47.0 (34.0-56.0)	52.0 (41.0-60.0)	< 0.001
Sex (n = 200), n (%)				0.951
Men	27 (33.8)	41 (34.2)	68 (34.0)
Women	53 (66.3)	79 (65.8)	132 (66.0)
BMI in kg/m², (mean)	27.06 ± 4.46	26.50 ± 5.6	26.8 ± 4.98	0.229
Hemoglobin in g/dL	11.8 (10.8-12.6)	11.6 (10.2-12.8)	11.75 (10.6-12.70)	0.523
TLC in cells/μL	8075.0 (6759.0-9801.0)	7830.0 (6705.0-8800.0)	7846.0 (6745.0-9440.0)	0.094
Lymphocytes in cells/μL	27.4 (21.2-31.0)	26.9 (22.0-31.0)	27.0 (22.0-31.0)	0.421
Monocytes in cells/mm³	5.7 (3.4-7.9)	6.0 (4.0-7.0)	6.0 (4.0-7.30)	0.604
Neutrophils in cells/mm³	63.1 (58.2-69.6)	63.0 (59.0-67.0)	63.0 (58.92-67.77)	0.816
Eosinophils, %	3.0 (1.2-4.0)	3.5 (2.0-4.4)	3.0 (2.0-4.10)	0.023
Basophils in cells/μL	0.5 (0.3-1.0)	0.4 (0.1-1.0)	0.50 (0.20-1.0)	0.351
Bilirubin in mg/dL
Total	0.9 (0.6-1.2)	0.8 (0.6-1.1)	0.87 (0.64-1.12)	0.251
Direct	0.3 (0.2-0.5)	0.3 (0.2-0.5)	0.30 (0.20-0.52)	0.621
Indirect	0.6 (0.4-0.7)	0.4 (0.3-0.6)	0.50 (0.36-0.65)	0.015
ALP in IU/L	119.5 (80.5-163.2)	109.0 (76.2-136.2)	111.0 (78.0-146.50)	0.019
SGOT in U/L	34.0 (27.2-43.0)	28.0 (24.0-34.0)	31.0 (25.0-36.0)	0.001
SGPT in U/L	27.0 (21.0-36.5)	23.0 (21.0-30.5)	24.0 (21.0-34.0)	0.012
INR	1.1 (1.0-1.1)	1.1 (1.0-1.1)	1.12 (1.10-1.12)	0.158
Serum creatinine in mg/dL	0.8 (0.7-0.9)	0.8 (0.7-0.9)	0.80 (0.68-0.97)	0.459
BUN in mg/dL	12.3 (9.0-14.4)	12.3 (9.9-14.5)	12.30 (5.0-12.0)	0.479
GB wall thickness in mm	12.0 (9.2-15.1)	6.0 (4.0-8.0)	8.0 (5.0-12.0)	< 0.001

Data shown as median (interquartile range), unless otherwise specified. Qualitative data between benign and carcinoma groups were analyzed using Mann-Whitney U-test and quantitative data were compared with the χ² test. ALP: Alkaline phosphate; BUN: Blood urea nitrogen; INR: International normalized ratio; IQR: Interquartile range; SGOT: Serum glutamic oxaloacetic transaminase; SGPT: Serum glutamic pyruvic transaminase; TLC: Total leukocyte count; GB: Gallbladder; GBC: Gallbladder cancer.

Table 2 Association of tumor markers with benign gallbladder disease and gallbladder cancer

All parameters	Benign, n = 120	Carcinoma, n = 80	P value
CA 19-9 in U/mL	3.1 (1.4-19.4)	112.9 (23.3-318.8)	< 0.001
CA 19-9, n (%)
Normal	108 (90.0)	23 (28.7)	< 0.001
Elevated	12 (10.0)	57 (71.3)	< 0.001
CA 125 in U/mL	8.6 (3.1-15.1)	24.5 (12.0-53.3)	< 0.001
CA 125, n (%)
Normal	112 (93.3)	49 (61.3)	< 0.001
Elevated	8 (6.7)	31 (38.8)	< 0.001
CEA in µg/L	2.3 (1.2-3.1)	3.1 (1.8-4.5)	< 0.003
CEA, n (%)
Normal	114 (94)	60 (75)	< 0.003
Elevated	6 (5.9)	20 (25)	< 0.003
CA 242 in U/mL	2.8 (1.5-9.8)	55.5 (32.7-96.5)	< 0.001
CA 242, n (%)
Normal	108 (90.0)	11 (13.7)	< 0.001
Elevated	12 (10.0)	69 (86.3)	< 0.001

Data shown as median (interquartile range). Qualitative data between benign and carcinoma groups were analyzed using Mann-Whitney U-test and quantitative data were compared with the χ² test. CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen.

Table 3 Association between tumor markers and clinical characteristics

Characteristics	CA 19-9		P value	CA 125		P value	CEA		P value	CA 242		P value
Characteristics	*Normal, n =* 131**	*Elevated, n =* 69**	P value	*Normal, n =* 161**	*Elevated, n =* 39**	P value	*Normal, n =* 181**	*Elevated, n =* 19**	P value	*Normal, n =* 119**	*Elevated,n =* 81**	P value
Age, yr	49.0 (39.0-59.0)	55.0 (45.0-63.5)	0.009	50.0 (39.0-59.0)	56.0 (50.0-69.0)	0.001	50.0 (40.0-59.5)	56.0 (45.0-65.0)	0.093	48.0 (34.0-56.0)	56.0 (47.5-64.5)	< 0.001
Sex
Male	46 (35.1)	22 (31.9)	0.754	51 (31.7)	17 (43.6)	0.112	62 (34.3)	6 (31.6)	> 0.05	41 (34.5)	27 (33.3)	0.881
Female	85 (64.9)	47 (68.1)	0.754	110 (68.3)	22 (56.4)	0.112	119 (65.7)	13 (68.4)	> 0.05	78 (65.5)	54 (66.7)	0.881
Gallstones
Absent	12 (9.2)	10 (14.5)	0.181	19 (11.8)	3 (7.7)	0.578	21 (11.6)	1 (5.3)	0.701	7 (5.9)	15 (18.5)	0.010
Present	119 (90.8)	59 (85.5)	0.181	142 (88.2)	36 (92.3)	0.578	160 (88.4)	18 (94.7)	0.701	112 (94.1)	66 (81.5)	0.010

Data shown as n (%). Test used: χ² test. CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen.

Table 4 Analyses of the sensitivity of tumor markers in different stages of gallbladder cancer

Clinical stages	*Patients, n =* 80**	CA 19-9	CEA	CA 125	CA 242
I	15 (18.6)	10 (66.7)	1 (6.7)	5 (33.3)	13 (86.7)
IIA	13 (16.3)	12 (92.3)	1 (7.7)	5 (38.5)	12 (92.3)
IIB	4 (5.0)	4 (100.0)	0	2 (50.0)	4 (100.0)
IIIA	4 (5.0)	4 (100.0)	0	2 (50.0)	4 (100.0)
IIIB	44 (55.0)	27 (61.3)	8 (18.1)	17 (38.6)	36 (81.8)

Data shown as n (%). CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen.

Table 5 Analyses of different combinations of markers in gallbladder cancer diagnosis

Group	n	1 marker	2 markers	3 markers	4 markers
Benign GB disease	120	29 (24.2)	6 (5.0)	1 (0.8)	0
GBC	80	14 (17.5)	27 (33.7)	25 (31.3)	3 (3.8)
Positive likelihood rate		0.5%	4.5%	25%	100%

GB: Gallbladder; GBC: Gallbladder cancer.

Table 6 Performance of markers for predicting gallbladder cancer

Variable	Sensitivity, %	Specificity, %	PPV, %	NPV, %	AUC (95%CI); P value
CA 19-9 (cutoff: 39.21 by ROC)	71.3	90.0	82.6	82.4	0.849 (0.791-0.907); < 0.001
CA 125 (cutoff: 36.00 by ROC)	38.8	93.3	79.5	69.6	0.758 (0.686-0.831); < 0.001
CEA (cutoff: 10.36 by ROC)	12.5	92.5	52.6	61.3	0.623 (0.542-0.703); 0.003
CA 242 (cutoff: 15.10 by ROC)	86.3	90.0	85.2	90.8	0.925 (0.881-0.969); < 0.001

AUC: Area under the curve; CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen; NPV: Negative predictive value; PPV: Positive predictive value; ROC: Receiver operating characteristic.

Table 7 Performance of combination of markers for predicting gallbladder cancer

Variable	Sensitivity, %	Specificity, %	PPV, %	NPV, %
Combination of any 2 markers	63.5	95.0	84.6	85.7
Combination of markers CA 19-9 and CA 242, n = 26	83.2	93.3	96.2	83.5
Combination of ≥ 3 markers	35.0	100.0	100.0	69.8

Any two markers: CA 19 -9 and CA 242 (n = 26); CA 19-9 and CEA (n = 3); CA 19-9 and CA 125 (n = 2); CEA and CA 242 (n = 7); CA 125 and CA 242 (n = 1). CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen; NPV: Negative predictive value; PPV: Positive predictive value.

Table 8 Correlations between carbohydrate antigen 19-9, carcinoembryonic antigen, carbohydrate antigen 125, and carbohydrate antigen 242 expression and lymph node metastasis

Marker level	*No LNM, n =* 36**	*LNM, n =* 44**	P value
CA 19-9 in U/mL	110.5 (54.2- 176.7)	221.8 (14.9-753.0)	< 0.05
CEA in µg/L	3.2 (1.4-4.0)	3.37 (1.9-6.2)	> 0.05
CA 125 in U/mL	23.0 (21.5-47.3)	33.0 (7.4-64.2)	> 0.05
CA 242 in U/mL	48.5 (36.1-84.7)	92.0 (25.8-112.0)	< 0.05

Data shown as median (interquartile range). Test: Independent sample t-test. CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen; LNM: Lymph node metastasis.

Table 9 Cox proportional hazards model for multivariate regression analysis

Prognostic factor	Parameter estimate	Wald χ²	P value	Hazard ratio	95% CI
CA 19-9	0	0.152	0.697	1	0.999-1.001
CEA	-0.137	1.415	0.234	0.872	0.696-1.093
CA 125	0.001	0.211	0.464	1.001	0.995-1.008
CA 242	0.017	10.422	0.001	1.017	1.007-1.027
LNM	-2.06	6.001	0.014	0.127	0.024-0.662
Age	-0.05	2.814	0.093	0.951	0.897-1.009
Sex	-0.264	0.098	0.755	0.768	0.146-4.027
BMI	0.038	0.478	0.489	1.038	0.933-1.155
GB wall thickness	-0.076	2.096	0.148	0.927	0.837-1.027
Stone size	-0.318	2.114	0.146	0.728	0.474-1.117

95%CI: 95% confidence interval; BMI: Body Mass Index; CA 19-9: Carbohydrate antigen 19-9; CA 125: Carbohydrate antigen 125; CA 242: Carbohydrate antigen 242; CEA: Carcinoembryonic antigen; GB: Gallbladder; LNM: Lymph node metastasis.

Citation: Sinha SR, Prakash P, Singh RK, Sinha DK. Assessment of tumor markers CA 19-9, CEA, CA 125, and CA 242 for the early diagnosis and prognosis prediction of gallbladder cancer. World J Gastrointest Surg 2022; 14(11): 1272-1284
URL: https://www.wjgnet.com/1948-9366/full/v14/i11/1272.htm
DOI: https://dx.doi.org/10.4240/wjgs.v14.i11.1272