Comparison of Postoperative Prognosis Among HBV-Related, HCV-Related, and Non-HBV Non-HCV Hepatocellular Carcinomas: A Systematic Review and Meta-analysis

Yue Zhao; Yuanyuan Jia; Sufen Qi; Chensi Wu; Jianhua Wu; Ruixing Zhang; Jing Li; Zhanjun Guo

doi:10.5812/hepatmon-121820

Comparison of Postoperative Prognosis Among HBV-Related, HCV-Related, and Non-HBV Non-HCV Hepatocellular Carcinomas: A Systematic Review and Meta-analysis

authors:

Yue Zhao ¹ , Yuanyuan Jia ² , Sufen Qi ³ , Chensi Wu ¹ , Jianhua Wu ⁴ , Ruixing Zhang ¹ , Jing Li ^{5
, *} , Zhanjun Guo ^{2
, **}

1 Department of Gastroenterology and Hepatology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China

2 Department of Rheumatology and Immunology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China

3 Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, P.R. China

4 Animal Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China

5 College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, Hebei, P.R. China

Corresponding Authors:

Hepatitis Monthly: Vol.22, issue 1; e121820

published online: August 1, 2022

article type: Systematic Review

received: December 17, 2021

revised: June 22, 2022

accepted: June 23, 2022

DOI: https://doi.org/10.5812/hepatmon-121820

how to cite: Zhao Y, Jia Y, Qi S, Wu C, Wu J, et al. Comparison of Postoperative Prognosis Among HBV-Related, HCV-Related, and Non-HBV Non-HCV Hepatocellular Carcinomas: A Systematic Review and Meta-analysis. Hepat Mon. 2022;22(1):e121820. https://doi.org/10.5812/hepatmon-121820.

Abstract

Context:

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and different hepatitis viruses might affect the prognosis of patients with HCC.

Objectives:

This study aimed to reveal the differences in the postoperative prognosis of patients with hepatitis B virus-related HCC (HBV-HCC), hepatitis C virus-related HCC (HCV-HCC), and non-HBV non-HCV hepatocellular carcinoma (NBNC-HCC).

Methods:

The databases PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for articles published until April 2022. Stata software version 12 and Review Manager version 5.4 were used to conduct the meta-analysis, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was adopted in this study.

Results:

In the present study, 26 papers on a total of 20381 participants who met the inclusion criteria were analyzed. The 5-year overall survival in the HBV-HCC and HCV-HCC groups was lower than in the NBNC-HCC group (HBV-HCC vs. NBNC-HCC, P = 0.005; HCV-HCC vs. NBNC-HCC, P = 0.001). Patients with HBV-HCC and HCV-HCC had worse 5-year recurrence-free survival than patients with NBNC-HCC (HBV-HCC vs. NBNC-HCC, P = 0; HCV-HCC vs. NBNC-HCC, P = 0). In addition, the 5-year recurrence-free rate in the HCV-HCC group was lower than in the HBV-HCC group (P = 0). The observed association between serum alpha-fetoprotein levels and the postoperative prognosis was inconsistent in different subgroups.

Conclusions:

Patients with NBNC-HCC had a signiﬁcantly better postoperative prognosis than those with virus-related HCC. The alpha-fetoprotein levels significantly correlated with the postoperative prognosis of patients with HCC.

Keywords

Alpha-Fetoprotein Hepatitis Hepatocellular Carcinoma Prognosis Survival

1. Context

Liver cancer is one of the most common malignancies and ranks sixth in incidence and third in mortality worldwide (1). Hepatocellular carcinoma (HCC) accounts for 75% - 85% of primary liver cancer cases. The leading causes of HCC include chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, heavy alcohol intake, metabolic syndrome, and aflatoxin-contaminated foodstuff (2-4). Chronic HBV infection and aflatoxin contamination are likely the predominant causes in high-risk HCC areas, such as China and sub-Saharan Africa, whereas the key determinant of HCC is chronic HCV infection in low-risk areas, such as Japan and southern and eastern Europe (1, 5). In recent years, rising obesity prevalence has contributed to the incidence of HCC in low-risk HCC areas (6, 7). Although treatments such as immune checkpoint inhibitors and anti-angiogenic targeted drugs have advanced vigorously in the past decade, the 5-year overall survival (OS) of patients with HCC is still lower than expected.

Hepatic resection is the leading treatment for early-stage HCC, while the high recurrence and metastasis rates after hepatectomy are still perplexing. Compared to postoperative prognosis, the results were controversial among patients with different hepatitis virus statuses in HCC. According to a study by Li et al. (8) on 413 patients, those with HCV-related HCC (HCV-HCC) had a lower 5-year survival rate accompanied by higher intrahepatic and multiple recurrence rates than those with HBV-related HCC (HBV-HCC) and non-HBV non-HCV HCC (NBNC-HCC) patients. However, a retrospective study found no difference in long-term outcomes (15 years) after hepatectomy between patients with NBNC-HCC and hepatitis virus HCC (666 patients) (9). Zhou et al. (10) reported that the 5-year disease-free survival (DFS) of patients with HBV/HCV-related HCC was lower than that of patients with NBNC-HCC. This study indicated a tendency toward the highest 5-year OS in the NBNC-HCC group. However, the differences were not statistically significant. There was no significant difference in the 5-year OS and DFS between the HBV-HCC and HCV-HCC groups (10).

2. Objectives

Meta-analysis is a rigorous and effective statistical tool that makes qualitative and quantitative evaluations of published scientific evidence to integrate the results better. Owing to the lack of recent, large-sample, multicenter research in the previous meta-analyses, this study aimed to compare the postoperative prognosis of HBV-HCC, HCV-HCC, and NBNC-HCC.

3. Methods

3.1. Data Sources

This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (11). Two independent reviewers performed screening and data extraction, and a third reviewer resolved the differences. A number of electronic databases, including PubMed, Embase, Cochrane, Web of Science, and Scopus, were systematically searched to identify all available articles published since April 15, 2022. The keywords or medical subject headings for reference were “hepatocellular carcinoma", “hepatitis B virus", “hepatitis C virus", “survival rate", and “hepatectomy". Only human studies published in English were included.

3.2. Inclusion Criteria

The inclusion criteria for the studies were (1) cohort study design; (2) subjects being patients with HCC who underwent radical resection confirmed by postoperative pathology; (3) study outcomes of 5-year survival data that could be obtained from the article or the survival curve; and (4) all patients being serologically tested for hepatitis virus prior to surgery.

3.3. Exclusion Criteria

The exclusion criteria entailed (1) being published multiple times; (2) lacking full text and the corresponding author’s response not received; (3) incomplete data and where data were extracted effectively; (4) patients undergoing palliative care; and (5) small sample size (sample size < 30) or a large amount of censored data (lost to follow-up rate > 10%).

3.4. Data Extraction and Evidence Evaluation

Data were extracted from the texts, tables, and figures of the selected studies. The following data were extracted from each study: Publication year, first author, the number of patients, population characteristics, preoperative serological indicators, operation-related indicators, preoperative viral status, inclusion and exclusion criteria, 5-year OS, and recurrence-free survival (RFS). When 5-year OS or RFS was not directly provided in the literature, the survival curve was extracted using the Engauge Digitizer software. The methodological quality of all selected studies was evaluated and scored using the Newcastle-Ottawa Scale (NOS), which includes three parts: participant selection, comparability, and outcome (12).

3.5. Statistical Analysis

Stata™ version 12 software was used for data analysis, and Review Manager™ version 5.4 was used for data collection. The dichotomous variables were analyzed using relative risk (RR) with a 95% confidence interval (95% CI), and continuous variables were analyzed utilizing weighted mean difference (WMD) with a 95% CI. P-value < 0.05 was considered statistically significant. Moreover, χ² and I² were used to evaluate heterogeneity in these studies (13). According to the relevant standards in the Cochrane Intervention System Evaluation Manual, the fixed-effect method was used if heterogeneity was acceptable (I² < 50%, P > 0.10). Once heterogeneity was established (I² ≥ 50% and P ≤ 0.10), the subgroup analyses were further conducted to explore between-study sources of heterogeneity. Descriptive analysis was used in cases where inter-group heterogeneity was excessive or difficult to merge. Publication bias was assessed using Begg’s test and Egger’s test, and P > 0.10 was considered no publication bias.

4. Results

4.1. Selection of Studies

The preliminary systematic search identified 733 relevant studies. After further screening, 30 papers met the inclusion criteria (8, 9, 14-41). Among these studies, four were excluded because of insufficient survival information or overlapping study populations (38-41). Finally, 26 articles involving 20381 participants were identified as eligible papers published during 1997 - 2021. Among these articles, 5, 16, 2, 1and 1 were from China, Japan, the United States, France, Italy, and a multicenter study, respectively. The study identification process is provided in Figure 1 details. The characteristics of the selected studies are presented in Table 1.

Figure 1.

Flow diagram of the selection process of the studies included in the systematic review

Table 1.

Characteristics of 26 Studies Included in the Systematic Review and Meta-analysis

Number	Author	Year	Country	Group	Number of Patients	Gender (Male/ Female)	Age (y)	Median Follow-up (Months)	5-year OS (%)	5-year RFS (%)
1	Li (8)	2007	China	HBV-HCC	251	212/39	51.2 ± 4.2	51.2	64.9	62.2
				HCV-HCC	75	62/13	63.2 ± 7.3		38.7	35.8
				NBNC-HCC	54	44/10	67.1 ± 5.7		68.5	67.7
2	Takeishi (9)	2015	Japan	HBV-HCC	94	71/23	55 ± 11	-- ^a	69.1	34.0
				HCV-HCC	451	290/161	68 ± 8	-- ^a	66.9	31.7
				NBNC-HCC	117	88/29	70 ± 10	-- ^a	64.1	34.2
3	Utsunomiya (14)	2015	Japan	HBV-HCC	2194	1796/398	57	19.2	65.0	41.0
				HCV-HCC	7018	5225/1793	67	20.4	59.0	31.0
				NBNC-HCC	2738	2253/485	67	18.0	68.0	47.0
4	Okuda (15)	2014	Japan	HBV-HCC	32	23/9	61.1 ± 13.6	20	49.1	29.2
				HCV-HCC	93	70/23	67.2 ± 6.6		65.0	27.6
				NBNC-HCC	76	67/9	71.0 ± 9.2		74.1	43.8
5	Cescon (16)	2009	Italy	HBV-HCC	25	24/1	60.2 ± 9.8	30	-- ^a	9.0
				HCV-HCC	130	90/40	65.2 ± 8.1		-- ^a	38.0
				NBNC-HCC	35	30/5	64.2 ± 9.1		-- ^a	34.0
6	Chen (17)	1998	Taiwan, China	HBV-HCC	57	40/17	51.6 ± 12.3	12.2	40.3	24.6
6	Chen (17)	1998	Taiwan, China	HCV-HCC	34	22/12	61.9 ± 10.0	12.2	38.2	29.4
7	Chirica (18)	2013	France	HBV-HCC	15	-- ^a	-- ^a	-- ^a	46.7	-- ^a
7	Chirica (18)	2013	France	HCV-HCC	30	-- ^a	-- ^a	-- ^a	38.0	-- ^a
8	Iida (19)	2015	Japan	HBV-HCC	144	-- ^a	60.3 ± 10.8	-- ^a	53.0	-- ^a
				HCV-HCC	550	-- ^a	69.4 ± 7.6	-- ^a	47.4	-- ^a
				NBNC-HCC	164	-- ^a	70.3 ± 7.8	-- ^a	54.0	-- ^a
9	Kaibori (20)	2012	Japan	HBV-HCC	85	68/17	59.3 ± 11.4	-- ^a	53.0	32.0
				HCV-HCC	351	272/79	66.5 ± 7.1	-- ^a	57.0	17.0
				NBNC-HCC	60	52/8	66.6 ± 13.3	-- ^a	62.0	35.0
10	Kao (21)	2011	Taiwan, China	HBV-HCC	609	516/93	56.3 ± 13.5	40.6	52.5	36.1
10	Kao (21)	2011	Taiwan, China	HCV-HCC	206	147/59	67.2 ± 9.1		55.0	35.1
11	Lee (22)	2014	United States	HBV-HCC	181	147/34	56.1	-- ^a	65.0	42.0
11	Lee (22)	2014	United States	HCV-HCC	74	58/16	62.9	-- ^a	58.0	48.6
12	Nagasue (23)	1998	Japan	HBV-HCC	15	12/3	50.6 ± 33.5	-- ^a	84.0	84.6
12	Nagasue (23)	1998	Japan	HCV-HCC	29	26/3	34.2 ± 26.3	-- ^a	26.0	10.7
13	Nanashima (24)	2007	Japan	HBV-HCC	76	61/15	59 ± 11	-- ^a	51.8	14.3
				HCV-HCC	124	99/25	67 ± 7	-- ^a	54.8	20.8
				NBNC-HCC	29	21/8	65 ± 8	-- ^a	53.9	44.0
14	Nishikawa (25)	2013	Japan	HBV-HCC	62	42/20	57.7 ± 12.3	49.2 ± 36.0	63.0	22.0
				HCV-HCC	284	194/90	69.1 ± 7.8	49.2 ± 34.8	53.0	20.0
				NBNC-HCC	129	104/25	68.6 ± 8.8	45.6 ± 34.8	63.0	26.0
15	Pawlik (26)	2004	Multi center	HBV-HCC	163	137/26	60	33	38.0	-- ^a
				HCV-HCC	79	49/30	60		45.6	-- ^a
				NBNC-HCC	126	90/36	51		33.3	-- ^a
16	Roayaie (27)	2000	United States	HBV-HCC	21	10/11	54.3 ± 15.3	-- ^a	52.4	47.6
16	Roayaie (27)	2000	United States	HCV-HCC	24	17/7	63.4 ± 8.5	-- ^a	33.3	8.3
17	Sasaki (28)	2006	Japan	HBV-HCC	66	49/17	-- ^a	-- ^a	69.0	54.0
17	Sasaki (28)	2006	Japan	HCV-HCC	351	268/83	-- ^a	-- ^a	62.0	24.0
18	Tanaka (29)	2006	Japan	HBV-HCC	60	51/9	56	33	44.7	39.7
				HCV-HCC	137	101/36	68		50.2	27.7
				NBNC-HCC	39	30/9	68		61.0	67.5
19	Wakiyama (30)	2017	Japan	HBV-HCC	36	33/3	52 ± 9	-- ^a	54.8	26.8
				HCV-HCC	57	46/11	67 ± 7	-- ^a	64.5	23.4
				NBNC-HCC	41	36/5	63 ± 12	-- ^a	71.4	44.9
20	Wu (31)	1999	Taiwan, China	HBV-HCC	131	110/21	54.3	34.5	57.0	29.0
				HCV-HCC	70	56/14	64.1		65.0	22.0
				NBNC-HCC	40	29/11	68.9		83.0	66.0
21	Yamanaka (32)	1997	Japan	HBV-HCC	27	24/3	51 ± 10	-- ^a	52.0	60.0
				HCV-HCC	151	125/26	63 ± 6.3	-- ^a	42.0	13.0
				NBNC-HCC	20	18/2	63 ± 6.4	-- ^a	64.0	46.0
22	Yamashita (33)	2014	Japan	HBV-HCC	110	83/27	55 ± 11	62.4	65.0	36.0
				HCV-HCC	474	304/170	68 ± 8		68.0	32.0
				NBNC-HCC	110	81/29	66 ± 10		67.0	37.0
23	Yokoi (34)	2005	Japan	HBV-HCC	25	19/6	57	-- ^a	59.1	40.0
				HCV-HCC	116	95/21	64	-- ^a	62.1	21.6
				NBNC-HCC	13	10/3	58	-- ^a	100	69.2
24	Zhang (35)	2015	China	HBV-HCC	409	373/36	-- ^a	-- ^a	35.0	34.5
24	Zhang (35)	2015	China	NBNC-HCC	64	53/11	-- ^a	-- ^a	62.0	51.2
25	Takenaka (36)	1995	Japan	HBV-HCC	30	22/8	57 ± 9.4	-- ^a	61.8	46.2
25	Takenaka (36)	1995	Japan	HCV-HCC	96	77/19	61.7 ± 6.9	-- ^a	52.8	23.2
26	Ohkura (37)	2015	Japan	HBV-HCC	167	144/23	54	-- ^a	81.6	48.6
				HCV-HCC	401	287/144	64	-- ^a	74.7	34.0
				NBNC-HCC	62	46/16	68	-- ^a	75.0	50.4

Abbreviations: HBV-HCC, hepatitis B virus-related hepatocellular carcinoma; HCV-HCC, hepatitis C virus-related hepatocellular carcinoma; NBNC-HCC, non-hepatitis B virus non-hepatitis C virus hepatocellular carcinoma; OS, overall survival; RFS, recurrence-free survival

^a Data could not be extracted.

4.2. Patients Characteristics

4.2.1. General Materials

The results from the overall meta-analysis are outlined in Table 2. The mean age of patients with HBV-HCC was significantly lower than that of patients with HCV-HCC and NBNC-HCC (P < 0.05). The incidence rate of male patients in the HCV-HCC group was lower than in the other two groups (P < 0.05).

Table 2.

Meta-analysis of Characteristics for Hepatocellular Carcinoma Patients with Different Hepatitis Virus Status

Characteristic	Group	Number of Studies	Number of Patients	Results	RR/WMD	95% CI	P-Value	I² (%)
Age (y)	HCV-HCC vs. HBV-HCC	14 (8, 9, 15-17, 19-21, 24, 25, 30, 32, 33, 36)	4714	HBV-HCC = 55.8 ± 11.7 HCV-HCC = 67.3 ± 7.9	10.06	8.62, 11.51	0.000	74.8
	HBV-HCC vs. NBNC-HCC	11 (8, 9, 15, 16, 19, 20, 24, 25, 30, 32, 33)	1777	HBV-HCC = 55.8 ± 10.4 NBNC-HCC = 68.2 ± 9.3	-10.52	-12.83, -8.22	0.000	82.3
	HCV-HCC vs. NBNC-HCC	11 (8, 9, 15, 16, 19, 20, 24, 25, 30, 32, 33)	3575	HCV-HCC = 67.6 ± 7.8 NBNC-HCC = 68.0 ± 9.6	-0.34	-1.65, 0.97	0.612	70.1
Male gender	HCV-HCC vs. HBV-HCC	22 (8, 9, 14-17, 20-28, 30-34, 36, 37)	15839	HBV-HCC = 81.6% HCV-HCC = 73.4%	0.92	0.88, 0.95	0.000	51.4
	HBV-HCC vs. NBNC-HCC	16 (8, 9, 14-16, 20, 24-26, 30-35, 37)	7909	HBV-HCC = 82.6% NBNC-HCC = 81.8%	1.02	0.98, 1.07	0.297	38.6
	HCV-HCC vs. NBNC-HCC	15 (8, 9, 14-16, 20, 24-, 30-34, 37)	14238	HCV-HCC = 73.5% NBNC-HCC = 81.8%	0.90	0.89, 0.92	0.000	0
Serum ALT level (IU/L)	HCV-HCC vs. HBV-HCC	13 (8, 9, 16, 17, 19, 20, 23, 25, 27, 30, 32, 33, 36)	3663	HBV-HCC = 48.6 ± 41.9 HCV-HCC = 60.3 ± 43.6	16.97	12.24, 21.70	0.000	45.1
	HBV-HCC vs. NBNC-HCC	9 (8, 9, 16, 19, 20, 25, 30, 32, 33)	1564	HBV-HCC = 48.1 ± 40.4 NBNC-HCC = 42.5 ± 34.2	4.13	0.74, 7.52	0.017	0
	HCV-HCC vs. NBNC-HCC	9 (8, 9, 16, 19, 20, 25, 30, 32, 33)	3253	HCV-HCC = 58.9 ± 42.4 NBNC-HCC = 42.6 ± 34.0	21.02	13.19, 28.85	0.000	85.4
Serum AST level (IU/L)	HCV-HCC vs. HBV-HCC	10 (9, 16, 17, 19, 23, 25, 30, 32, 33, 36)	2856	HBV-HCC = 48.7 ± 44.5 HCV-HCC = 60.9 ± 39.8	14.19	11.22, 17.17	0.000	29.5
	HBV-HCC vs. NBNC-HCC	7 (9, 16, 19, 25, 30, 32, 33)	1114	HBV-HCC = 46.7 ± 43.0 NBNC-HCC = 42.6 ± 37.5	0.51	-4.75, 5.78	0.848	43.2
	HCV-HCC vs. NBNC-HCC	7 (9, 16, 19, 25, 30, 32, 33)	2713	HCV-HCC = 59.5 ± 38.8 NBNC-HCC = 46.6 ± 37.5	16.63	7.71, 25.55	0.000	87.1
Serum ALB level (g/dL)	HCV-HCC vs. HBV-HCC	12 (8, 9, 16, 19, 20, 23, 25, 27, 30, 32, 33, 36)	3572	HBV-HCC = 4.0 ± 0.5 HCV-HCC = 3.7 ± 0.4	-0.25	-0.34, -0.15	0.000	84.8
	HBV-HCC vs. NBNC-HCC	9 (8, 9, 16, 19, 20, 25, 30, 32, 33)	1564	HBV-HCC = 4.0 ± 0.5 NBNC-HCC = 4.0 ± 0.5	-0.04	-0.09, 0.01	0.156	13.1
	HCV-HCC vs. NBNC-HCC	9 (8, 9, 16, 19, 20, 25, 30, 32, 33)	3253	HCV-HCC = 3.7 ± 0.4 NBNC-HCC = 4.0 ± 0.5	-0.25	-0.36, -0.13	0.000	87.9
ICG R15 (%)	HCV-HCC vs. HBV-HCC	8 (9, 19, 20, 23, 30, 32, 33, 36)	2700	HBV-HCC = 15.0 ± 10.6 HCV-HCC = 19.9 ± 11.5	5.25	4.29, 6.21	0.000	32.0
	HBV-HCC vs. NBNC-HCC	6 (9, 19, 20, 30, 32, 33)	1008	HBV-HCC = 15.2 ± 10.8 NBNC-HCC = 15.4 ± 10.2	-0.26	-1.49, 0.97	0.680	0
	HCV-HCC vs. NBNC-HCC	6 (9, 19, 20, 30, 32, 33)	2546	HCV-HCC = 19.9 ± 11.5 NBNC-HCC = 15.4 ± 10.2	4.56	3.03, 6.10	0.000	52.7
Serum T-Bil level (mg/dL)	HCV-HCC vs. HBV-HCC	12 (8, 9, 16, 17, 19, 20, 23, 25, 27, 30, 33, 36)	3485	HBV-HCC = 0.9 ± 0.6 HCV-HCC = 0.9 ± 0.6	0.03	-0.05, 0.12	0.413	76.3
	HBV-HCC vs. NBNC-HCC	8 (8, 9, 16, 19, 20, 25, 30, 33)	1517	HBV-HCC = 0.9 ± 0.4 NBNC-HCC = 0.8 ± 0.4	0.11	0.004, 0.22	0.042	83.9
	HCV-HCC vs. NBNC-HCC	8 (8, 9, 16, 19, 20, 25, 30, 33)	3082	HCV-HCC = 0.9 ± 0.6 NBNC-HCC = 0.8 ± 0.4	0.11	0.01, 0.21	0.035	87.5
Platelet count (×10³ mm)	HCV-HCC vs. HBV-HCC	12 (8, 9, 16, 17, 19, 20, 23, 25, 27, 30, 33, 36)	3485	HBV-HCC = 174.9 ± 114.2 HCV-HCC = 140.6 ± 200.1	-27.57	-41.27, -13.87	0.000	72.0
	HBV-HCC vs. NBNC-HCC	8 (8, 9, 16, 19, 20, 25, 30, 33)	1517	HBV-HCC = 173.5 ± 116.0 NBNC-HCC = 181.5 ± 122.4	-19.79	-35.07, -4.51	0.011	63.7
	HCV-HCC vs. NBNC-HCC	8 (8, 9, 16, 19, 20, 25, 30, 33)	3082	HCV-HCC = 141.2 ± 206.9 NBNC-HCC = 181.5 ± 122.4	-40.91	-48.65, -33.17	0.000	15.1
Child’s grade A	HCV-HCC vs. HBV-HCC	13 (8, 14, 17, 19-22, 24, 26, 28, 33, 34, 37)	13981	HBV-HCC = 87.7% HCV-HCC = 84.3%	0.96	0.93, 0.99	0.007	62.9
	HBV-HCC vs. NBNC-HCC	9 (8, 14, 20, 24, 26, 33-35, 37)	6736	HBV-HCC = 87.8% NBNC-HCC = 89.9%	0.97	0.91, 1.03	0.307	85.9
	HCV-HCC vs. NBNC-HCC	8 (8, 14, 20, 24, 26, 33, 34, 37)	11830	HCV-HCC = 85.2% NBNC-HCC = 89.8%	0.94	0.93, 0.96	0.000	26.7
Tumor size (cm)	HCV-HCC vs. HBV-HCC	14 (8, 9, 16, 17, 19, 20, 22, 23, 25, 27, 30, 32, 33, 36)	3918	HBV-HCC = 4.4 ± 3.4 HCV-HCC = 3.4 ± 2.2	-0.78	-1.12, -0.44	0.000	72.0
	HBV-HCC vs. NBNC-HCC	9 (8, 9, 16, 19, 20, 25, 30, 32, 33)	1564	HBV-HCC = 3.8 ± 2.9 NBNC-HCC = 4.8 ± 3.6	-0.59	-1.01, -0.17	0.006	65.4
	HCV-HCC vs. NBNC-HCC	9 (8, 9, 16, 19, 20, 25, 30, 32, 33)	3253	HCV-HCC = 3.3 ± 2.1 NBNC-HCC = 4.8 ± 3.6	-1.37	-1.91, -0.83	0.000	87.0
Serum AFP level	HCV-HCC vs. HBV-HCC	10 (9, 16, 19, 20, 24, 25, 27, 30, 33, 36)	3224	HBV-HCC = 8932.6 ± 6456.4 HCV-HCC = 1145.6 ± 7081.8	-2103.05	-4445.86, 239.75	0.079	92.7
	HBV-HCC vs. NBNC-HCC	8 (9, 16, 19, 20, 24, 25, 30, 33)	1317	HBV-HCC = 9122.0 ± 66516.2 NBNC-HCC = 4349.1 ± 36879.9	2051.21	-5.26, 4107.68	0.051	88.7
	HCV-HCC vs. NBNC-HCC	8 (9, 16, 19, 20, 24, 25, 30, 33)	3106	HCV-HCC = 1088.5 ± 6849.7 NBNC-HCC = 4584.5 ± 39144.8	-650.49	-1.50, 221.25	0.144	49.9
Capsule formation	HCV-HCC vs. HBV-HCC	10 (8, 15-17, 23, 25, 31, 32, 34, 36)	2139	HBV-HCC = 52.8% HCV-HCC = 64.5%	1.03	0.92, 1.16	0.587	51.9
	HBV-HCC vs. NBNC-HCC	8 (8, 15, 16, 25, 31, 32, 34, 35)	1566	HBV-HCC = 61.1% NBNC-HCC = 61.4%	1.04	0.89, 1.21	0.616	61.8
	HCV-HCC vs. NBNC-HCC	7 (8, 15, 16, 25, 31, 32, 34)	1699	HCV-HCC = 64.1% NBNC-HCC = 58.6%	1.10	0.99, 1.22	0.074	18.4
Intrahepatic metastases/ satellite nodules	HCV-HCC vs. HBV-HCC	9 (9, 14-16, 24, 28, 31, 36)	1112	HBV-HCC = 22.3% HCV-HCC = 16.7%	0.72	0.56, 0.91	0.007	60.9
	HBV-HCC vs. NBNC-HCC	7 (9, 14-16, 24, 31, 34)	5625	HBV-HCC = 21.8% NBNC-HCC = 27.3%	1.18	0.73, 1.90	0.507	75.6
	HCV-HCC vs. NBNC-HCC	7 (9, 14-16, 24, 31, 34)	11050	HCV-HCC = 16.3% NBNC-HCC = 27.3%	0.71	0.54, 0.95	0.022	43.6
Vascular invasion	HCV-HCC vs. HBV-HCC	10 (8, 17, 21-24, 26-28, 32)	2613	HBV-HCC = 22.9% HCV-HCC = 21.2%	0.79	0.53, 1.17	0.242	78.6
	HBV-HCC vs. NBNC-HCC	4 (8, 24, 26, 32)	746	HBV-HCC = 15.7% NBNC-HCC = 9.2%	1.62	0.93, 2.83	0.090	17.4
	HCV-HCC vs. NBNC-HCC	4 (8, 24, 26, 32)	658	HCV-HCC = 12.1% NBNC-HCC = 9.2%	1.12	0.43, 2.89	0.813	60.0
Coexisting cirrhosis	HCV-HCC vs. HBV-HCC	19 (8, 9, 14, 15, 17, 20-22, 24-26, 28, 29, 31-34, 36, 37)	14984	HBV-HCC = 48.6% HCV-HCC = 50.0%	1.09	1.01, 1.08	0.029	63.6
	HBV-HCC vs. NBNC-HCC	14 (8, 9, 14, 15, 20, 24-26, 29, 31-34, 37)	7071	HBV-HCC = 49.6% NBNC-HCC = 27.9%	1.57	1.34, 1.84	0.000	67.7
	HCV-HCC vs. NBNC-HCC	14 (8, 9, 14, 15, 20, 24-26, 29, 31-34, 37)	13425	HCV-HCC = 49.4% NBNC-HCC = 27.9%	1.67	1.50, 1.87	0.000	45.2

Abbreviations: RR, risk ratio; WMD, weighted mean difference; CI, confidence interval; HBV-HCC, hepatitis B virus-related hepatocellular carcinoma; HCV-HCC, hepatitis C virus-related hepatocellular carcinoma; NBNC-HCC, non-HBV non-HCV hepatocellular carcinoma; AFP, alpha-fetoprotein; ALB, serum albumin; ICG R15, indocyanine green retention rate at 15 min

4.2.2. Liver Function

The preoperative serum alanine aminotransferase, aspartate aminotransferase levels, and indocyanine green retention rate at 15 min (ICG R15) were higher in the HCV-HCC group than in the HBV-HCC and NBNC-HCC groups (P < 0.05). The NBNC-HCC group had a lower serum total bilirubin level and a higher platelet count than the other two groups (P < 0.05). The preoperative serum albumin (ALB) level and proportion of Child-Pugh grade A in the HBV-HCC and NBNC-HCC groups were higher than in the HCV-HCC group (P < 0.05).

4.2.3. Tumor Characteristics

The mean tumor size in the NBNC-HCC group was the largest among the three groups (P < 0.05). The incidence of intrahepatic metastases/satellite nodules was lower in the HCV-HCC group than in the other two groups (P < 0.05). The proportion of patients with cirrhosis in the HCV-HCC, HBV-HCC, and NBNC-HCC groups gradually increased (P < 0.05).

4.3. Survival

4.3.1. Five-Year Overall Survival

A total of 25 studies reported 5-year OS, including 24 with HCV-HCC and HBV-HCC, 17 with HBV-HCC and NBNC-HCC, and 16 with HCV-HCC and NBNC-HCC. The results showed that 5-year OS was not significantly different between the HCV-HCC and HBV-HCC groups (HR: 1.06, 95% CI: 0.99 - 1.12, P = 0.076). The 5-year OS rates were lower in the HBV-HCC (HR: 1.14, 95% CI: 1.04 - 1.24, P = 0.005) and HCV-HCC groups (HR: 1.14, 95% CI: 1.06 - 1.23, P = 0.001) than in the NBNC-HCC group. The above results showed high heterogeneity (HCV-HCC vs. HBV-HCC, I²: 48.7%, P = 0.004; HBV-HCC vs. NBNC-HCC, I²: 66.5%, P = 0; HCV-HCC vs. NBNC-HCC, I²: 63.7%, P = 0; Figure 2A, C, and E).

Figure 2.

Results of the meta-analysis on 5-year OS and 5-year RFS. A, HCV-HCC vs. HBV-HCC 5-year OS; B, HCV-HCC vs. HBVHCC 5-year RFS; C, HBV-HCC vs. NBNC-HCC 5-year OS; D, HBVHCC vs. NBNC-HCC 5-year RFS; E, HCV-HCC vs. NBNC-HCC 5- year OS; F, HCV-HCC vs. NBNC-HCC 5-year RFS

4.3.2. Five-Year Recurrence-Free Survival

A total of 23 studies reported 5-year RFS, including 22 with HCV-HCC and HBV-HCC, 16 with HBV-HCC and NBNC-HCC, and 15 with HCV-HCC and NBNC-HCC. There were significant differences in 5-year RFS between patients with different hepatitis virus statuses. Compared to cases with NBNC-HCC, patients with HBV-HCC or HCV-HCC had lower 5-year RFS (HBV-HCC vs. NBNC-HCC, HR: 1.33, 95% CI: 1.16 - 1.52, P = 0; HCV-HCC vs. NBNC-HCC, HR: 1.71, 95% CI: 1.46 - 2, P = 0, respectively). In addition, the 5-year RFS in the HCV-HCC group was lower than in the HBV-HCC group (HR: 1.38, 95% CI: 1.19 - 1.59, P = 0). All the above results showed high heterogeneity (HCV-HCC vs. HBV-HCC, I²: 73.1%, P = 0; HBV-HCC vs. NBNC-HCC, I²: 58.7%, P = 0.002; HCV-HCC vs. NBNC-HCC, I²: 72.1%, P = 0; Figure 2B, D, and F).

4.4. Sensitivity Analysis

The random deletion of the literature in this study had little impact on the results, which means that our results were reasonably robust (Appendix 1).

4.5. Subgroup Analysis According to Hepatitis Virus Status

According to the extracted data and basic information from all selected studies, a subgroup analysis was performed based on the mean tumor size (diameter ≥ 5 cm and diameter < 5 cm), serum alpha-fetoprotein (AFP) level (AFP ≥ 1000 ng/mL and AFP < 1000 ng/mL), serum ALB level (ALB ≥ 4 g/dL and ALB < 4 g/dL), and country. Detailed results are provided in Tables 3 - 5. The observed association between serum AFP levels and the postoperative prognosis was inconsistent among the different subgroups. In the AFP ≥ 1000 ng/mL subgroup, the HCV-HCC group had a lower 5-year OS than the HBV-HCC group (HR: 1.10, 95% CI: 1.06 - 1.14, P = 0). Meanwhile, the 5-year OS rate was lower in the HBV-HCC and HCV-HCC groups than in the NBNC-HCC group (HBV-HCC vs. NBNC-HCC, HR: 1.04, 95% CI: 1.01 - 1.08, P = 0.024; HCV-HCC vs. NBNC-HCC, HR: 1.10, 95% CI: 1.03 - 1.17, P = 0.007). Similarly, virus-related patients had a worse 5-year RFS than patients with NBNC-HCC (HBV-HCC vs. NBNC-HCC, HR: 1.14, 95% CI: 1.07 - 1.21, P = 0; HCV-HCC vs. NBNC-HCC, HR: 1.40, 95% CI: 1.18 - 1.67, P = 0). The mentioned results had low heterogeneity (5-year OS: HCV-HCC vs. HBV-HCC, I²: 0.0%, P = 0.557; HBV-HCC vs. NBNC-HCC, I²: 0.0%, P = 0.747; HCV-HCC vs. NBNC-HCC, I²: 38.0%, P = 0.140; 5-year RFS: HBV-HCC vs. NBNC-HCC, I²:0.0%, P = 0.865; HCV-HCC vs. NBNC-HCC, I²: 58%, P = 0.547). However, the heterogeneity of each group was high in the AFP < 1000 ng/mL subgroup (5-year OS: HCV-HCC vs. HBV-HCC, I²: 67.5%, P = 0.009; HBV-HCC vs. NBNC-HCC, I²: 60.8%, P = 0.037; HCV-HCC vs. NBNC-HCC, I²: 82.0%, P = 0; 5-year RFS: HCV-HCC vs. HBV-HCC, I²: 69.7%, P = 0.006; HBV-HCC vs. NBNC-HCC, I²:55.8%, P = 0.060; HCV-HCC vs. NBNC-HCC, I²: 75.5%, P = 0.003). In addition, the heterogeneity of the mean tumor size, serum ALB level, and country subgroups did not significantly change compared to before grouping. Therefore, these factors were considered to have little correlation with heterogeneity. In summary, AFP had a certain impact on the prognosis of patients with HCC and might be one of the sources of heterogeneity. For those with differences between groups, the results of the two-way comparison were P > 0.05, indicating that they were balanced and comparable. Similarly, no statistically significant differences were observed between subgroups.

Table 3.

Subgroup Analysis of Hepatitis C Virus-Related Hepatocellular Carcinoma and Hepatitis B Virus-Related Hepatocellular Carcinoma

Characteristics and Subgroups	5-Year OS (HCV-HCC vs. HBV-HCC)					5-Year RFS (HCV-HCC vs. HBV-HCC)
	HR [95% CI]	P ^a	P	Heterogeneity		HR [95% CI]	P ^a	P	Heterogeneity
	HR [95% CI]	P ^a	P	I² (%)	P	HR [95% CI]	P ^a	P	I² (%)	P
Tumor size (cm)		0.53					0.75
≥ 5	0.99 [0.74, 1.33]		0.969	28.8	0.246	1.50 [0.68, 3.32]		0.313	66.9	0.049
< 5	1.10 [1.00, 1.20]		0.054	65.3	0.001	1.32 [1.09, 1.58]		0.003	68.6	0.000
AFP (ng/mL)		0.33					0.77
≥ 1000	1.10 [1.06, 1.14]		0.000	0.0	0.557	1.31 [0.96, 1.75]		0.069	50.8	0.071
< 1000	0.99 [0.81, 1.22]		0.939	67.5	0.009	1.23 [0.87, 1.72]		0.239	69.7	0.006
ALB (g/dL)		-- ^b					-- ^b
≥ 4	-- ^b		-- ^b	-- ^b	-- ^b	-- ^b		-- ^b	-- ^b	-- ^b
< 4	1.04 [0.94, 1.16]		0.457	15.6	0.314	1.39 [0.86, 2.26]		0.182	79.5	0.000
Country		0.73					0.56
Japan	1.06 [1.00, 1.13]		0.065	42.5	0.037	1.49 [1.26, 1.76]		0.000	70.7	0.000
China	1.09 [0.82, 1.44]		0.555	78.3	0.003	1.23 [0.90, 1.70]		0.196	63.4	0.042
United States	1.16 [0.94, 1.43]		0.175	0.0	0.363	1.97 [0.29, 13.23]		0.486	86.1	0.007

Abbreviations: OS, overall survival; RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval; AFP, alpha-fetoprotein; ALB, albumin; HCV-HCC, hepatitis C virus-related hepatocellular carcinoma; HBV-HCC, hepatitis B virus-related hepatocellular carcinoma

^a Between-group statistically significant

^b Data could not be extracted.

Table 4.

Subgroup Analysis of Hepatitis B Virus-Related Hepatocellular Carcinoma and Non-hepatitis B Virus Non-hepatitis C Virus Hepatocellular Carcinoma

Characteristics and Subgroups	5-Year OS (HBV-HCC vs. NBNC-HCC)					5-Year RFS (HBV-HCC vs. NBNC-HCC)
	HR [95% CI]	P ^a	P	Heterogeneity		HR [95% CI]	P ^a	P	Heterogeneity
	HR [95% CI]	P ^a	P	I² (%)	P	HR [95% CI]	P ^a	P	I² (%)	P
Tumor size (cm)		0.13					0.10
≥ 5	1.20 [0.98, 1.46]		0.083	50.7	0.087	1.54 [1.07, 2.22]		0.019	59.9	0.058
< 5	1.01 [0.91, 1.11]		0.900	0.0	0.800	1.09 [0.89, 1.34]		0.415	25.3	0.260
AFP (ng/mL)		0.18					0.11
≥ 1000	1.04 [1.01, 1.08]		0.024	0.0	0.747	1.14 [1.07, 1.21]		0.000	0.0	0.865
< 1000	1.22 [0.97, 1.53]		0.086	60.8	0.037	1.52 [1.08, 2.13]		0.016	55.8	0.060
ALB (g/dL)		0.09					0.43
≥ 4	1.04 [1.01,1.08]		0.024	0.0	0.979	1.14 [1.07, 1.21]		0.000	0.0	0.920
< 4	1.25 [1.02, 1.53]		0.031	0.0	0.583	1.33 [0.91, 1.95]		0.142	24.3	0.266
Country		0.09					0.32
Japan	1.07 [0.99, 1.15]		0.086	32.8	0.120	1.23 [1.07, 1.41]		0.003	34.0	0.120
China	1.39 [1.03, 1.87]		0.030	82.9	0.003	1.51 [1.02, 2.24]		0.038	84.0	0.002

Abbreviations: OS, overall survival; RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval; AFP, alpha-fetoprotein; ALB, albumin; HBV-HCC, hepatitis B virus-related hepatocellular carcinoma; NBNC-HCC, non -hepatitis B virus non-hepatitis C virus hepatocellular carcinoma

^a Between-group statistically significant

Table 5.

Subgroup Analysis of Hepatitis C Virus-Related Hepatocellular Carcinoma and Non-hepatitis B Virus Non-hepatitis C Virus Hepatocellular Carcinoma

Characteristics and Subgroups	5-Year OS (HCV-HCC vs. NBNC-HCC)					5-Year RFS (HCV-HCC vs. NBNC-HCC)
	HR [95% CI]	P ^a	P	Heterogeneity		HR [95% CI]	P ^a	P	Heterogeneity
	HR [95% CI]	P ^a	P	I² (%)	P	HR [95% CI]	P ^a	P	I² (%)	P
Tumor size (cm)		-- ^b					-- ^b
≥ 5	-- ^b		-- ^b	-- ^b	-- ^b	-- ^b		-- ^b	-- ^b	-- ^b
< 5	1.12 [0.96, 1.30]		0.139	69.4	0.011	1.28 [1.01, 1.62]		0.044	55.8	0.060
AFP (ng/mL)		0.39					0.70
≥ 1000	1.10 [1.03,1.17]		0.007	38.0	0.140	1.40 [1.18, 1.67]		0.000	58.0	0.547
< 1000	1.24 [0.94, 1.63]		0.121	82.0	0.000	1.84 [1.26, 2.69]		0.002	75.5	0.003
ALB (g/dL)		-- ^b					-- ^b
≥ 4	-- ^b		-- ^b	-- ^b	-- ^b	-- ^b		-- ^b	-- ^b	-- ^b
< 4	1.25 [1.05, 1.50]		0.014	66.6	0.018	1.98 [1.33, 2.96]		0.001	74.0	0.002
Country		0.17					0.20
Japan	1.13 [1.05, 1.21]		0.001	56.6	0.006	1.69 [1.43, 2.00]		0.000	71.0	0.000
China	1.46 [1.02, 2.08]		0.037	68.3	0.076	2.32 [1.47, 3.65]		0.000	55.4	0.134

Abbreviations: OS: overall survival, RFS: recurrence-free survival, HR: hazard ratio, CI: confidence interval, AFP: alpha-fetoprotein, ALB: albumin

^a Between-group statistically significant

^b Data could not be extracted.

4.6. Publication Bias

According to the results of Begg’s test and Egger’s test, the 5-year OS of the HBV-HCC vs. NBNC-HCC group, 5-year RFS of the HBV-HCC vs. NBNC-HCC group, and 5-year RFS of the HCV-HCC vs. NBNC-HCC group were accompanied by significant publication bias, whereas little publication bias was detected for the other groups (Table 6). To remove the influence of publication bias on the combined results, the trim-and-fill analysis was used to handle this bias. Finally, the trim-and-fill method adjusted results were consistent with the original analysis, showing that the combined effect was trustworthy (Appendix 2).

Table 6.

Symmetry Test of the Funnel Plot

Survival	Group	Begg’s Test	Egger’s Test
Five-year overall survival	HCV-HCC vs. HBV-HCC	0.309	0.699
	HBV-HCC vs. NBNC-HCC	0.044	0.132
	HCV-HCC vs. NBNC-HCC	0.499	0.934
Five-year recurrence-free survival	HCV-HCC vs. HBV-HCC	0.735	0.614
	HBV-HCC vs. NBNC-HCC	0.034	0.035
	HCV-HCC vs. NBNC-HCC	0.048	0.201

Abbreviations: HBV-HCC: hepatitis B virus-related hepatocellular carcinoma, HCV-HCC: hepatitis C virus-related hepatocellular carcinoma, NBNC-HCC: non-hepatitis B virus non-hepatitis C virus hepatocellular carcinoma.

5. Discussion

Hepatitis B virus and HCV are both hepatotropic viral infections with significantly different molecular carcinogenic mechanisms. The carcinogenic potential of HBV is due to its ability to integrate into the DNA of host cells, directly activate adjacent cellular genes, and provide selective growth advantages for hepatocytes (42). In contrast, HCV is a positive-strand RNA virus that cannot integrate into the genome of liver cells. Therefore, it likely promotes hepatocarcinogenesis through chronic inflammation, liver regeneration, and fibrosis rather than direct carcinogenesis (43). In addition, the carcinogenic mechanism of NBNC-HCC is significantly different from that of virus-related HCC. The exact molecular mechanism for the increase in the NBNC-HCC incidence rate is still indistinct, possibly caused partly by the changing prevalence of non-alcoholic steatohepatitis and metabolic syndrome (1). The difference in the etiology and pathogenesis of HCC might lead to unique clinicopathological characteristics and prognosis in patients with HCC. The present study examined the differences in the postoperative prognosis of HCC with distinct viral statuses and found that the prognosis of patients with NBNC-HCC was superior to patients with HBV-HCC and HCV-HCC in terms of OS and RFS. Meanwhile, patients with HBV-HCC had a more prolonged RFS than patients with HCV-HCC. Furthermore, our research found that HBV-HCC, HCV-HCC, and NBNC-HCC differed significantly in terms of clinical features, liver function, and tumor characteristics.

Previous studies compared the prognostic differences between virus-related HCC and NBNC-HCC with inconsistent results (10, 14, 44). A retrospective single-center study reported that viral hepatitis did not significantly affect long-term prognosis after surgical treatment in patients with HCC (44). A meta-analysis of 4744 cases showed that patients with NBNC-HCC had better 5-year DFS and a tendency toward higher 5-year OS (not statistically significant) than HCC patients with HBV or HCV infection. However, there was no difference in survival between the HBV-HCC and HCV-HCC groups (10). Another large-sample study on 11950 cases revealed that the NBNC-HCC group had a significantly lower risk of recurrence than the HBV-HCC and HCV-HCC groups (14). Similarly, our data from 20381 patients confirmed that patients with NBNC-HCC had better 5-year OS and RFS than those with HBV-HCC or HCV-HCC. Cancer-promoting factors in the inflammatory microenvironment of hepatitis result in gene mutation and chromosomal instability in hepatocytes, leading to intrahepatic recurrence, which is the main cause of death in patients with HCC postoperatively (45, 46). Therefore, we believe that the improved survival rate of NBNC-HCC is because of the absence of a chronic viral attack, and patients with NBNC-HCC maintained good liver function following the initial hepatectomy. These biological advantages provide more opportunities for antitumor treatment (34). Furthermore, we found that the 5-year RFS rate of patients with HCV-HCC was lower than patients with HBV-HCC. Franssen et al. (47) found that the postoperative recurrence rate of HBV-HCC was lower than that of HCV-HCC. Previous studies demonstrated that HCC with different viral etiologies has unique molecular signatures and immune landscapes. Compared to HBV-HCC, HCV-HCC leads to the downregulation of T-cell-related genes within the tumor and the upregulation of oxidative stress genes outside the tumor, and the persistent necrotic inflammatory environment might cause recurrence (48). Consequently, effective therapy could prevent postoperative recurrence and improve the OS of patients with virus-related HCC through viral inhibition and anti-inflammatory effects (49). A large prospective study published in 2021 indicated that direct-acting antiviral (DAA) medication enhanced the survival of patients with HCV-HCC after liver transplantation and was comparable to patients with HBV-HCC (50).

Our analysis indicated that the mean age of patients in the HBV-HCC group was the lowest compared to those in the HCV-HCC and NBNC-HCC groups because chronic HBV infections usually result from the maternal vertical transmission, whereas HCV is mainly caused by blood transmission, such as drug abuse and transfusion, mainly in adulthood. Similarly, NBNC-HCC mainly occurs with long-term excessive drinking and metabolic syndrome for decades. The latter finding was consistent with a previous study that the age of onset in patients with HBV-HCC was lower than in patients with HCV-HCC and NBNC-HCC (10). It is well known that the HCC incidence and mortality rates in men are significantly higher than in women worldwide (1). Our data showed that the proportion of male patients was lower in the HCV-HCC group than in the other two groups. Previous investigations have also reported that the proportion of male patients was smaller for the HCV-HCC than for the HBV-HCC or NBNC-HCC groups (51, 52). Gender significantly contributes to the shape of immune responses and initiates differences in the pathogenesis of infectious diseases (53). Androgens directly interact with the HBV genome integrated into the cell nucleus and activate the transcription of HBV oncoproteins (54). These findings may partially explain the male gender preference for HBV-related HCC.

The finding that the HCV-HCC group had the lowest liver reserve function and the highest ratio of cirrhosis among the three groups was similar to the conclusions of previous studies (10, 14). The complex interaction between HCV and host proteins can cause host responses, increase inflammation and fibrosis, and finally lead to liver cirrhosis (55).

Consistent with the results of Watabe et al. (56), the tumor diameter in the NBNC-HCC group was significantly larger than in the hepatitis virus-related HCC group, which may be attributed to the lack of a regular review of liver diseases in patients with NBNC-HCC. Tumors in patients with NBNC-HCC might be detected only when the tumors are enlarged and cause subjective symptoms. The proportions of vascular invasion and tumor capsule formation were not significantly different between the three etiology-related HCC cases, which is also in line with previous meta-analyses (10). In addition, a published meta-analysis showed that the incidence of intrahepatic metastasis and satellite nodules was similar in the three etiology-related HCC, while we found the incidence of intrahepatic metastasis and satellite nodules in the HCV-HCC group was lower than in the HBV-HCC and NBNC-HCC groups. The high incidence of intrahepatic metastasis in the HBV-HCC group is probably related to the biological behavior of HBV. The expression of HBx in HBV-related hepatocytes can activate the Wnt/β-catenin signaling pathway and further promote the development and progression of HCC (57).

We found that heterogeneity among the groups significantly changed when AFP was used as the grouping basis after subgroup analysis for tumor diameter, AFP, ALB, and country, suggesting that AFP had a certain impact on the prognosis of patients. The same result that AFP level affects the prognosis of patients with HCC was also reported by Al-Ameri et al. (58). Many factors, including surgical margin, vascular invasion, capsule integrity, transarterial chemoembolization, antiviral treatment, and targeted therapy, might initiate heterogeneity, making the survival analysis for patients with the HCC of various etiologies challenging to calculate.

This study had some limitations. First, because of the important heterogeneities between the investigations, we adopted the random-effects model to eliminate the effect of heterogeneity partially. Second, all our analyzed data came from retrospective studies with inherent limitations and inevitable selection bias. Third, since HCC studies without the evaluation of survival were excluded, there might be a certain degree of bias in the results of HCC characteristics. However, the large sample size of this review (26 studies on 20381 participants) is reasonable and feasible to represent the clinical characteristics of the HCC patients of diverse etiologies to a large extent. Fourth, most studies included here were Asian (5 from China and 16 from Japan) owing to the highest incidence rates in China and other parts of East Asia. As a result, the data may not be extrapolated to the non-Asian population. Fifth, the influence of confounding factors from three small studies (40 - 50 patients) cannot be excluded. Finally, this review was not registered, but this meta-analysis was carried out strictly with the PRISMA statement. Based on the above limitations, multicenter, high-quality, and large-sample-size studies must be discussed further.

This study indicated that patients with NBNC-HCC had a signiﬁcantly better postoperative prognosis than patients with virus-related HCC. Although the 5-year RFS rate of HBV-HCC was higher than HCV-HCC, the difference was relatively small. Moreover, the AFP levels correlated with the postoperative prognosis of patients with HCC. In addition to the tumor stage or hepatic reserve function, our findings suggest that treatment screening for HCC should also be based on hepatitis viral infection status. Antiviral therapy may be a cost-effective and efficient strategy to improve the prognosis of patients with virus-related HCC.

Footnotes

Authors' Contribution: Y. Z.: Study concept and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript; Y. J.: Acquisition of data and analysis and interpretation of data; S. Q.: Analysis and interpretation of data, administrative, technical, and material support; C. W.: statistical analysis; J. W.: Statistical analysis; J. L.: Critical revision of the manuscript for important intellectual content and study supervision; R. Z.: Critical revision of the manuscript for important intellectual content and study supervision; Z. G.: Study concept and design, critical revision of the manuscript for important intellectual content and study supervision.
Conflict of Interests: The authors declare that the research was conducted without any commercial or financial relationships construed as a potential conflict of interest.
Data Reproducibility: No new data were created or analyzed in this study. Data sharing does not apply to this article.
Funding/Support: This work was supported by the S&T Program of Hebei Province of China (grant numbers 20377726D).

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