Liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma: A multicenter study

Table 1 Baseline characteristics

	Before PSM			After PSM
	HCC (n = 141)	cHCC-CC (n = 111)	P value	HCC (n = 70)	cHCC-CC (n = 70)	P value
Donor
Sex (male)	89 (63.1)	69 (62.2)	0.896	47 (67.1)	45 (64.3)	0.859
Age (yr)	30 (16-68)	32 (11-60)	0.217	27 (16-63)	33 (11-58)	0.048
Body mass index (kg/m2)	23.1 (17.3-36.3)	23.0 (17.6-35.7)	0.679	23.3 (17.3-36.3)	23.5 (18.1-32.9)	0.839
Recipient
Sex (male)	127 (90.1)	95 (85.6)	0.329	65 (92.9)	60 (85.7)	0.274
Age (yr)	56 (37-70)	54 (31-66)	0.027	55 (37-60)	57 (31-66)	0.125
Body mass index (kg/m2)	24.3 (17.3-36.7)	24.0 (18.7-35.0)	0.35	23.9 (18.3-34.6)	24.1 (18.7-35.0)	0.94
Underlying liver disease			0.639			0.223
HBV	123 (87.2)	91 (82.0)		63 (90.0)	56 (80.0)
HCV	6 (4.3)	5 (4.5)		2 (2.9)	2 (2.9)
NBNC	6 (4.3)	8 (7.2)		1 (1.4)	6 (8.6)
Alcoholic	6 (4.3)	7 (6.3)		4 (5.7)	6 (8.6)
Diabetes	27 (19.1)	25 (22.5)	0.534	13 (18.6)	16 (22.9)	0.677
Hypertension	17 (12.1)	14 (12.6)	0.894	6 (8.6)	7 (10.0)	0.771
Child-Pugh class			0.613			0.914
A	66 (46.8)	46 (40.5)		30 (42.9)	30 (42.9)
B	44 (31.2)	43 (38.7)		24 (34.3)	25 (35.7)
C	31 (22.0)	23 (20.7)		16 (22.9)	15 (21.4)
MELD	10 (6-35)	11 (6-40)	0.455	11 (6-33)	11 (6-40)	0.82
WBC (/mL)	3300 (1050-16120)	3500 (1100-14300)	0.15	3325 (1050-16120)	3510 (1100-10700)	0.098
Hemoglobin (g/dL)	12.4 (6.0-16.7)	11.7 (5.9-16.4)	0.026	12.2 (7.3-15.5)	11.9 (7.0-15.9)	0.461
Platelets (1000/mL)	72000 (16000-233000)	43000 (26000-223000)	< 0.001	64500 (21000-233000)	42000 (26000-200000)	< 0.001
INR	1.20 (093-5.21)	1.25 (0.90-5.98)	0.183	1.21 (0.94-3.68)	1.23 (0.90-5.98)	0.91
Albumin (g/dL)	3.7 (2.4-4.8)	3.1 (1.8-4.7)	< 0.001	3.7 (2.4-4.8)	3.4 (1.8-4.7)	0.032
Total bilirubin (mg/dL)	1.2 (0.3-32.9)	1.5 (0.3-42.1)	0.078	1.3 (0.4-32.9)	1.4 (0.3-42.1)	0.778
AST (U/L)	37 (16-229)	42 (10-1387)	0.063	38 (16-192)	44 (10-1387)	0.137
ALT (U/L)	28 (7-205)	28 (6-1249)	0.437	26 (7-205)	29 (6-1249)	0.626
ALP (U/L)	90 (29-891)	102 (30-653)	0.013	100 (29-486)	98 (30-653)	0.423
Creatinine (mg/dL)	0.82 (0.44-1.75)	0.77 (0.20-4.58)	0.049	0.82 (0.57-1.38)	0.76 (0.20-4.58)	0.03

Data are presented as n (%) or median (range). HBV: Hepatitis B virus; HCV: Hepatitis C virus; NBNC: Non-B; non-C hepatitis; MELD: Model for end-stage liver disease; WBC: White blood cell; INR: International normalized ratio; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; PSM: Propensity score matching; HCC: Hepatocellular carcinoma; cHCC-CC: Combined hepatocellular carcinoma and cholangiocarcinoma.

Table 2 Pretransplant treatments, n (%)

	Before PSM			After PSM
	HCC (n = 141)	cHCC-CC (n = 111)	P value	HCC (n = 70)	cHCC-CC (n = 70)	P value
Locoregional therapy prior to LT	112 (79.4)	74 (66.7)	0.03	50 (71.4)	52 (74.3)	0.849
TACE	102 (72.3)	65 (58.6)	0.023	45 (64.3)	46 (65.7)	0.859
Liver resection	24 (17.0)	20 (18.0)	0.868	10 (14.3)	14 (20.0)	0.502
RFA	46 (32.6)	17 (15.3)	0.002	17 (24.3)	12 (17.1)	0.404
Radiation therapy	13 (9.2)	8 (7.2)	0.65	6 (8.6)	6 (8.6)	0.618
Number of locoregional therapies before LT > 3	56 (39.7)	34 (30.6)	0.147	27 (38.6)	26 (37.1)	0.862
AFP > 20 ng/mL	37 (26.2)	56 (50.5)	< 0.001	23 (32.9)	25 (35.7)	0.859
PIVKA-II > 40 mAU/mL	50 (35.5)	40 (39.2)	0.591	30 (42.9)	19 (30.2)	0.152

LT: Liver transplantation; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; AFP: Alpha-fetoprotein; PIVKA-II prothrombin-induced by vitamin K absence-II; HCC: Hepatocellular carcinoma; PSM: Propensity score matching; cHCC-CC: Combined hepatocellular carcinoma and cholangiocarcinoma.

Table 3 Perioperative and pathologic characteristics

	Before PSM			After PSM
	HCC (n = 141)	cHCC-CC (n = 111)	P value	HCC (n = 70)	cHCC-CC (n = 70)	P value
Perioperative
Operation (LDLT)	141 (100)	95 (85.6)	< 0.001	70 (100)	57 (44.9)	< 0.001
ABO-incompatibility	35 (24.8)	8 (7.2)	< 0.001	17 (24.3)	7 (10.0)	0.042
Macro-steatosis (%)	5 (0-20)	3 (0-30)	< 0.001	5 (1-20)	5 (0-30)	0.062
Micro-steatosis (%)	5 (1-70)	1 (0-90)	< 0.001	5 (1-40)	3 (0-90)	< 0.001
GRWR (%)	1.00 (0.65-1.71)	1.11 (0.67-3.89)	0.001	0.94 (0.67-1.70)	1.15 (0.67-3.89)	< 0.001
Cold ischemic time (min)	89 (45-168)	97 (30-1414)	0.029	95 (47-144)	97 (30-1414)	0.185
Warm ischemic time (min)	37 (16-81)	44 (20-90)	< 0.001	37 (17-81)	45 (22-87)	0.002
Operation time (min)	550 (336-960)	664 (270-1265)	< 0.001	544 (336-838)	639 (270-1265)	0.006
Hospitalization stay (d)	25 (17-445)	23 (4-262)	0.008	25 (17-94)	24 (4-262)	0.321
In-hospital mortality	2 (1.4)	4 (3.6)	0.41	1 (1.4)	4 (5.7)	0.366
Pathology
Tumor size > 3 cm	34 (24.3)	43 (38.7)	0.019	26 (37.1)	22 (31.4)	0.593
Tumor number > 3	22 (15.6)	28 (25.2)	0.079	13 (18.6)	20 (28.6)	0.232
Beyond Milan criteria	47 (33.3)	45 (40.5)	0.292	29 (41.4)	28 (40.0)	0.863
Tumor grade 3 or 4	19 (13.5)	33 (29.7)	0.002	10 (14.3)	14 (20.0)	0.502
Encapsulation	36 (25.5)	31 (27.9)	0.67	17 (24.3)	18 (25.7)	0.895
Tumor necrosis	55 (39.0)	55 (49.5)	0.098	24 (34.3)	38 (54.3)	0.027
Microvascular invasion	57 (40.4)	32 (28.8)	0.064	33 (47.1)	15 (21.4)	0.002
PVTT	7 (5.0)	15 (13.5)	0.023	4 (5.7)	7 (10.0)	0.532
BDTT	3 (2.1)	3 (2.7)	0.766	3 (4.3)	2 (2.9)	0.649
Intrahepatic metastasis	34 (24.1)	19 (17.1)	0.213	20 (28.6)	13 (18.6)	0.232
Multicentric occurrence	34 (24.1)	27 (24.3)	0.969	19 (27.1)	16 (22.9)	0.697
Lymph node metastasis	0 (0)	3 (2.7)	0.084	0 (0)	1 (1.4)	0.316

Data are presented as n (%) or median (range). LDLT: Living donor liver transplantation; GRWR: Graft-to-weight ratio; PVTT: Portal vein tumor thrombosis; BDTT: Bile duct tumor thrombosis; HCC: Hepatocellular carcinoma; PSM: Propensity score matching; cHCC-CC: Combined hepatocellular carcinoma and cholangiocarcinoma.

Table 4 Risk factors for tumor recurrence and death in the combined hepatocellular carcinoma and cholangiocarcinoma group

Tumor recurrence				Death
	OR	95%CI	P value		OR	95%CI	P value
Univariate				Univariate
Sex (male)	4.763	1.155-19.640	0.031	Sex (male)	6.464	0.883-47.317	0.066
Recipient age	0.999	0.958-1.041	0.957	Recipient age	1.005	0.957-1.057	0.833
Locoregional therapy before LT	1.724	0.907-3.274	0.096	Locoregional therapy before LT	1.924	0.891-4.153	0.096
TACE before LT	1.826	0.989-3.371	0.054	TACE before LT	2.188	1.039-4.609	0.039
Liver resection before LT	2.594	1.387-4.852	0.003	Liver resection before LT	0.941	0.365-2.428	0.9
RFA before LT	1.616	0.781-3.340	0.196	RFA before LT	2.284	1.025-5.090	0.043
Radiation therapy before LT	0.718	0.174-2.962	0.646	Radiation therapy before LT	0.654	0.089-4.813	0.677
Number of locoregional therapies before LT > 3	1.068	1.002-1.138	0.043	Number of locoregional therapies before LT > 3	1.733	0.865-3.473	0.121
MELD	0.993	0.950-1.038	0.742	MELD	1.012	0.965-1.063	0.617
Type of LT (DDLT)	0.934	0.397-2.198	0.875	Type of LT (DDLT)	1.518	0.626-3.680	0.365
ABO-incompatibility	1.563	0.618-3.952	0.345	ABO-incompatibility	0.79	0.189-3.297	0.746
Tumor size > 3cm	3.013	1.707-5.317	< 0.001	Tumor size > 3 cm	3.462	1.740-6.888	< 0.001
Tumor number > 3	1.35	0.723-2.520	0.346	Tumor number > 3	1.463	0.694-3.084	0.318
Milan criteria (beyond)	2.495	1.403-4.436	0.002	Milan criteria (beyond)	2.813	1.395-5.670	0.004
Tumor grade 3 or 4	1.465	0.809-2.651	0.208	Tumor grade 3 or 4	1.229	0.586-2.580	0.585
Microvascular invasion	2.417	1.360-4.297	0.003	Microvascular invasion	2.28	1.153-4.507	0.018
PVTT	1.416	0.661-3.032	0.37	PVTT	1.302	0.502-3.376	0.587
BDTT	0.047	0.000-36.844	0.368	BDTT	0.048	0.000-333.805	0.5
Intrahepatic metastasis	1.357	0.676-2.722	0.39	Intrahepatic metastasis	1.182	0.515-2.716	0.693
Multicentric occurrence	1.148	0.607-2.170	0.671	Multicentric occurrence	1.125	0.526-2.403	0.762
Encapsulation	1.269	0.582-2.766	0.549	Encapsulation	0.952	0.367-2.471	0.92
Tumor necrosis	2.361	1.302-4.281	0.005	Tumor necrosis	3.22	1.531-6.773	0.002
Dominant type (CC)	0.995	0.495-2.003	0.989	Dominant type (CC)	0.823	0.375-1.805	0.627
Lymph node metastasis	13.954	3.065-63.526	0.001	Lymph node metastasis	24.719	4.683-130.472	< 0.001
AFP > 20 ng/mL	1.563	0.880-2.777	0.128	AFP > 20 ng/mL	1.527	0.769-3.033	0.226
PIVKA-II > 40 mAU/mL	1.067	0.576-1.975	0.837	PIVKA-II > 40 mAU/mL	1.762	0.865-3.589	0.118
Multivariate				Multivariate
Number of locoregional therapies before LT > 3	1.813	1.012-3.248	0.046	Tumor size > 3 cm	4.591	1.851-11.390	0.001
Tumor size > 3 cm	2.378	1.321-4.280	0.004
Lymph node metastasis	8.585	1.822-40.453	0.007

OR: Odds ratio; CI: Confidence interval; LT: Liver transplantation; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; MELD: Model for end-stage liver disease; DDLT: Deceased donor liver transplantation; PVTT: Portal vein tumor thrombosis; BDTT: Bile duct tumor thrombosis; CC: Cholangiocarcinoma; AFP: Alpha-fetoprotein; PIVKA-II: Prothrombin-induced by vitamin K absence-II.

Table 5 Risk factors for tumor recurrence and death after propensity score matching

Tumor recurrence				Death
	OR	95%CI	P value		OR	95%CI	P value
Univariate				Univariate
Group (cHCC-CC)	2.15	1.162-3.977	0.015	Group (cHCC-CC)	2.134	1.142-3.987	0.018
Sex (male)	2.467	0.597-10.199	0.212	Sex (male)	1.536	0.475-4.964	0.474
Recipient age	0.973	0.928-1.021	0.266	Recipient age	1.009	0.962-1.057	0.725
Locoregional therapy before LT	1.78	0.855-3.706	0.123	Locoregional therapy before LT	2.304	1.026-5.171	0.043
Number of locoregional therapies before LT > 3	2.185	1.207-3.957	0.01	Number of locoregional therapies before LT > 3	1.241	0.683-2.254	0.478
MELD	0.944	0.889-1.002	0.056	MELD	0.993	0.947-1.041	0.758
Type of LT (DDLT)	0.771	0.239-2.493	0.664	Type of LT (DDLT)	1.999	0.891-4.488	0.093
ABO-incompatibility	1.094	0.526-2.277	0.81	ABO-incompatibility	0.439	0.157-1.228	0.117
Tumor size > 3 cm	2.541	1.406-4.592	0.002	Tumor size > 3 cm	2.426	1.341-4.386	0.003
Tumor number > 3	1.81	0.957-3.422	0.068	Tumor number > 3	1.458	0.749-2.839	0.267
Milan criteria (beyond)	2.893	1.573-5.322	0.001	Milan criteria (beyond)	2.261	1.242-4.119	0.008
Tumor grade 3 or 4	1.247	0.599-2.596	0.554	Tumor grade 3 or 4	1.268	0.610-2.639	0.525
Microvascular invasion	1.936	1.068-3.510	0.03	Microvascular invasion	1.873	1.032-3.400	0.039
PVTT	1.389	0.497-3.885	0.531	PVTT	1.836	0.722-4.669	0.202
BDTT	0.595	0.082-4.322	0.608	BDTT	2.035	0.487-8.504	0.33
Intrahepatic metastasis	2.192	1.172-4.101	0.014	Intrahepatic metastasis	1.742	0.923-3.289	0.087
Multicentric occurrence	1.313	0.687-2.512	0.41	Multicentric occurrence	0.967	0.489-1.915	0.924
Encapsulation	1.447	0.701-2.986	0.317	Encapsulation	1.305	0.626-2.723	0.478
Tumor necrosis	2.245	1.229-4.101	0.009	Tumor necrosis	2.56	1.383-4.740	0.003
AFP > 20 ng/mL	1.053	0.569-1.946	0.87	AFP > 20 ng/mL	1.333	0.733-2.425	0.346
PIVKA-II > 40 mAU/mL	1.202	0.639-2.263	0.568	PIVKA-II > 40 mAU/mL	1.422	0.762-2.651	0.268
Multivariate				Multivariate
Group (cHCC-CC)	2.531	1.191-5.376	0.016	Group (cHCC-CC)	2.281	1.057-4.922	0.036
Microvascular invasion	3.232	1.486-7.029	0.003	Tumor size > 3 cm	1.343	1.123-1.605	0.001
Number of locoregional therapies before LT > 3	2.33	1.235-4.396	0.009	Tumor number > 3	1.032	1.004-1.061	0.026

OR: Odds ratio; CI: Confidence interval; cHCC-CC: Combined hepatocellular carcinoma-cholangiocarcinoma; LT: Liver transplantation; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; MELD: Model for end-stage liver disease; DDLT: Deceased donor liver transplantation; PVTT: Portal vein tumor thrombosis; BDTT: Bile duct tumor thrombosis; AFP: Alpha-fetoprotein; PIVKA-II: Prothrombin-induced by vitamin K absence-II.