Patterns, Risk Factors, and Outcomes of Recurrence After Hepatectomy for Hepatocellular Carcinoma with and without Microvascular Invasion

Figures & data

Table 1 Baseline Characteristics of Patients with Hepatocellular Carcinoma (HCC) in Microvascular Invasion (MVI) Positive and Negative Groups

Characteristics	Entire cohort			Propensity score-matched cohort (2:1 ratio)
	MVI^(-) group (n=1175)	MVI^(+) group (n=581)	P value	MVI^(-) group (n=778)	MVI^(+) group (n=528)	P value
Age*, years	52.0 [16–86]	50.0 [15–88]	0.022	51.0 [16–85]	50.0 [15–88]	0.488-
Sex male, n (%)	1012 (86.1)	519 (89.3)	0.073	688 (88.4)	469 (88.8)	0.826
HBsAg positive, n (%)	949 (80.8)	479 (82.4)	0.396	634 (81.5)	434 (82.2)	0.746
Cirrhosis yes, n (%)	835 (71.1)	419 (72.1)	0.646	552 (71.0)	377 (71.4)	0.860
ALT*, U/L	36.5 [6.8–280.2]	37.0 [7.5–305.3]	0.328	36.8 [8.0–280.2]	37.0 [7.5–305.3]	0.645
CRE*, μmol/L	71.2[32.0–127.3]	71.6[32.5–145.8]	0.306	71.2[32.0–127.3]	70.3[31.5–140.0]	0.712
Hemoglobin*, g/dL	14.0 [10.0–19.6]	13.9 [9.8–19.1]	0.317	14.0 [10.0–19.6]	14.0 [10.2–19.1]	0.957
Platelet*, 10^9/L	179 [65–468]	197 [77–565]	<0.001	186 [65–468]	191 [77–565]	0.308
NLR*	1.83 [0.2–7.9]	2.11 [0.1–8.6]	0.037	1.91 [0.2–7.9]	2.01 [0.1–8.1]	0.469
Blood loss *, mL	300[100–1500]	300[100–1800]	<0.001	300[100–1500]	300[100–1800]	0.130
Tumor size *, cm	6.0 [1.0–22.0]	7.4 [1.0–23.0]	<0.001	6.8 [1.0–22.0]	7.0 [1.0–22.0]	0.170
Tumor number, n (%)  Solitary  multiple	965 (82.1) 210 (17.9)	467 (80.3) 114 (19.7)	0.374	646 (83.0) 132 (17.0)	425 (80.5) 103 (19.5)	0.241
Tumor capsule, n (%)  Complete  Incomplete	899 (76.5) 276 (23.5)	348 (59.9) 233 (40.1)	<0.001	518 (66.6) 260 (33.4)	339 (64.2) 189 (35.7)	0.375
ALBI grade, n (%)  Grade 1  Grade 2  Grade 3	762 (64.9) 411 (35.0) 2 (0.1)	297 (51.1) 284 (48.9) 9 (1.5)	<0.001	455 (58.5) 321 (41.3) 2 (0.2)	286 (54.2) 239 (45.3) 3 (0.5)	0.223
AFP, n (%)  ≤400 μg /L  >400 μg /L	810 (68.9) 365 (31.1)	286 (54.2) 242 (45.8)	<0.001	433 (55.7) 345 (44.3)	282 (53.4) 246 (46.6)	0.423
BCLC stage, n (%)  0-A  B	975 (83.0) 200 (17.0)	471 (81.2) 110 (18.9)	0.323	651 (83.7) 127 (16.3)	429 (81.3) 99 (18.7)	0.255
Type of resection, n (%)  Anatomic  Non-anatomic	396 (33.7) 779 (66.3)	262 (45.1) 319 (54.9)	<0.001	312 (40.1) 466 (59.9)	224 (42.4) 304 (57.6)	0.403
Resection margin, n (%)  ≤1.0 cm  >1.0 cm	805 (68.5) 370 (31.5)	393 (67.6) 188 (32.4)	0.713	521 (67.0) 257 (33.0)	357 (67.6) 171 (32.4)	0.807
Blood transfusion, n (%)  No  Yes	968 (82.3) 207 (17.7)	429 (73.8) 152 (26.2)	<0.001	612 (78.6) 166 (21.4)	402 (76.1) 126 (23.9)	0.282
Differentiation, n (%)  I-II  III-IV	1059 (90.1) 116 (9.9)	444 (76.4) 137 (23.6)	<0.001	653 (83.9) 125 (16.1)	430 (81.4) 98 (18.6)	0.240

Notes: Data are n (%) and ranges. *Presented as median and ranges.

Abbreviations: HBsAg, hepatitis B surface antigen; ALT, alanine aminotransferase; CRE, creatinine; NLR, neutrophil to lymphocyte ratio; ALBI, albumin-bilirubin; AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer;

Figure 1 Flow chart of patient selection.

Figure 2 Cumulative recurrence curves of hepatocellular carcinoma (HCC) patients with or without microvascular invasion (MVI). The cumulative 2-year recurrence rate of patients with and without MVI in the entire cohort (Figure 2A) and in the propensity score-matched cohort (Figure 2B), and the cumulative 5-year recurrence rates of patients with late recurrence in the entire cohort (Figure 2C) and in the propensity score-matched cohort (Figure 2D).

Table 2 Characteristics and Treatments of Recurrent Tumors

Variables	Early Recurrence				Late Recurrence
	Total No. (n=875)	MVI^(+) (n=384)	MVI^(-) (n=491)	P value	Total No. (n=176)	MVI^(+) (n=40)	MVI^(-) (n=136)	P value
Site of recurrence
Intrahepatic	621 (71.0)	262 (68.2)	359 (73.1)	0.097	124 (73.9)	27 (67.5)	104 (76.4)	0.504
Extrahepatic	94 (10.7)	40 (10.4)	55 (11.2)		23 (13.1)	7 (17.5)	16 (11.8)
Both	160 (18.3)	82 (21.6)	77 (15.7)		29 (13.0)	6 (15.0)	16 (11.8)
Total number of recurrent foci
Solitary	308 (35.2)	116 (30.2)	193 (39.3)	<0.001	104 (59.1)	26 (65.0)	78 (57.4)	0.684
2–3	171 (19.5)	63 (16.4)	109 (22.2)		37 (21.0)	7 (17.5)	30 (22.1)
>3	389 (45.3)	205 (53.4)	189 (38.5)		35 (19.9)	7 (17.5)	28 (20.5)
Treatment for recurrent tumor
Curative treatment	300 (34.3)	112 (29.2)	189 (38.5) ‡	0.015	99 (56.3)	22 (55.0)	77 (56.6)§	0.925
Palliative treatment	398 (45.5)	187 (48.7)	210 (42.8)		55 (33.0)	13 (32.5)	45 (33.1)
Supportive care	177 (20.2)	85 (22.1)	92 (18.7)		22 (10.7)	5 (12.5)	14 (10.3)

Note: Curative treatment includes repeat resection, radiofrequency ablation and salvage liver transplantation; Palliative treatment includes transcatheter arterial chemoembolization (TACE) alone or with sorafenib or sorafenib only; ‡included 1 patient underwent liver transplantation. § included 2 patients underwent salvage liver transplantation. Values in parentheses are percentage.

Figure 3 Overall survival (OS) curves of patients with early and late recurrence in the subset of patients with or without microvascular invasion. Overall survival in the entire cohort (3A) and in the propensity score-matched cohort (3B) of patients with early recurrence, and overall survival in the entire cohort (3C) and in the propensity score-matched cohort (3D) of patients with late recurrence.

Table 3 Risk Factors Associated with Early and Late Tumor Recurrence Identified by Cox Multivariate Analysis in the Entire Cohort, MVI⁽⁺⁾ and MVI^(-) Subset

Variables	Entire cohort (n=1756)		MVI^(+) group (n=581)		MVI^(-) group (n=1175)
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Early recurrence
Age (year), ≤50 vs >50	0.806 (0.703–0.924)	0.020	0.809 (0.661–0.991)	0.040	0.798 (0.664–0.959)	0.016
HBsAg, positive vs negative	1.229 (1.021–1.480)	0.029	NA		1.396 (1.083–1.799)	0.010
Cirrhosis, yes vs no	NA		1.765 (1.253–1.982)	<0.001	NA
NLR, >1.9 vs ≤1.9^†	1.230 (1.067–1.417)	0.004	NA		1.505 (1.250–1.811)	<0.001
AFP (μg/L), >400 vs ≤400	1.376 (1.195–1.585)	<0.001	1.422 (1.161–1.742)	0.001	1.000 (1.000–1.000)	<0.001
Tumor size (cm), >5 vs ≤5	1.448 (1.223–1.715)	<0.001	1.469 (1.124–1.919)	0.005	1.314 (1.067–1.618)	0.001
Tumor number, multiple vs solitary	1.541 (1.310–1.813)	<0.001	1.222 (1.056–1.416)	0.007	1.542 (1.340–1.773)	<0.001
Differentiation, III-IV vs I-II	1.352 (1.215–1.504)	<0.001	NA		NA
MVI, positive vs negative	1.655 (1.435–1.909)	<0.001	-		-
Blood transfusion, yes vs no	1.307 (1.115–1.531)	0.001	NA		1.658 (1.336–2.058)	<0.001
Resection margin, >1cm vs ≤1cm	0.816 (0.701–0.955)	0.010	0.684 (0.538–0.870)	0.002	NA
Late recurrence
AFP (μg/L), >400 vs ≤400	0.415 (0.279–0.618)	<0.001	NA		0.350 (0.209–0.586)	<0.001
Differentiation, III-IV vs I-II	1.644 (1.274–2.132)	<0.001	1.687 (1.255–1.973)	0.041	NA
Sex, male vs female	0.517 (0.291–0.919)	0.024	NA		0.485 (0.253–0.927)	0.029
HBsAg, positive vs negative	NA		NA		1.940 (1.171–3.215)	0.010
Cirrhosis, yes vs no	1.970 (1.428–2.717)	<0.001	2.753 (1.380–5.492)	0.004	2.014 (1.413–20,871)	<0.001
ALBI grade, 2–3 vs 1	1.585 (1.161–2.164)	0.004	NA		1.703 (1.184–2.449)	0.004

Notes: ^†1.9 was the median value of NLR in the primary cohort.

Abbreviations: HR, hazard ratio; CI, confidence interval; NLR, neutrophil to lymphocyte ratio; HBsAg, hepatitis B surface antigen; AFP, alpha fetoprotein, MVI, microvascular invasion; ALBI, albumin to bilirubin.