Severe hepatic steatosis as a protective prognostic factor in combined hepatocellular-cholangiocarcinoma: A multicenter pathological study

Table 1 Baseline characteristics of all patients, n (%)

Characteristics	All patients (n = 310)	Grade 0 (n = 156)	Grade 1 (n = 127)	Grade 2 (n = 25)	Grade 3 (n = 2)	P value	Negligible (n = 283)	Severe (n = 27)	P value
Age (year), mean ± SD	52.7 ± 10.3	53.4 ± 10.3	52.3 ± 10.6	51.2 ± 8.7	54.5 ± 4.9	0.695	52.9 ± 10.4	51.5 ± 8.4	0.431
Sex						0.900	-		0.551
Female	39 (12.6)	21 (13.5)	16 (12.6)	2 (8.0)	0 (0.0)		37 (13.1)	2 (7.4)
Male	271 (87.4)	135 (86.5)	111 (87.4)	23 (92.0)	2 (100.0)		246 (86.9)	25 (92.6)
BMI, kg/m2	24.2 (22.3; 26.2)	22.9 (21.0; 24.8)	25.4 (23.5; 26.6)	26.6 (24.9; 28.0)	26.6 (25.8; 27.4)	< 0.001	23.9 (22.1; 26.0)	26.6 (24.9; 28.0)	< 0.001
Hypertension						0.199	-		0.288
No	238 (76.8)	126 (80.8)	94 (74.0)	17 (68.0)	1 (50.0)		220 (77.7)	18 (66.7)
Yes	72 (23.2)	30 (19.2)	33 (26.0)	8 (32.0)	1 (50.0)		63 (22.3)	9 (33.3)
Diabetes						0.592	-		0.757
No	272 (87.7)	140 (89.7)	109 (85.8)	21 (84.0)	2 (100.0)		249 (88.0)	23 (85.2)
Yes	38 (12.3)	16 (10.3)	18 (14.2)	4 (16.0)	0 (0.0)		34 (12.0)	4 (14.8)
TBIL, μmol/L	13.6 (10.7; 17.5)	13.4 (10.9; 17.2)	13.6 (10.6; 17.6)	15.5 (11.8; 17.9)	12.2 (10.5; 13.9)	0.675	13.6 (10.6; 17.4)	15.5 (11.7; 17.7)	0.403
DBIL, μmol/L	5.2 (4.0; 6.9)	5.0 (4.1; 6.8)	5.4 (4.0; 7.0)	5.2 (4.1; 7.8)	4.0 (3.6; 4.4)	0.674	5.2 (4.0; 6.8)	5.0 (4.0; 7.7)	0.833
IBIL, μmol/L	8.1 (6.5; 10.7)	7.9 (6.6; 10.6)	8.0 (6.2; 10.6)	9.3 (8.0; 11.1)	8.2 (6.9; 9.5)	0.397	8.0 (6.5; 10.6)	9.3 (7.8; 10.9)	0.112
TBA, μmol/L	6.6 (4.4; 11.4)	7.1 (4.5; 11.9)	6.0 (4.0; 11.7)	6.2 (5.3; 8.1)	7.8 (7.2; 8.4)	0.643	6.6 (4.3; 11.7)	6.2 (5.5; 8.1)	0.816
TP, g/L	68.9 (65.7; 73.2)	68.3 (65.7; 73.2)	69.5 (66.2; 73.2)	69.1 (64.9; 72.2)	68.9 (67.5; 70.4)	0.854	68.9 (65.8; 73.2)	69.1 (65.1; 72.0)	0.692
ALB, g/L	42.0 (39.7; 44.3)	41.7 (39.0; 44.2)	42.1 (40.0; 44.2)	42.5 (41.3; 44.6)	43.8 (43.1; 44.4)	0.477	41.9 (39.5; 44.2)	42.5 (41.3; 44.6)	0.187
GLB, g/L	26.8 (24.4; 30.3)	26.9 (24.6; 30.4)	27.4 (24.4; 30.7)	26.0 (23.8; 28.1)	25.2 (24.4; 26.0)	0.524	27.0 (24.4; 30.5)	26.0 (23.7; 27.6)	0.156
PA, mg/L	212.9 ± 65.2	206.5 ± 66.2	215.4 ± 62.1	238.6 ± 71.4	214.5 ± 20.5	0.140	210.5 ± 64.4	236.8 ± 69.1	0.067
ALT, U/L	32.0 (21.0; 48.0)	27.5 (18.8; 41.2)	34.0 (23.0; 50.0)	37.0 (24.0; 57.0)	45.5 (40.8; 50.2)	0.008	32.0 (20.0; 47.0)	37.0 (25.0; 56.0)	0.118
AST, U/L	30.0 (22.0; 40.0)	29.5 (22.8; 42.0)	30.5 (22.0; 39.8)	28.0 (22.0; 35.0)	30.5 (30.2; 30.8)	0.949	30.0 (22.0; 41.0)	28.0 (22.5; 34.5)	0.892
ASTm, U/L	5.0 (4.0; 8.0)	5.0 (4.0; 8.0)	6.0 (4.0; 8.0)	5.0 (4.0; 8.0)	4.0 (3.5; 4.5)	0.652	6.0 (4.0; 8.0)	5.0 (4.0; 8.0)	0.460
GGT, U/L	60.5 (35.0; 111.0)	56.0 (31.0; 107.0)	63.0 (34.2; 114.2)	73.0 (44.0; 132.0)	48.5 (40.2; 56.8)	0.577	58.0 (32.5; 111.0)	65.0 (43.5; 109.5)	0.429
ALP, U/L	85.0 (68.8; 109.0)	86.0 (71.0; 117.5)	83.0 (67.2; 103.8)	71.0 (61.0; 92.0)	67.0 (67.0; 67.0)	0.027	85.0 (70.0; 110.0)	69.0 (61.5; 91.0)	0.022
LDH, U/L	162.0 (142.0; 187.0)	162.0 (142.0; 189.0)	166.0 (146.0; 187.0)	149.0 (136.0; 173.5)	116.0 (108.5; 123.5)	0.044	162.0 (144.0; 189.0)	143.0 (131.0; 173.0)	0.016
SCR, μmol/L	70.0 (62.0; 79.0)	70.0 (60.8; 82.0)	70.0 (63.0; 79.0)	71.0 (66.0; 79.0)	71.5 (70.2; 72.8)	0.956	70.0 (62.0; 79.5)	71.0 (66.0; 79.0)	0.576
WBC, 109/L	5.5 (4.4; 6.6)	5.3 (4.3; 6.4)	5.6 (4.3; 6.6)	6.2 (5.2; 7.0)	6.0 (5.8; 6.2)	0.261	5.4 (4.3; 6.6)	6.2 (5.2; 7.0)	0.078
NE, 109/L	3.4 (2.5; 4.2)	3.3 (2.4; 4.1)	3.4 (2.5; 4.3)	3.4 (2.8; 4.3)	3.7 (3.6; 3.9)	0.719	3.3 (2.4; 4.2)	3.5 (2.8; 4.2)	0.458
LY, 109/L	1.6 (1.3; 1.9)	1.5 (1.2; 1.8)	1.6 (1.3; 1.9)	1.9 (1.7; 2.1)	1.7 (1.6; 1.8)	0.013	1.5 (1.2; 1.9)	1.9 (1.6; 2.1)	0.003
MO, 109/L	0.4 (0.3; 0.5)	0.4 (0.3; 0.5)	0.4 (0.3; 0.5)	0.4 (0.3; 0.5)	0.4 (0.4; 0.5)	0.898	0.4 (0.3; 0.5)	0.4 (0.3; 0.5)	0.799
EO, 109/L	0.1 (0.1; 0.2)	0.1 (0.1; 0.2)	0.1 (0.1; 0.2)	0.2 (0.1; 0.3)	0.1 (0.1; 0.2)	0.283	0.1 (0.1; 0.2)	0.2 (0.1; 0.3)	0.144
BA, 109/L	< 0.1 (< 0.1; < 0.1)	< 0.1 (< 0.1; < 0.1)	< 0.1 (< 0.1; < 0.1)	< 0.1 (< 0.1; < 0.1)	< 0.1 (< 0.1; < 0.1)	0.938	< 0.1 (< 0.1; < 0.1)	< 0.1 (< 0.1; < 0.1)	0.562
RBC, 1012/L	4.6 ± 0.5	4.5 ± 0.6	4.7 ± 0.5	4.6 ± 0.5	4.4 ± 0.3	0.100	4.6 ± 0.5	4.6 ± 0.5	0.863
PLT, 109/L	150.5 (108.2; 195.8)	145.5 (105.5; 195.5)	152.0 (106.0; 191.5)	162.0 (130.0; 196.0)	197.0 (181.5; 212.5)	0.510	149.0 (105.5; 193.5)	163.0 (130.5; 197.5)	0.237
INR	1.0 (0.9; 1.1)	1.0 (1.0; 1.1)	1.0 (0.9; 1.0)	1.0 (0.9; 1.0)	0.9 (0.9; 0.9)	0.236	1.0 (0.9; 1.1)	1.0 (0.9; 1.0)	0.122
PT, second	11.9 (11.4; 12.7)	12.0 (11.5; 12.8)	12.0 (11.4; 12.6)	11.7 (11.3; 12.6)	11.2 (11.1; 11.4)	0.310	12.0 (11.4; 12.7)	11.6 (11.3; 12.4)	0.215
AFP, μg/L	57.2 (8.3; 399.6)	67.4 (8.8; 558.1)	37.1 (6.7; 244.4)	122.7 (9.2; 615.4)	234.4 (132.7; 336.1)	0.551	51.4 (8.1; 395.8)	122.7 (9.9; 526.6)	0.494
CEA, μg/L	2.7 (1.7; 4.1)	2.7 (1.6; 3.8)	2.8 (1.9; 4.4)	2.6 (1.6; 3.9)	1.2 (1.2; 1.3)	0.162	2.7 (1.7; 4.2)	2.4 (1.6; 3.8)	0.529
CA199, U/mL	22.2 (11.5; 49.4)	22.5 (12.6; 48.9)	20.9 (9.5; 48.7)	32.1 (18.5; 57.1)	25.6 (17.2; 33.9)	0.395	21.5 (11.0; 49.1)	32.1 (18.1; 54.8)	0.189
HBsAg						0.515	-		1.000
Negative	53 (17.1)	28 (17.9)	21 (16.5)	3 (12.0)	1 (50.0)		49 (17.3)	4 (14.8)
Positive	257 (82.9)	128 (82.1)	106 (83.5)	22 (88.0)	1 (50.0)		234 (82.7)	23 (85.2)
HBsAb						0.178	-		0.509
Negative	277 (89.4)	143 (91.7)	111 (87.4)	22 (88.0)	1 (50.0)		254 (89.8)	23 (85.2)
Positive	33 (10.6)	13 (8.3)	16 (12.6)	3 (12.0)	1 (50.0)		29 (10.2)	4 (14.8)
HBeAg						0.418	-		1.000
Negative	240 (77.4)	126 (80.8)	93 (73.2)	19 (76.0)	2 (100.0)		219 (77.4)	21 (77.8)
Positive	70 (22.6)	30 (19.2)	34 (26.8)	6 (24.0)	0 (0.0)		64 (22.6)	6 (22.2)
HBeAb						0.930	-		1.000
Negative	99 (31.9)	50 (32.1)	40 (31.5)	9 (36.0)	0 (0.0)		90 (31.8)	9 (33.3)
Positive	211 (68.1)	106 (67.9)	87 (68.5)	16 (64.0)	2 (100.0)		193 (68.2)	18 (66.7)
HBcAb						0.331	-		0.522
Negative	8 (2.6)	2 (1.3)	5 (3.9)	1 (4.0)	0 (0.0)		7 (2.5)	1 (3.7)
Positive	302 (97.4)	154 (98.7)	122 (96.1)	24 (96.0)	2 (100.0)		276 (97.5)	26 (96.3)
HBV DNA load						0.190	-		0.585
NA	10 (3.2)	5 (3.2)	5 (3.9)	0 (0.0)	0 (0.0)		10 (3.5)	0 (0.0)
≤ 1 × 103 IU/mL	177 (57.1)	100 (64.1)	63 (49.6)	13 (52.0)	1 (50.0)		163 (57.6)	14 (51.9)
> 1 × 103 IU/mL	123 (39.7)	51 (32.7)	59 (46.5)	12 (48.0)	1 (50.0)		110 (38.9)	13 (48.1)
HCV						0.785	-		1.000
Negative	305 (98.4)	154 (98.7)	124 (97.6)	25 (100.0)	2 (100.0)		278 (98.2)	27 (100.0)
Positive	5 (1.6)	2 (1.3)	3 (2.4)	0 (0.0)	0 (0.0)		5 (1.8)	0 (0.0)
Ascites						0.815	-		1.000
Negative	284 (91.6)	141 (90.4)	118 (92.9)	23 (92.0)	2 (100.0)		259 (91.5)	25 (92.6)
Positive	26 (8.4)	15 (9.6)	9 (7.1)	2 (8.0)	0 (0.0)		24 (8.5)	2 (7.4)
Macrovascular invasion						0.902	-		0.774
Negative	240 (77.4)	118 (75.6)	100 (78.7)	20 (80.0)	2 (100.0)		218 (77.0)	22 (81.5)
Positive	70 (22.6)	38 (24.4)	27 (21.3)	5 (20.0)	0 (0.0)		65 (23.0)	5 (18.5)
Large bile duct invasion						1.000	-		1.000
Negative	296 (95.5)	149 (95.5)	121 (95.3)	24 (96.0)	2 (100.0)		270 (95.4)	26 (96.3)
Positive	14 (4.5)	7 (4.5)	6 (4.7)	1 (4.0)	0 (0.0)		13 (4.6)	1 (3.7)
Pringle maneuver						0.911	-		0.789
No	52 (16.8)	26 (16.7)	21 (16.5)	5 (20.0)	0 (0.0)		47 (16.6)	5 (18.5)
Yes	258 (83.2)	130 (83.3)	106 (83.5)	20 (80.0)	2 (100.0)		236 (83.4)	22 (81.5)
Transfusion						0.447	-		0.150
No	264 (85.2)	131 (84.0)	107 (84.3)	24 (96.0)	2 (100.0)		238 (84.1)	26 (96.3)
Yes	46 (14.8)	25 (16.0)	20 (15.7)	1 (4.0)	0 (0.0)		45 (15.9)	1 (3.7)
Surgery						0.662	-		1.000
Anatomic	73 (23.5)	41 (26.3)	26 (20.5)	6 (24.0)	0 (0.0)		67 (23.7)	6 (22.2)
Non-anatomic	237 (76.5)	115 (73.7)	101 (79.5)	19 (76.0)	2 (100.0)		216 (76.3)	21 (77.8)
Surgical margin						0.023	-		0.158
> 0.1 cm	138 (44.5)	58 (37.2)	64 (50.4)	14 (56.0)	2 (100.0)		122 (43.1)	16 (59.3)
≤ 0.1 cm	172 (55.5)	98 (62.8)	63 (49.6)	11 (44.0)	0 (0.0)		161 (56.9)	11 (40.7)
Tumor diameter, cm	4.4 (2.8; 6.9)	5.0 (3.0; 8.5)	4.1 (2.8; 6.0)	3.5 (2.1; 5.3)	3.3 (3.2; 3.4)	0.044	4.5 (2.8; 7.0)	3.5 (2.2; 5.2)	0.040
Tumor number						0.631	-		1.000
Single	208 (67.1)	101 (64.7)	89 (70.1)	16 (64.0)	2 (100.0)		190 (67.1)	18 (66.7)
Multiple	102 (32.9)	55 (35.3)	38 (29.9)	9 (36.0)	0 (0.0)		93 (32.9)	9 (33.3)
Lymph node metastasis						0.241	-		1.000
Negative	278 (89.7)	138 (88.5)	115 (90.6)	24 (96.0)	1 (50.0)		253 (89.4)	25 (92.6)
Positive	32 (10.3)	18 (11.5)	12 (9.4)	1 (4.0)	1 (50.0)		30 (10.6)	2 (7.4)
Distant metastasis						0.785	-		1.000
Negative	305 (98.4)	154 (98.7)	124 (97.6)	25 (100.0)	2 (100.0)		278 (98.2)	27 (100.0)
Positive	5 (1.6)	2 (1.3)	3 (2.4)	0 (0.0)	0 (0.0)		5 (1.8)	0 (0.0)
Tumor component proportion						0.337	-		0.231
HCC-dominant	93 (30.0)	42 (26.9)	42 (33.1)	9 (36.0)	0 (0.0)		84 (29.7)	9 (33.3)
Balanced	103 (33.2)	54 (34.6)	37 (29.1)	10 (40.0)	2 (100.0)		91 (32.2)	12 (44.4)
CCA-dominant	114 (36.8)	60 (38.5)	48 (37.8)	6 (24.0)	0 (0.0)		108 (38.2)	6 (22.2)
Tumor differentiation						0.326	-		0.136
Well-moderate	114 (36.8)	57 (36.5)	43 (33.9)	13 (52.0)	1 (50.0)		100 (35.3)	14 (51.9)
Poor	196 (63.2)	99 (63.5)	84 (66.1)	12 (48.0)	1 (50.0)		183 (64.7)	13 (48.1)
MVI						0.734	-		1.000
Negative	138 (44.5)	68 (43.6)	58 (45.7)	12 (48.0)	0 (0.0)		126 (44.5)	12 (44.4)
Positive	172 (55.5)	88 (56.4)	69 (54.3)	13 (52.0)	2 (100.0)		157 (55.5)	15 (55.6)
PNI						0.739	-		0.591
Negative	260 (83.9)	133 (85.3)	103 (81.1)	22 (88.0)	2 (100.0)		236 (83.4)	24 (88.9)
Positive	50 (16.1)	23 (14.7)	24 (18.9)	3 (12.0)	0 (0.0)		47 (16.6)	3 (11.1)
Capsule						0.016	-		1.000
Negative	61 (19.7)	41 (26.3)	15 (11.8)	5 (20.0)	0 (0.0)		56 (19.8)	5 (18.5)
Positive	249 (80.3)	115 (73.7)	112 (88.2)	20 (80.0)	2 (100.0)		227 (80.2)	22 (81.5)
Intratumoral mTLS						0.222	-		0.743
Negative	251 (81.0)	130 (83.3)	98 (77.2)	22 (88.0)	1 (50.0)		228 (80.6)	23 (85.2)
Positive	59 (19.0)	26 (16.7)	29 (22.8)	3 (12.0)	1 (50.0)		55 (19.4)	4 (14.8)
Cirrhosis						0.585	-		0.726
Negative	168 (54.2)	89 (57.1)	63 (49.6)	15 (60.0)	1 (50.0)		152 (53.7)	16 (59.3)
Positive	142 (45.8)	67 (42.9)	64 (50.4)	10 (40.0)	1 (50.0)		131 (46.3)	11 (40.7)
Prognostic nutritional index	50.2 (46.5; 53.3)	49.2 (46.0; 52.6)	50.5 (47.3; 53.5)	52.5 (49.1; 54.2)	52.4 (51.3; 53.5)	0.033	50.0 (46.2; 53.0)	52.5 (49.3; 54.4)	0.014
TNM						0.143	-		0.164
I-II	236 (76.1)	115 (73.7)	97 (76.4)	23 (92.0)	1 (50.0)		212 (74.9)	24 (88.9)
III-IV	74 (23.9)	41 (26.3)	30 (23.6)	2 (8.0)	1 (50.0)		71 (25.1)	3 (11.1)

BMI: Body mass index; TBIL: Total bilirubin; DBIL: Direct bilirubin; IBIL: Indirect bilirubin; TBA: Total biliary acid; TP: Total protein; ALB: Albumin; GLB: Globulin; PA: Prealbumin; ALT: Alanine amino transferase; AST: Aspartate amino transferase; ASTm: Aspartate transaminase mitochondrial; GGT: γ-glutamyl transpeptidase; ALP: Alkaline phosphatase; LDH: Lactate dehydrogenase; SCR: Serum creatinine; WBC: White blood cell; NE: Neutrophil; LY: Lymphocyte; MO: Monocyte; EO: Eosinophil; BA: Basophil; RBC: Red blood cell; PLT: Platelet; INR: International normalized ratio; PT: Prothrombin time; AFP: Alpha fetoprotein; CEA: Carcinoembryonic antigen; CA199: Carbohydrate antigen 19-9; HBsAg: Hepatitis B surface antigen; HBsAb: Hepatitis B surface antibody; HBeAg: Hepatitis B e antigen; HBeAb: Hepatitis B e antibody; HBcAb: Hepatitis B core antibody; HBV DNA: Hepatitis B virus deoxyribonucleic acid; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; MVI: Microvascular invasion; PNI: Perineural invasion; mTLS: Mature tertiary lymphoid structure; TNM: Tumor-node-metastasis.

Table 2 Multivariate logistic analysis of the predictive factors of hepatic steatosis

Characteristics	OR (95%CI)	P value
BMI, kg/m2	1.300 (1.127-1.494)	< 0.001
LDH, U/L	0.980 (0.960-0.994)	0.008
LY, 109/L	2.730 (1.252-5.958)	0.012

BMI: Body mass index; LDH: Lactate dehydrogenase; LY: Lymphocyte; OR: Odds ratio; CI: Confidence interval.

Table 3 Multivariate Cox regression analysis of recurrence-free survival

Characteristics	HR (95%CI)	P value
Age, years	0.982 (0.969-0.995)	0.007
Macrovascular invasion, positive	1.621 (1.156-2.271)	0.005
Tumor diameter, cm	1.048 (1.011-1.087)	0.011
Tumor number, multiple	1.937 (1.466-2.560)	< 0.001
Tumor component proportion, balanced	1.706 (1.216-2.393)	0.002
Tumor component proportion, CCA-dominant	1.524 (1.101-2.109)	0.011
MVI, positive	1.685 (1.292-2.197)	< 0.001
PNI, positive	1.445 (1.027-2.035)	0.035
Hepatic steatosis, severe	0.614 (0.383-0.984)	0.043

CCA: Cholangiocarcinoma; MVI: Microvascular invasion; PNI: Perineural invasion; HR: Hazard ratio; CI: Confidence interval.

Table 4 Multivariate Cox regression analysis of overall survival

Characteristics	HR (95%CI)	P value
LY, 109/L	0.725 (0.559-0.940)	0.015
Macrovascular invasion, positive	1.980 (1.417-2.766)	< 0.001
Tumor diameter, cm	1.058 (1.016-1.102)	0.006
Tumor number, multiple	1.752 (1.313-2.339)	< 0.001
MVI, positive	2.115 (1.578-2.835)	< 0.001
PNI, positive	1.732 (1.215-2.467)	0.002
Intratumoral mTLS, positive	0.676 (0.460-0.993)	0.046

LY: Lymphocyte; MVI: Microvascular invasion; PNI: Perineural invasion; mTLS: Mature tertiary lymphoid structure; HR: Hazard ratio; CI: Confidence interval.

Table 5 Multivariate Cox regression analysis of early recurrence-free survival

Characteristics	HR (95%CI)	P value
Age, years	0.984 (0.971-0.997)	0.016
Macrovascular invasion, positive	1.597 (1.129-2.261)	0.008
Tumor diameter, cm	1.051 (1.011-1.092)	0.011
Tumor number, multiple	1.925 (1.438-2.577)	< 0.001
MVI, positive	1.783 (1.332-2.386)	< 0.001
PNI, positive	1.512 (1.068-2.142)	0.020
Hepatic steatosis, severe	0.577 (0.339-0.983)	0.043

MVI: Microvascular invasion; PNI: Perineural invasion; HR: Hazard ratio; CI: Confidence interval.

Table 6 Multivariate Cox regression analysis of late recurrence-free survival

Characteristics	HR (95%CI)	P value
ALB, g/L	0.875 (0.792-0.967)	0.009
BA, 109/L	0.000 (0.000-0.014)	0.024
Tumor number, multiple	3.485 (1.002-12.110)	0.050

ALB: Albumin; BA: Basophil; HR: Hazard ratio; CI: Confidence interval.