Cancer-associated fibroblasts, clinicopathological characteristics and prognosis of liver cancer: A systematic review and meta-analysis based on real-world research

Table 1 Summary of included studies in meta-analysis

Ref.	Country	Study type	Total (Male:Female:Unknown)	Follow-up (months)	NOS score	Sample	Cut-off value	Detecting methods	Index (ECM target)	Number (High:Low) (n)	Tumor size (cm) (> 5)	High AFP (> 200)	Venous infiltration	TNM stage (advanced)	Differentiation	Prognosis	Analysis type
Fang et al[25], 2018	China	Retrospective cohort	90:11	41	7	HCC tissue	The mean value of thickness of the stroma > 238.6 μm	IHC staining	α-SMA	52:48	41:33	29:18	23:24	25:28	NA	NA	NA
Eguchi et al[24], 2023	Japan	Retrospective cohort	49:22	NA	7	iCCA resected specimens	no	IHC staining	α-SMA	22:49	NA	NA	17:27	15:27	NA	OS	Multivariate
Cioca et al[23], 2017	Romania	Cross-sectional study	50:22	NA	6	HCC tissue	no	IHC staining	Podoplanin	23:49	9:17	NA	6:19	5:21	NA	NA	NA
Lan et al[26], 2022	Japan	Retrospective cohort	88:77	34.8	7	iCCA	Positive (> 0)	IHC staining	CAV1	78:80	NA	NA	NA	NA	28:23	OS	Multivariate
Zhang et al[30], 2017	China	Retrospective cohort	33:38	1.3-63.2	7	iCCA	IHC staining score ≥ 2	IHC staining	α-SMA	45:26	27:12	NA	4:1	23:12	20:5	OS	Multivariate
							IHC staining score ≥ 2	IHC staining	FSP-1	60:11	33:7	NA	5:0	32:3	24:1	OS	Univariate
							IHC staining score ≥ 2	IHC staining	PDGFRβ	56:15	29:10	NA	4:1	29:6	19:6	OS	Univariate
Amer et al[22], 2022	Egypt	Retrospective cohort	47:13	NA	6	HCC tissue	NA	IHC staining	Podoplanin	41:19	37:15	NA	3:8	NA	NA	NA	NA
Guan et al[31], 2018	China	Retrospective cohort	105	NA	5	HCC tissue	30% positive staining	IHC staining	Cav-1	NA	NA	NA	NA	NA	NA	OS	Univariate
Peng et al[27], 2022	China	Retrospective cohort	253:121	NA	6	HCC tissues and normal tissues	According to the median expression value of RAB42	IHC staining	RAB42	186:187	NA	66:51	NA	121:139	NA	OS	Univariate
Peng et al[28], 2022	China	Retrospective cohort	253:122	NA	6	HCC tissues and normal liver tissues	According to the median expression value of RAB6B	IHC staining	RAB6B	186:187	NA	59:58	NA	125:135	NA	OS	Univariate
Wang et al[29], 2016	China	Retrospective cohort	124	60	5	HCC tissues	NA	IHC staining	α-SMA	NA	NA	NA	NA	NA	NA	OS	Multivariate

NOS: Newcastle-Ottawa Scale; ECM: Extracellular matrix; AFP: Alpha-fetoprotein; TNM: Tumor-node-metastasis; HCC: Hepatocellular carcinoma; IHC: Immunohistochemistry; α-SMA: Α-smooth muscle actin; NA: Not available; iCCA: Intrahepatic cholangiocarcinoma; OS: Overall survival; CAV1: Caveolin 1; FSP-1: Fibroblast specific protein 1; PDGFRβ: Platelet-derived growth factor receptor; RAB42: Ras-related protein rab-42; RAB6B: Ras-related protein Rab-6B.

Table 2 All pooled results in meta-analysis

Marker	Outcome	Cancer type	Number of cohorts	Pooled effect size		heterogeneity		Publication bias with Egger’s test (P value)
				OR/HR (95%CI)	P value	P value	I2 (%)
All markers	Tumor size (cm) (> 5)	LC	6	1.27 (0.81-1.99)	0.3	0.503	< 0.01%	0.832
		HCC	3	1.60 (0.86-2.96)	0.138	0.734	< 0.01%	0.506
		iCCA	3	0.98 (0.51-1.89)	0.949	0.275	22.50%	0.284
	High AFP (> 200)	HCC	3	1.32 (0.99-1.76)	0.061	0.257	26.50%	0.383
	Venous infiltration	LC	6	1.06 (0.63-1.77)	0.84	0.376	6.30%	0.416
		HCC	2	0.70 (0.37-1.33)	0.28	0.608	< 0.01%	NA
		iCCA	4	2.31 (0.95-5.61)	0.065	0.911	< 0.01%	0.355
	TNM stage (advanced)	LC	8	0.81 (0.63-1.05)	0.109	0.162	33.40%	0.061
		HCC	4	0.68 (0.51-0.90)	0.007	0.662	< 0.01%	0.278
		iCCA	4	1.66 (0.95-2.90)	0.077	0.776	< 0.01%	0.052
	Low differentiation	iCCA	4	1.62 (0.98-2.67)	0.061	0.169	40.50%	0.244
	OS	LC	9	1.62 (1.34-1.97)	< 0.001	0.03	52.90%	0.256
		HCC	5	1.67 (1.34-2.07)	< 0.001	0.022	65.10%	0.649
		iCCA	4	1.47 (0.97-2.23)	0.07	0.153	43.10%	0.402
SMA	Venous infiltration	LC	3	1.25 (0.67-2.34)	0.479	0.176	42.50%	0.544
		HCC	1	0.79 (0.36-1.74)	0.564	NA	NA	NA
		iCCA	2	2.70 (0.97-7.49)	0.057	0.921	< 0.01%	NA
	TNM stage (advanced)	LC	3	1.01 (0.60-1.72)	0.96	0.321	12.00%	0.098
		HCC	1	0.66 (0.30-1.46)	0.305	NA	NA	NA
		iCCA	2	1.44 (0.70-2.93)	0.321	0.624	< 0.01%	NA
	OS	LC	3	2.13 (1.30-3.51)	0.003	0.969	< 0.01%	0.652
		HCC	1	2.29 (1.01-5.22)	0.048	NA	NA	NA
		iCCA	2	2.04 (1.09-3.81)	0.025	0.902	< 0.01%	NA

LC: Liver cancer; HCC: Hepatocellular carcinoma; iCCA: Intrahepatic cholangiocarcinoma; AFP: Alpha-fetoprotein; TNM: Tumor-node-metastasis; OS: Overall survival; OR: Odds ratio; HR: Hazard ratio; CI: Confidence interval; NA: Not available.