SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation

Table 1 Pretransplant donor and tumour characteristics

	No. (%)
Donor age (/years)
Median (Min.-Max.)	54 (12-83)
Donor sex
Male	146 (62.4)
Female	88 (37.6)
Donor type
DBD	126 (53.8)
DCD	108 (46.2)
Tumour largest size (cm)
≤ 5	226 (98.3)
> 5	4 (1.7)
Median (range)	2.4 (1-6.7)
Number of tumours
≤ 3	225 (97)
> 3	7 (3)
Median	1 (1-6)
AFP-listing
< 100	205 (88.8)
100-500	21 (9)
500-1000	1 (0.4)
> 1000	4 (1.7)
Median (range)	7 (1-2634)
TACE	93 (39.7)
Ablation	57 (24.4)
MELD
Median (range)	9 (4-24)
UKELD
Median (range)	49 (41-65)

AFP: Alpha fetoprotein; DCD: Donation after circulatory death; DBD: Donation after brain stem death; TACE: Transarterial chemoembolization; MELD: Model for End-Stage Liver Disease; UKELD: United Kingdom Model for End-Stage Liver Disease.

Table 2 Survival with and without recurrence post-liver transplantation for hepatocellular carcinoma

	Total No.	No. of dead	Mean (years)	1 year (%)	3 years (%)	5 years (%)	End of study (%)	Log rank
								χ2	P value
Non-recurrence	209	44	9.59	90.9	83.0	81.2	75.3	96.401	< 0.001
Recurrence	25	25	1.87	72.0	12.0	0.0	0.0

Table 3 Univariate and multivariate analysis of predictors of hepatocellular carcinoma recurrence following liver transplantation, n (%)

	No-recurrence (n = 209)	Recurrence (n = 25)	Univariate		Multivariate
			HR (LL-UL 95%CI)	P value	HR (LL-UL 95%CI)	P value
LT era
2010-2013	64 (30.6)	7 (28.0)	2.146 (0.446-10.330)	0.341
2014-2017	106 (50.7)	16 (64.0)	2.700 (0.621-11.745)	0.185
2018-2020	39 (18.7)	2 (8.0)	1.000
RETREAT score
≤ 3	135 (68.2)	8 (32.0)	1.000		1.000
> 3	63 (31.8)	17 (68.0)	4.403 (1.900-10.206)	0.001	1.011 (0.315-3.238)	0.986
Donor type
DBD	110 (52.6)	16 (64.0)	1.475 (0.652-3.337)	0.351
DCD	99 (47.4)	9 (36.0)	1.000
Listing to transplant interval (months)
< 1	45 (21.5)	9 (36.0)	1.000
1-3	82 (39.2)	6 (24.0)	0.414 (0.147-1.164)	0.095
> 3	82 (39.2)	10 (40.0)	0.692 (0.281-1.704)	0.423
Within Milan criteria	199 (95.2)	24 (96.0)	1.359 (0.184-10.046)	0.764
Within United Kingdom criteria	204 (97.6)	25 (100.0)	0.048 (7.721 × 10-7–2965.3)	0.589
Tumour largest size (cm)
≤ 5	203 (98.5)	23 (95.8)	1.000
> 5	3 (1.5)	1 (4.2)	2.380 (0.321-17.629)	0.396
Number of tumours
≤ 3	200 (96.6)	25 (100.0)	1.000
> 3	7 (3.4)	0 (0.0)	0.047 (0.000-519.138)	0.520
AFP-listing
< 100	185 (89.8)	20 (80.0)	1.000		1.000
100-500	18 (8.7)	3 (12.0)	1.468 (0.436-4.941)	0.536	0.723 (0.201-2.596)	0.619
> 500	3 (1.5)	2 (8.0)	5.170 (1.207-22.138)	0.027	8.958 (1.689-47.503)	0.010
Bridging	117 (56.0)	21 (84.0)	3.707 (1.272-10.801)	0.016
The trend of size between listing and LT on imaging
Decrease	94 (52.5)	7 (29.2)	1.000		1.000
Same	20 (11.2)	2 (8.3)	1.243 (0.258-5.986)	0.786	0.851 (0.153-4.738)	0.854
Increase	65 (36.3)	15 (62.5)	3.097 (1.263-7.598)	0.014	1.180 (0.392-3.554)	0.768
The trend of AFP between listing and LT
Decrease	57 (29.1)	4 (16.0)	1.000
Same	94 (48.0)	11 (44.0)	1.697 (0.540-5.329)	0.365
Increase	45 (23.0)	10 (40.0)	2.912 (0.913-9.284)	0.071
Size change between explant viable largest tumour and listing largest tumour
Decrease	119 (57.5)	7 (28.0)	1.000
Same	22 (10.6)	3 (12.0)	2.090 (0.540-8.082)	0.285
Increase	66 (31.9)	15 (60.0)	3.842 (1.566-9.424)	0.003
Explant viable tumour number
≤ 3	152 (84.4)	18 (75.0)	1.000
> 3	28 (15.6)	6 (25.0)	1.889 (0.750-4.759)	0.177
Microvascular invasion	98 (46.9)	21 (84.0)	6.087 (2.089-17.735)	0.001	3.014 (0.697-13.032)	0.140
Macrovascular invasion	8 (3.8)	6 (24.0)	5.320 (2.121-13.348)	< 0.001	2.888 (0.907-9.198)	0.073
Satellite nodules	11 (5.3)	6 (24.0)	4.728 (1.887-11.845)	0.001	3.673 (1.204-11.210)	0.022
Tumor grade
Complete necrosis	31 (15.0)	1 (4.0)	0.235 (0.032-1.736)	0.156
Well-differentiated	48 (23.2)	2 (8.0)	0.311 (0.073-1.320)	0.113
Moderately differentiated	112 (54.1)	11 (44.0)	0.673 (0.305-1.481)	0.325
Poorly differentiated	16 (7.7)	11 (44.0)	7.805 (3.536-17.230)	< 0.001	3.727 (1.428-9.730)	0.007

AFP: Alpha fetoprotein; DCD: Donation after circulatory death; DBD: Donation after brain stem death; RETREAT: Risk Estimation of Tumor Recurrence After Transplant; LT: Liver transplantation.

Table 4 SIMAP500 score

Factor score
Satellite nodules	2
Increased viable tumour size from listing to LT	1
Microvascular invasion	3
AFP at listing > 500	4
Poorly differentiated HCC grade	3

LT: Liver transplantation; AFP: Alpha fetoprotein; HCC: Hepatocellular carcinoma.

Table 5 Comparison between SIMAP500 and RETREAT scoring systems

Characteristic	SIMAP500 score	RETREAT score
Consider the presence of satellite nodules on explant histology	Yes	No
Consider the tumour differentiation grade on explant histology	Yes	No
AFP capture	At listing with a cutoff point of 500	At LT with AFP divided into four intervals (very wide range between 100-999 receiving 2 points)
Consider the increase in the size of the tumour while on the waiting list	Yes	No
Consider microvascular invasion on explant histology	Yes	Yes
AUC	0.807	0.703

RETREAT: Risk Estimation of Tumor Recurrence After Transplant; SIMAP500: Satellite nodules, Increase in size, Microvascular invasion, AFP > 500, Poor differentiation; LT: Liver transplantation; AFP: Alpha fetoprotein; AUC: Area under the curve.

Table 6 Relation between SIMAP500 score and recurrence rate, time to recurrence

SIMAP500 score	Recurrence No. (%)	Median time between LT and recurrence (years)
0	3 (12.0)	1.44 (1.16-2.18)
1-3	3 (12.0)	1.68 (0.90-1.78)
4	4 (16.0)	1.56 (1.32-2.19)
5	2 (8.0)	0.94 (0.74-1.14)
≥ 6	13 (52.0)	0.70 (0.21-2.95)

SIMAP500: Satellite nodules, increase in size, microvascular invasion, AFP > 500, poor differentiation; LT: Liver transplantation.