Early extrahepatic recurrence as a pivotal factor for survival after hepatocellular carcinoma resection: A 15-year observational study

doi:10.3748/wjg.v28.i36.5351

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Sep 28, 2022 (publication date) through Feb 18, 2025

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World Journal of Gastroenterology

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Observational Study

World J Gastroenterol. Sep 28, 2022; 28(36): 5351-5363
Published online Sep 28, 2022. doi: 10.3748/wjg.v28.i36.5351

Table 1 Baseline characteristics of the enrolled patients

	Patients without early EHR (n = 705)	Patients with early EHR (n = 74)	P value
Age (yr)	59.49 ± 10.08	56.51 ± 10.37	0.020
Male sex (n, %)	603 (85.5)	64 (86.5)	0.824
BMI (kg/m²)	23.89 ± 3.03	24.10 ± 2.98	0.790
Etiology of hepatitis, n (%)			0.569
HBV/HCV	425 (63.2)/55 (8.2)	53 (73.6)/8 (11.1)
Alcohol/combined	40 (10.4)/49 (7.0)	5 (6.9)/2 (2.8)
NASH/unknown	1 (0.1)/73 (10.8)	0/4 (5.6)
ALP (U/L)	89.25 ± 44.04	113.23 ± 106.76	0.059
Albumin (mg/dL)	4.36 ± 0.45	4.19 ± 0.48	0.002
ALBI grade ≥ 2, n (%)	97 (13.8)	16 (21.9)	0.063
ICG R15	12.02 ± 7.29	12.58 ± 7.62	0.566
Preoperative serum AFP > 400 (IU/mL)	127 (18.6)	24 (32.9)	0.004
Sum of tumor size	4.17 ± 2.44	6.06 ± 3.38	< 0.001
Tumor numbers	1.19 ± 0.54	1.32 ± 0.82	0.176
BCLC stage, n (%)			< 0.001
0/A/≥ B	89 (12.7)/491 (69.9)/122 (17.4)	3 (4.1)/44 (59.5)/27 (36.5)
Pathological mUICC stage, n (%)			< 0.001
I/II/≥ III	111 (15.8)/431 (61.4)/160 (22.8)	2 (2.7)/32 (43.2)/40 (54.1)
Radiological mUICC stage, n (%)			< 0.001
I/II/≥ III	112 (15.9%)/463 (66.0%)/127 (18.1%)	4 (5.4)/43 (58.1)/27 (36.5)
Beyond Milan criteria, n (%)	179 (25.4)	40 (54.1)	< 0.001
Macrovascular invasion, n (%)	32 (4.6)	11 (14.9)	< 0.001
Hospital stay, days (median, range)	13.3 ± 7.1	15.6 ± 75.6	0.049
Follow-up duration, years (median, range)	4.8 (0.23-15.36)	1.8 (0.31-1.43)	< 0.001

Values are presented as mean ± SD. SD: Standard deviation; EHR: Extrahepatic recurrence; BMI: Body mass index; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AST: Aspartate transaminase; ALT: Alanine transaminase; ALP: Alkaline phosphatase; AFP: Alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; mUICC: Modified Union for International Cancer Control.

Table 2 Comparison of surgical findings and clinical outcomes in patients with and without extrahepatic recurrence

	Patients without early EHR (n = 705)	Patients with early EHR (n = 74)	P value
Margin involvement, n (%)	16 (2.3%)	4 (5.5%)	0.104
Metastatic lymph nodes, n (%)	1 (0.1)	3 (4.1)	< 0.001
Microvascular invasion, n (%)	114 (16.3)	33 (44.6)	< 0.001
Serosal invasion, n (%)	13 (1.9)	4 (5.4)	0.052
Bile duct invasion, n (%)	9 (1.3)	1 (1.4)	0.975
Capsule formation, n (%)	456 (66.7)	53 (71.6)	0.389
Multicentricity, n (%)	54 (7.8)	8 (10.8)	0.372
Satellite nodule, n (%)	84 (12.2)	17 (23.0)	0.009
Intrahepatic metastasis, n (%)	8 (1.2)	2 (2.7)	0.268
Necrosis, n (%)	286 (41.5)	61 (82.4)	< 0.001
Haemorrhage, n (%)	296 (43.0)	46 (62.2)	0.002
Fatty change, n (%)	246 (36.0)	15 (20.5)	0.008
Major Edmondson-Steiner grade, n (%)			0.243
1/2	30 (4.4)/352 (51.8)	2 (2.7)/30 (41.1)
3/4	274 (40.3)/24 (3.5)	38 (52.1)/3 (4.1)
Worst Edmondson-Steiner grade, n (%)			0.094
1/2	8 (1.1)/130 (18.9)	1 (1.4)/5 (6.8)
3/4	357 (51.8)/194 (28.2)	40 (54.1)/28 (37.8)
Serum AFP > 400 IU/mL on first recurrence	34 (10.2)	22 (31.0)	< 0.001
Recurrence-free survival, mo (median, range)	32.4 (2.24-177.34)	5.21 (2.04-20.28)	< 0.001
mUICC T stage on first recurrence, n (%)			< 0.001
0/1	6 (1.8)/144 (43.6)	10 (13.7)/23 (31.5)
2/3	131 (39.7)/39 (11.8)	14 (19.2)/20 (27.4)
4	10 (3.0)	6 (8.2)
Second treatment modality			0.070
Surgery/RFA	46 (6.5)/95 (13.5)	9 (12.2)/10 (13.5)
TACE/RFA + TACE	156(22.1)/14 (2.0)	13 (17.6)/6 (8.1)
RT/systemic chemotherapy/BSC	20 (2.8)/11 (1.5)/20 (2.8)	3 (4.1)/1 (1.4)

AFP: Alpha-fetoprotein; mUICC: Modified Union for International Cancer Control stage; RFA: Radiofrequency ablation; TACE: Trans-arterial chemoembolization; RT: Radiotherapy; BSC: Best supportive care.

Table 3 Univariate and multivariate analyses of factors associated with early extrahepatic recurrence

	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Serum albumin < 4.0 g/dL	2.27 (1.56-3.29)	< 0.001	2.19 (1.45-3.31)	< 0.001
Serum ALP > 100 U/L	1.76 (1.24-2.52)	0.002	1.59 (1.08-2.32)	0.018
ALBI grade ≥ 2	1.71 (1.12-2.59)	0.012
Surgical margin involvement	2.30 (1.07-4.93)	0.032	2.53 (1.09-5.90)	0.032
Pathological mUICC stage (III, IVa)	2.94 (2.09-4.12)	< 0.001
Multiple tumors¹	3.21 (1.57-6.56)	0.002
Venous/lymphatic involvement²	2.98 (2.09-4.25)	< 0.001	1.90 (1.28-2.83)	0.002
Serosa invasion	2.86 (1.33-6.12)	0.007
Bile duct invasion	3.25 (1.20-8.83)	0.020
Satellite nodule	2.69 (1.83-3.94)	< 0.001	1.73 (1.14-2.63)	0.011
Intrahepatic metastasis	2.99 (1.10-8.09)	0.032
Tumor necrosis	3.18 (2.20-4.61)	<0.001	1.92 (1.29-2.79)	0.001
Tumor hemorrhage	1.81 (1.28-2.55)	0.001
Sum of tumor size ≥ 7 cm	3.25 (2.23-4.73)	< 0.001	1.84 (1.21-2.77)	0.004
Macrovascular invasion	2.48 (1.37-4.50)	0.003	2.30 (1.24-4.26)	0.008
Serum AFP > 1500 IU/mL	1.99 (1.27-3.12)	0.003

¹Number of tumors examined during pathological evaluation.

²Confirmed findings during pathological evaluation.

HR: Hazards ratio; CI: Confidence interval; ALP: Alkaline phosphatase; ALBI: Albumin-bilirubin; mUICC: Modified Union for International Cancer Control; AFP: Alpha-fetoprotein.

Table 4 Univariate and multivariate analysis of factors associated with overall survival

	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Serum albumin < 4.0 g/dL	2.14 (1.61-2.85)	< 0.001	2.44 (1.79-3.32)	< 0.001
ALBI grade ≥ 2	1.84 (1.36-2.51)	< 0.001
Serum ALP > 100 U/L	1.84 (1.41-2.41)	< 0.001	1.62 (1.22-2.16)	0.001
Single tumor¹	1.87 (1.21-2.91)	0.005
Major Edmondson-Steiner grade ≥ 3	1.64 (1.26-2.13)	< 0.001	1.45 (1.10-1.90)	0.008
Venous/lymphatic involvement²	2.44 (1.84-3.22)	< 0.001
Pathological mUICC stage (III, IVa)	2.59 (2.00-3.35)	< 0.001	1.63 (1.21-2.22)	0.002
Bile duct invasion	2.72 (1.21-6.13)	0.016
Intrahepatic metastasis	3.66 (1.72-7.77)	0.001
Multicentricity	1.91 (1.29-2.82)	0.001
Satellite nodule	2.45 (1.82-3.30)	< 0.001	1.92 (1.38-2.69)	< 0.001
Tumor necrosis	2.12 (1.63-2.77)	< 0.001	1.35 (1.030-1.78)	0.030
Tumor hemorrhage	1.58 (1.21-2.05)	0.001
Sum of tumor size ≥ 7 cm	2.21 (1.63-3.00)	< 0.001
Beyond Milan criteria	1.79 (1.38-2.33)	< 0.001
Serum AFP > 1500 IU/mL	1.47 (1.01-2.15)	0.046
Early extrahepatic recurrence	7.72 (5.67-10.51)	< 0.001	6.77 (4.81-9.52)	< 0.001

¹Number of tumors examined during pathological evaluation.

²Confirmed findings during pathological evaluation.

HR: Hazards ratio; CI: Confidence interval; ALBI: Albumin-bilirubin; ALP: Alkaline phosphatase; mUICC: Modified Union for International Cancer Control; AFP: Alpha-fetoprotein.

Citation: Yoon JH, Choi SK, Cho SB, Kim HJ, Ko YS, Jun CH. Early extrahepatic recurrence as a pivotal factor for survival after hepatocellular carcinoma resection: A 15-year observational study. World J Gastroenterol 2022; 28(36): 5351-5363
URL: https://www.wjgnet.com/1007-9327/full/v28/i36/5351.htm
DOI: https://dx.doi.org/10.3748/wjg.v28.i36.5351