Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study

Table 1 Patient characteristics and biomarkers, n (%)

               

	Total	Stage 0	Stage A	Stage B	Stage C	Stage D	P valuea
	(n = 115)	(n = 13)	(n = 27)	(n = 36)	(n = 16)	(n = 23)
Age (mean ± SD)	60.83 ± 12.93	60.69 ± 11.64	61.07 ± 11.34	58.67 ± 15.03	62.00 ± 12.73	63.22 ± 12.48	0.754
Male	98 (85.2)	11 (84.6)	22 (81.5)	31 (86.1)	15 (93.8)	19 (82.6)	0.849
BMI (kg/m2)	23.12 ± 3.5	24.31 ± 3.12	23.43 ± 2.74	23.06 ± 3.33	22.98 ± 5.06	22.26 ± 3.53	0.543
Symptom at first presentation
Abdominal pain	44 (38.3)	1 (7.7)	7 (25.9)	16 (44.4)	10 (62.5)	10 (43.5)	0.02
Jaundice	7 (6.1)	1 (7.7)	0 (0)	1 (2.8)	1 (6.3)	4 (17.4)	0.106
Anemia	1 (0.9)	0 (0)	0 (0)	1 (2.8)	0 (0)	0 (0)	0.697
Ascites	9 (7.8)	2 (15.4)	1 (3.7)	1 (2.8)	2 (12.5)	3 (13)	0.368
Weight loss	7 (6.1)	0 (0)	0 (0)	5 (13.9)	0 (0)	2 (8.7)	0.102
Fever	1 (0.9)	1 (7.7)	0 (0)	0 (0)	0 (0)	0 (0)	0.095
Edema	4 (3.5)	0 (0)	1 (3.7)	0 (0)	2 (12.5)	1 (4.3)	0.223
Abdominal mass	3 (2.6)	0 (0)	0 (0)	3 (8.3)	0 (0)	0 (0)	0.154
GI bleeding	12 (10.4)	1 (7.7)	0 (0)	2 (5.6)	5 (31.3)	4 (17.4)	0.012
Asymptomatic	39 (33.9)	8 (61.5)	17 (63)	11 (30.6)	1 (6.3)	2 (8.7)	< 0.001
Etiology
CHB	43 (37.4)	8 (61.5)	7 (25.9)	18 (50)	5 (31.3)	5 (21.7)	0.043
CHC	14 (12.2)	1 (7.7)	5 (18.5)	3 (8.3)	3 (18.8)	2 (8.7)	0.615
Alcohol	17 (14.8)	2 (15.4)	4 (14.8)	5 (13.9)	2 (12.5)	4 (17.4)	0.995
MAFLD	9 (7.8)	1 (7.7)	4 (14.8)	2 (5.6)	1 (6.3)	1 (4.3)	0.64
CHB with alcohol	20 (17.4)	0 (0)	4 (14.8)	4 (11.1)	5 (31.3)	7 (30.4)	0.069
CHC with alcohol	12 (10.4)	1 (7.7)	3 (11.1)	4 (11.1)	0 (0)	4 (17.4)	0.526
Cirrhosis	92 (80)	9 (69.2)	21 (77.8)	27 (75)	12 (75)	23 (100)	0.108
CTP-A/B/C (%)	56.5/34.8/8.7	88.9/11.1/0	81/19/0	70.4/29.6/0	50/50/0	8.7/56.5/34.8	< 0.001
MELD (mean ± SD)	10.31 ± 7.28	7.54 ± 7.24	8.78 ± 6.73	8.28 ± 6.33	10.5 ± 6.98	16.74 ± 6.17	< 0.001
Performance status
0-1	79 (68.7)	12 (92.3)	26 (96.3)	36 (100)	4 (25)	1 (4.3)	< 0.001
2	2 (1.7)	0 (0)	1 (3.7)	0 (0)	0 (0)	1 (4.3)	0.613
3	15 (13)	0 (0)	0 (0)	0 (0)	10 (62.5)	5 (21.7)	< 0.001
4	19 (16.5)	1 (7.7)	0 (0)	0 (0)	2 (12.5)	16 (69.6)	< 0.001
Tumor size (cm)
≤ 2	23 (20)	12 (92.3)	8 (29.6)	1 (2.8)	0 (0)	2 (8.7)	< 0.001
2.1-3	14 (12.2)	1 (7.7)	12 (44.4)	0 (0)	0 (0)	1 (4.3)	< 0.001
3.1-5	14 (12.2)	0 (0)	7 (25.9)	4 (11.1)	0 (0)	3 (13)	0.065
> 5	64 (55.7)	0 (0)	0 (0)	31 (86.1)	16 (100)	17 (73.9)	< 0.001
Tumor number
1	50 (43.5)	13 (100)	14 (51.9)	17 (47.2)	2 (12.5)	4 (17.4)	< 0.001
2	35 (30.4)	0 (0)	10 (37)	8 (22.2)	10 (62.5)	7 (30.4)
≥ 3	30 (26.1)	0 (0)	3 (11.1)	11 (30.6)	4 (25)	12 (52.2)
Tumor characteristic
Macrovascular invasion	16 (13.9)	0 (0)	0 (0)	2 (5.6)	8 (50)	6 (26.1)	< 0.001
PV thrombosis	25 (21.7)	0 (0)	0 (0)	1 (2.8)	11 (68.8)	13 (56.5)	< 0.001
Metastasis	10 (8.7)	0 (0)	0 (0)	0 (0)	6 (37.5)	4 (17.4)	< 0.001
Liver function test
Albumin (mg/dL)	3.7	3.8	4.1	3.9	3.55	2.7	< 0.001
	(3.1, 4.2)	(3.7, 4.4)	(3.5, 4.3)	(3.45, 4.25)	(3.15, 3.7)	(2.3, 3.4)
Total bilirubin (mg/dL)	1.04	0.91	0.69	0.86	1.35	3.44	< 0.001
	(0.63, 1.84)	(0.69, 1.12)	(0.56, 1.64)	(0.55, 1.5)	(1.17, 1.83)	(0.92, 5.19)
AST (IU/L)	79 (47, 130)	34 (29, 67)	52 (36, 68)	79 (53, 116.5)	145 (94.5, 207.5)	141 (93, 479)	< 0.001
ALT (IU/L)	41 (24, 65)	24 (20, 43)	35 (20, 43)	53 (38, 71)	41 (20.5, 124)	48 (24, 97)	0.017
ALP (IU/L)	136 (92, 237)	86 (71, 108)	108 (79, 130)	143.5 (102, 271.5)	176 (152, 276.5)	201 (159, 314)	< 0.001
Biomarker (median, 25-75 quartile)
AFP (ng/mL)	38.9	3.1	10	50	22146.3	79	< 0.001
	(5.4, 3305.3)	(1.7, 50)	(2.8, 61)	(13.2, 2482.65)	(190.55, 163697)	(17.2, 23475)
AFP- L3 (%)	7	4.55	4.83	6.07	25.8	30.5	< 0.001
	(1, 34.1)	(0.5, 6.76)	(0.5, 8.1)	(0.9, 24.7)	(3.95, 63.9)	(8.16, 74.7)
PIVKA II (mAU/mL)	604	26	55	7820	20188	4807	< 0.001
	(54, 21878)	(20,35)	(37, 220)	(139, 44019.5)	(761, 91915)	(581, 203031)
GALAD score
Median (range)	3.08	-2.27	-0.62	4.15	9.59	7.22	< 0.001
	(-0.56, 9.09)	(-3.9, 1.2)	(-1.81, 1.86)	(1.21, 8.81)	(6.17, 13.33)	(3.7, 10.12)

^aP value < 0.05 is statistically significant, ANOVA test, Kruskal–Wallis test, Chi-square test, or Fisher’s exact test were used.

AFP: Alpha-fetoprotein; AFP-L3: Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; BMI: Body mass index; CTP: Child Turcotte Pugh; CHB: Chronic hepatitis B; CHC: Chronic hepatitis C; GI: Gastrointestinal; MAFLD: Metabolic associated fatty liver disease; MELD: Model for end stage liver disease; PIVKA II: Protein induced by vitamin K absence- II; PV: Portal vein.

Table 2 Diagnostic performances of GALAD score and other biomarkers on Barcelona Clinic Liver Cancer staging, aggressive features, and prognostic performances for 1-year mortality of hepatocellular carcinoma

Scores	Barcelona Clinic Liver Cancer staging		Aggressive featuresa,2	1-year mortality3
	0 vs A2	0/A vs B/C/D2
GALAD
AUC (95%CI)	0.6097 (0.40–0.82)	0.8677 (0.80–0.93)	0.8385 (0.75–0.92)	0.7108 (0.60–0.82)
Cutoff values	≥ -1.95	≥ 2.65	≥ 7.22	≥ 6.83
Sensitivity/Specificity (%)	81.48/53.85	74.67/85.00	75.00/85.54	60.00/72.63
PPV/NPV (%)	78.57/58.33	90.32/64.15	66.67/89.87	31.58/89.61
Positive/Negative LR	1.77/0.34	4.98/0.30	5.19/0.29	2.19/0.55
Correctly classified (%)	72.50	78.26	82.61	70.43
PIVKA-II
AUC (95%CI)	0.7236 (0.54–0.91)	0.8970 (0.84–0.95)	0.7718 (0.68–0.86)	0.7395 (0.63–0.85)
Cutoff values	≥ 37	≥ 354	≥ 581	≥ 2959
Sensitivity/Specificity (%)	77.78/76.92	81.33/92.50	93.75/63.86	75.00/68.42
PPV/NPV (%)	87.50/62.50	95.31/72.55	50.00/96.36	33.33/92.86
Positive/Negative LR	3.37/0.29	10.84/0.20	2.59/0.10	2.38/0.37
Correctly classified (%)	77.50	85.22	72.17	69.57
AFP
AUC (95%CI)	0.5655 (0.36–0.77)	0.7525 (0.67–0.84)	0.7613 (0.65–0.87)	0.5405 (0.39–0.69)
Cutoff values	≥ 4.4	≥ 16	≥ 79	≥ 79
Sensitivity/Specificity (%)	74.07/53.85	74.67/60.00	75.00/71.08	50.00/60.00
PPV/NPV (%)	76.92/50.00	77.78/55.81	50.00/88.06	20.83/85.07
Positive/Negative LR	1.60/0.48	1.87/0.42	2.59/0.35	1.25/0.83
Correctly classified (%)	67.50	69.57	72.17	58.26
AFP-L3
AUC (95%CI)	0.5128 (0.32–0.70)	0.7058 (0.61–0.80)	0.6969 (0.58–0.82)	0.7361 (0.61–0.86)
Cutoff values	≥ 4.83	≥ 7.4	≥ 12.3	≥ 14.5
Sensitivity/Specificity (%)	51.85/53.85	64.00/77.50	65.63/71.08	65.00/72.63
PPV/NPV (%)	70.00/35.00	84.21/53.45	46.67/84.29	33.33/90.79
Positive/Negative LR	1.12/0.89	2.84/0.46	2.27/0.48	2.38/0.48
Correctly classified (%)	52.50	68.70	69.57	71.30
Comparison of AUC
GALAD and PIVKA-II	P = 0.1798	P = 0.2353	P = 0.0683	P = 0.5349
GALAD and AFP	P = 0.3721	P < 0.001a	P = 0.0136a	P < 0.001a
GALAD and AFP-L3	P = 0.2992	P < 0.001a	P = 0.0152a	P = 0.6656
PIVKA-II and AFP	P = 0.1100	P < 0.001a	P = 0.8476	P = 0.0086a
PIVKA-II and AFP-L3	P = 0.0409a	P < 0.001a	P = 0.2801	P = 0.9610

^aP value < 0.05 is statistically significant.

¹Macrovascular invasion or portal vein thrombosis or extrahepatic metastasis.

²Optimal cutoff points were determined to the point closest-to- (0,1) corner in the receiver operating characteristic plane (Euclidean distance).

³Cutoff values were adapted based on the Euclidean distance criteria to maximize specificity for predicting the 1-year mortality with acceptable sensitivity.

AFP: Alpha-fetoprotein; AFP-L3: Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein; AUC: Area under the curve; LR: The likelihood ratio; NPV: Negative predictive value; PIVKA-II: Protein induced by vitamin K absence- II; PPV: Positive predictive value; ROC: Receiver operating characteristic.