Imaging-Derived Biomarkers Integrated with Clinical and Laboratory Values Predict Recurrence of Hepatocellular Carcinoma After Liver Transplantation

Figures & data

Figure 1 Study flow diagram.

Table 1 Summary of Baseline Characteristics and Imaging Features of Patients

Variable
Clinical and laboratory factors
Sex
Female	38 (21.3%)
Male	140 (78.7%)
Age at liver transplantation, median (IQR)	59.0 (10.0)
Listing to transplant (days), median (IQR)	169.5 (206.8)
Etiology of liver disease
Chronic alcoholism	52 (29.2%)
HBV	25 (14.0%)
HCV	53 (29.8%)
HBV + HCV	6 (3.4%)
Cryptogenic	12 (6.7%)
NASH	11 (6.1%)
Others	19 (10.7%)
INR, median (IQR)	1.2 (0.3)
MELD score, median (IQR)	10.0 (6.8)
Bilirubin (mg/dl), median (IQR)	1.5 (1.7)
ALT (U/L), median (IQR)	40.5 (49.5)
AST (U/L), median (IQR)	62.0 (62.8)
ALP (U/L), median (IQR)	146.0 (81)
GGT (U/L), median (IQR)	107.5 (141.3)
AFP (ng/mL), median (IQR)	7.2 (32.2)
Imaging factors
Liver cirrhosis	153 (86.0%)
Biliary dilatation	21 (11.8%)
Varices	108 (60.7%)
Ascites	70 (39.3%)
Pleural effusion	11 (6.2%)
Small lesions	62 (34.8%)
Diameter of the largest lesion (mm), median (IQR)	31.6 (18.1)
Number of tumors > 3	17 (9.5%)
Atypical HCC enhancement pattern	11 (6.1%)
Capsule	29 (16.3%)
Irregular margin	101 (56.7%)
Satellite nodules	15 (8.4%)
Peritumoral enhancement	21 (11.8%)
Nodule-in-nodule	34 (19.1%)
HU of tumor on arterial phase, mean (SD)	84.8 (21.0)
HU of tumor on portal phase, mean (SD)	93.3 (19.5)
History of bridging therapies	135 (75.8%)
Follow-up
Recurrence	31 (17.4%)

Abbreviations: AFP, Alpha fetoprotein; ALP, Alkaline phosphatase; ALT, Alanine transaminase; AST, Aspartate transaminase; GGT, Gamma-glutamyl transferase; HBV, Hepatitis B; HCC, Hepatocellular carcinoma; HCV, Hepatitis C; HU, Hounsfield Unit; INR, International normalized ratio; IQR, Interquartile range; MELD, Model for End-Stage Liver Disease; NASH, Non-alcoholic steatohepatitis.

Figure 2 Kaplan–Meier curves comparing time-to-recurrence. (a) tumor margin (p=0.023), (b) presence of satellite nodules (p=0.02), (c) presence of small lesions (p=0.031), (d) peritumoral enhancement (p<0.001), (e) diameter of largest tumor (p<0.001), (f) number of tumors (p<0.001), (g) history of bridging therapies (p<0.001).

Table 2 Univariable Cox Proportional Hazards Regression Analysis for Prediction of the Recurrence of HCC After Transplantation

Parameter	Univariable Analysis
	HR (95% CI)	Raw p value	Adjusted p value
Clinical and laboratory factors
Age at liver transplantation (>60 vs ≤60)	1.298 (0.632–2.668)	0.48	0.56
Sex (Male vs Female)	1.576 (0.605–4.107)	0.35	0.49
Listing to transplant (>160 days vs ≤160 days)	0.654 (0.320–1.335)	0.24	0.46
AFP (>400 vs ≤400 ng/mL)	4.685 (2.009–10.930)	<0.001	0.002
Imaging factors
Irregular margin	2.462 (1.100–5.506)	0.03	0.09
Satellite nodules	2.765 (1.133–6.752)	0.03	0.09
Peritumoral enhancement	6.374 (3.088–13.160)	<0.001	<0.001
Small lesions	2.134 (1.055–4.317)	0.04	0.11
Diameter of largest tumor > 3 cm	5.156 (1.979–13.430)	<0.001	0.003
Number of tumors > 3	5.455 (2.613–11.390)	<0.001	<0.001
History of bridging therapies	0.257 (0.127–0.521)	<0.001	0.001
Nodule-of-nodule	1.873 (0.836–4.193)	0.13	0.27
Atypical HCC enhancement pattern	0.487 (0.066–3.577)	0.48	0.56
Capsule	1.947 (0.869–4.361)	0.11	0.26
Biliary dilatation	1.467 (0.563–3.826)	0.43	0.56
Ascites	0.877 (0.420–1.832)	0.73	0.77
Varices	0.696 (0.344–1.408)	0.31	0.49
Pleural effusion	1.076 (0.257–4.512)	0.92	0.92
Liver cirrhosis	1.270 (0.444–3.637)	0.66	0.73
HU of tumor on arterial phase	1.008 (0.992–1.025)	0.33	0.49
HU of tumor on portal phase	0.990 (0.972–1.009)	0.30	0.49

Abbreviations: AFP, Alpha fetoprotein; HCC, Hepatocellular carcinoma; HU, Hounsfield Unit.

Bold indicates statistical significance.

Figure 3 Multivariable Cox proportional hazards regression analysis of variable selected by LASSO for prediction the recurrence of HCC after transplantation.

Figure 4 The nomogram for predicting 1-, 3-, and 5-year time-to-recurrence probabilities.

Figure 5 Calibration curves of the nomogram for predicting 1-, 3-, and 5-year time-to-recurrence probabilities.

Figure 6 Receiver operating characteristic (ROC) curves of 1- (blue line), 3- (green line), and 5-year (red line) time-to-recurrence based on the nomogram.