Predictive Value of Preoperative Serum AFP, CEA, and CA19-9 Levels in Patients with Single Small Hepatocellular Carcinoma: Retrospective Study

Figures & data

Figure 1 Flowchart of patient selection.

Table 1 Characteristics of 409 Enrolled Patients Grouped by TMS

Variable	Cases	Tumor Maker Score (TMS)			P value
		0 (n=142)	1 (n=171)	≥2 (n=96)
AFP, ng/mL, median [IQR]	10.64 [4.06,187.30]	3.69 [2.58,5.53]	56.55 [7.41,374.70]	103.33 [22.65,633.18]	0.000
CEA, ng/mL, median [IQR]	2.75 [1.80,4.13]	2.39 [1.63,3.02]	2.72 [1.58,3.66]	5.19 [2.83,6.52]	0.000
CA19-9, U/mL, median [IQR]	18.77 [10.68,33.09]	12.72 [9.58,19.34]	18.32 [11.82,29.33]	40.20 [31.14,64.31]	0.000
Age, years, mean [SD]	57.12 [9.39]	56.89 [9.27]	56.29 [9.67]	58.96 [8.89]	0.077
Age, years, n (%)					0.129
≤ 65	337 (82.4)	115 (81.0)	148 (86.5)	74 (77.1)
> 65	72 (17.6)	27 (19.0)	23 (13.5)	22 (22.9)
Sex, n (%)					0.253
Female	100 (24.4)	28 (19.7)	45 (26.3)	27 (28.1)
Male	309 (75.6)	114 (80.3)	126 (73.7)	69 (71.9)
Tumor size, cm, median [IQR]	2.3 [1.8,2.8]	2.5 [1.8,2.8]	2.2 [1.6,2.6]	2.3 [1.9,2.7]	0.333
Tumor size type, n (%)					0.362
≤2cm	178 (43.5)	55 (38.7)	79 (46.2)	44 (45.8)
>2cm	231 (56.5)	87 (61.3)	92 (53.8)	52 (54.2)
Tumor location, n (%)					0.247
S1	9 (2.2)	2 (1.4)	5 (2.9)	2 (2.1)
S2	24 (5.9)	5 (3.5)	13 (7.6)	6 (6.3)
S3	21 (5.1)	4 (2.8)	8 (4.7)	9 (9.4)
S4a	22 (5.4)	3 (2.1)	12 (7.0)	7 (7.3)
S4b	19 (4.6)	8 (5.6)	6 (3.5)	5 (5.2)
S5	92 (22.5)	39 (27.5)	37 (21.6)	16 (16.7)
S6	88 (21.5)	34 (23.9)	37 (21.6)	17 (17.7)
S7	62 (15.2)	25 (17.6)	22 (12.9)	15 (15.6)
S8	72 (17.6)	22 (15.5)	31 (18.1)	19 (19.8)
Surgery					0.612
RFA	181 (44.3)	63 (44.4)	71 (41.5)	47 (49.0)
NAR	103 (25.2)	39 (27.5)	45 (26.3)	19 (19.8)
AR	125 (30.6)	40 (28.2)	55 (32.2)	30 (31.3)
Hepatitis, n (%)					0.051
No	63 (15.4)	26 (18.3)	29 (17.0)	8 (8.3)
HBV	302 (73.8)	101 (71.1)	119 (69.6)	82 (85.4)
HCV	44 (10.8)	15 (10.6)	23 (13.5)	6 (6.3)
HBeAg status, n (%)					0.006
Negative	317 (77.5)	117 (82.4)	137 (80.1)	63 (65.6)
Positive	92 (22.5)	25 (17.6)	34 (19.9)	33 (34.4)
Liver cirrhosis, n (%)					0.008
No	76 (18.6)	36 (25.4)	31 (18.1)	9 (9.4)
Yes	333 (81.4)	106 (74.6)	140 (81.9)	87 (90.6)
Child-Pugh classification, n (%)					0.000
A	392 (95.8)	140 (98.6)	168 (98.2)	84 (87.5)
B	17 (4.2)	2 (1.4)	3 (1.8)	12 (12.5)
BCLC stage, n (%)					0.362
0	178 (43.5)	55 (38.7)	79 (46.2)	44 (45.8)
A	231 (56.5)	87 (61.3)	92 (53.8)	52 (54.2)
TNM eighth stage, n (%)					0.362
IA	178 (43.5)	55 (38.7)	79 (46.2)	44 (45.8)
IB	231 (56.5)	87 (61.3)	92 (53.8)	52 (54.2)
Platelet count	140.0 [101.0,180.0]	152.0 [124.8,200.3]	138.0 [100.0,176.0]	117.5 [91.0,150.8]	0.000
Prothrombin time	11.2 [10.5,12.0]	11.0 [10.3,11.6]	11.3 [10.6,12.0]	11.4 [11.0,12.2]	0.000
ALBI grade					0.001
1	308 (75.3)	119 (83.8)	130 (76.0)	59 (61.5)
2	98 (24.0)	23 (16.2)	41 (24.0)	34 (35.4)
3	3 (0.7)	0 (0.0)	0 (0.0)	3 (3.1)

Note: Bold values: statistically significant P values.

Abbreviations: TMS, tumor marker score; IQR, interquartile ranges; SD, standard deviation; AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; RFA, radio frequency ablation; NAR, none-anatomical resection; AR, anatomical resection; HBV, hepatitis B virus; HCV, hepatitis C virus; HBeAg, hepatitis B virus e antigen; BCLC, the Barcelona Clinic Liver Cancer; TNM, tumor-node-metastasis; ALBI, albumin–bilirubin.

Figure 2 K–M curves of recurrence-free survival after surgery for single small HCC. K–M curves showing RFS of patients grouped by optimal cutoff values of AFP (A), CEA (B), CA19-9 (C) and TMS (D and E (TMS2 and TMS3 were collectively called TMS2 in (E)).

Abbreviations: PFS, progression-free survival; K-M, Kaplan–Meier.

Table 2 Univariate and Multivariate Analyses of Prognostic Factors Based on RFS

Variable	Univariate		Multivariate
	HR (95% CI)	P value	HR (95% CI)	P value
Age (years)	1.021 (1.005–1.037)	0.010	1.018 (1.001,1.035)	0.041
Sex (male/female)	1.134 (0.807–1.595)	0.468
Hepatitis (yes/no)
No	Reference
HBV	1.350 (0.893–2.041)	0.154
HCV	1.345 (0.747–2.422)	0.323
HBeAg positive (yes/no)	1.487 (1.077–2.053)	0.016	1.419 (1.015,1.985)	0.041
Liver cirrhosis (yes/no)	1.370 (0.911–2.061)	0.131
Platelet count	0.996 (0.993–0.998)	0.001	0.999 (0.996–1.002)	0.579
Prothrombin time	1.271 (1.121–1.440)	0.000	1.129 (0.965–1.320)	0.129
ALBI grade
1	Reference
2	1.707 (1.252–2.328)	0.001	1.183 (0.822–1.701)	0.365
3	9.255 (2.906–29.480)	0.000	2.958 (0.735–11.900)	0.127
Tumor size (cm)	1.139 (0.904–1.437)	0.270
Tumor size type (>2/≤2cm)	1.118 (0.836–1.495)	0.451
Tumor location
S1	Reference
S2	0.394 (0.136–1.137)	0.085
S3	0.778 (0.283–2.142)	0.627
S4a	1.073 (0.407–2.830)	0.887
S4b	0.596 (0.206–1.719)	0.338
S5	0.567 (0.238–1.348)	0.199
S6	0.686 (0.292–1.611)	0.386
S7	0.641 (0.264–1.553)	0.324
S8	0.817 (0.345–1.938)	0.647
Surgery
RFA	Reference
NAR	0.867 (0.604–1.246)	0.441
AR	0.964 (0.689–1.348)	0.831
Child-Pugh classification (B/A)	2.433 (1.407–4.207)	0.001	0.992 (0.503–1.956)	0.982
BCLC stage (A/0)	1.118 (0.836–1.495)	0.451
TNM eighth stage (IB/IA)	1.118 (0.836–1.495)	0.451
TMS
0	Reference		Reference
1	2.086 (1.409–3.088)	0.000	2.015 (1.358,2.990)	0.001
2	4.261 (2.865–6.339)	0.000	3.459 (2.276,5.258)	0.000

Note: Bold values: statistically significant P values.

Abbreviations: HR, hazard ratios; 95% CI, 95% confidence interval; HBeAg, hepatitis B virus e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ALBI, albumin-bilirubin; RFA, radio frequency ablation; NAR, none-anatomical resection; AR, anatomical resection; BCLC, the Barcelona Clinic Liver Cancer; TNM, tumor-node-metastasis; TMS, tumor marker score.

Figure 3 HR of univariable Cox regression analysis for postoperative recurrence comparing TMS in different subgroups of some group.

Abbreviation: HR; hazard ratios.

Figure 4 Receiver operating characteristic curve of TMS at 1-, 3-, and 5-year recurrence-free survival.

Figure 5 Time-dependent ROC curves of the seven models for predicting recurrence-free survival.

Abbreviations: TMS, tumor marker score; AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; ALBI, albumin–bilirubin; TNM, tumor-node-metastasis.