Magnetic resonance imaging-based rim enhancement could effectually predict poor prognosis in hepatocellular carcinoma: a meta-analysis

Abstract

Recent studies have initially shown that MRI-based rim enhancement associates with poor prognosis in hepatocellular carcinoma (HCC) patients, but their sample sizes are small, leading to a necessary of comprehensive analyses to make a relatively solid statement. Thus, this meta-analysis aimed to summarize the correlation between MRI-based rim enhancement and prognosis in HCC patients. Until March 2023, a literature search was conducted on Web of Science, PubMed, EMBASE, Cochrane, CNKI, Wangfang, and CQVIP databases in order to identify studies that report the correlation between MRI-based rim enhancement and the prognosis of HCC patients. MRI-based rim enhancement and prognostic data were extracted and analyzed. In our study, eight studies containing 1816 HCC patients were analyzed. Generally, the presence of MRI-based rim enhancement was related to shortened disease-free survival (DFS) [hazard ratio (HR): 2.77, 95% confidence interval (CI): 2.11–3.62, P < 0.001], and worse overall survival (OS) (HR: 5.43, 95% CI: 2.14–13.79, P < 0.001). While no other prognostic data could be retrieved. Funnel plots, Begg’s test, and Egger’s test all indicated that no publication bias existed; and the risk score by Newcastle-Ottawa Scale criteria ranged from 7–9 points, suggesting a generally low risk of bias. Meanwhile, the sensitivity analysis showed that the significant findings did not change by omitting each study. Then, subgroup analyses revealed that no matter stratified by tumor size, treatment option, or sample size, rim enhancement was linked with unsatisfied DFS (all P < 0.05). Conclusively, MRI-based rim enhancement could effectually estimate poor survival in HCC patients, indicating its good prognostic value.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers and causes the fourth-highest cancer mortality worldwide [1]. In China, it has been estimated that there were approximately 395 000 new cases of HCC in 2020, accounting for 24% of newly diagnosed HCC cases worldwide [2]. Currently, surgical resection and radiofrequency ablation (RFA) are viewed as radical treatments for early-stage HCC patients [3–5]. Nevertheless, the outcome of HCC patients is still unfavorable, with a 5-year recurrence rate ranging from 60 to 70% [6–8]. Considering that HCC is a major public health concern, prognosis prediction is crucial to promote the management of HCC patients.

MRI, a preoperative imaging examination, plays a crucial role in the diagnosis, staging, treatment planning, and prognostic evaluation of HCC patients [9,10]. Several studies have reported that MRI-based rim enhancement plays a predictive role in prognosis among HCC patients [9,11–17]. For instance, MRI-based rim enhancement is independently related to recurrence in HCC patients undergoing RFA as first-line treatment [17]. Furthermore, another study also showed that the presence of MRI-based rim enhancement is related to an elevated rate of extrahepatic metastasis and unfavorable overall survival (OS) among HCC patients [15]. However, the application of MRI-based rim enhancement as an indicator for the prognosis of HCC is a relatively novel concept, and the sample size of related studies is relatively small, which means that it is hard to acquire a confident conclusion by each single study. Therefore, a meta-analysis is required to promote its application in clinical practice. Nevertheless, no previous meta-analysis has been conducted to explore the prognostic value of MRI-based rim enhancement in HCC.

Thus, to provide more persuasive evidence, this meta-analysis was conducted to compare the survival between HCC patients with and without MRI-based rim enhancement, aiming to further improve the management of HCC patients.

Methods

Study search

A computerized search of the Web of Science, PubMed, EMBASE, Cochrane, CQVIP, Wangfang, and CNKI databases was conducted to screen studies concerning the correlation of rim-enhanced phenomenon in MRI with the prognosis of HCC. The search included studies published up to March 2023. The search terms ‘hepatocellular carcinoma’, ‘hepatocellular cancer’, ‘HCC’, ‘liver cancer’, ‘rim’, ‘enhance’, ‘MRI’, and ‘MRI’ were used as medical subject headings or keywords for searching. In addition, the bibliographies of retrieved articles were also searched and identified. The detailed search formula was presented in Supplementary Table 1, supplemental digital content 1, http://links.lww.com/EJGH/A994.

Eligibility criteria

The relevant studies were reviewed by two independent researchers to ensure that they met the eligibility criteria. A cross-discussion or consultation with a third reader was carried out when there were disagreements. The eligibility criteria for study screening were as follows: (1) HCC patients; (2) patients who underwent MRI for MRI-based rim enhancement evaluation; (3) studies that reported prognoses such as local tumor progression (LTP)-free survival, progression-free survival, recurrence-free survival, disease-free survival (DFS), and OS; (4) study reported correlation analysis between MRI-based rim enhancement and prognosis; (5) study was not case report, systematic review, meta-analysis, or animal study; (6) study language was English or Chinese.

Data extraction and risk of bias evaluation

After determining the included studies, the information containing the first author’s name, year, age, gender, sample size, country, maximum tumor size, treatment, and prognosis was extracted by two researchers independently and verified by a third researcher. For this study, DFS and OS were extractable and sufficient for analysis. The endpoint events of DFS were LTP, recurrence, and death, while the endpoint event of OS was death. In addition, the qualities of the included records were evaluated by two independent researchers via the Newcastle‒Ottawa Scale criteria, involving 3 domains: selection, comparability, and outcome [18].

Statistics

The hazard ratio (HR) with 95% confidence intervals (CI) was calculated to evaluate the impact of MRI-based rim enhancement on prognosis. For heterogeneity assessment, I² ≤ 50.0% and P ≥ 0.05 were considered to indicate the absence of heterogeneity, and the fixed-effect model was applied. Publication bias was analyzed by Begg’s and Egger’s tests and shown via Deeks’ funnel plots. Sensitivity analysis (kicked out studies one by one) was used to assess the robustness and reliability of the results. Stata v.14.0 (Stata Corp, USA) was used for data analysis. P < 0.05 indicated statistical significance.

Results

Process for study selection

A total of 1552 records were identified through the Web of Science, PubMed, EMBASE, Cochrane, CQVIP, Wanfang, and CNKI databases. Then, 1106 duplicates were excluded. Subsequently, 446 records were assessed by reading the title and abstract, among which 424 records were excluded (including 385 irrelevant studies, 16 systematic reviews, 16 meta-analyses, and 7 case reports or animal studies). Then, 22 records were assessed through full-text reading, of which 14 records were excluded (including 9 records that had no correlation of MRI-based rim enhancement with prognosis and 5 records that did not assess MRI-based rim enhancement). Finally, 8 records about the correlation of MRI-based rim enhancement with prognosis were included in the meta-analysis (Fig. 1).

Fig. 1.

Study flow.

Features of the included studies

In total, 8 studies with 1816 HCC patients were included [9,11–17]. Among the analyzed studies. There were 4 studies from Korea and 4 studies from China. In addition, there were 5 studies reporting patients with a maximum tumor size ≤5 cm and 3 studies presenting patients with unlimited/unclear tumor size. Meanwhile, 5 studies reported patients receiving hepatic resection, and 3 studies presented patients receiving RFA. More details of the features of the included studies are presented in Table 1.

Table 1.

Features of included studies

Study	Age (years), mean/median	Male/Female, n	Sample size	Country	Maximum tumor size	Treatment
Hyungjin Rhee, 2019 [11]	56.1a	65/19	84	Korea	Unclear	Hepatic resection
Zhouchao Hu, 2020 [12]	58.2a	81/24	105	China	≤5 cm	RFA
Wencui Li, 2020 [13]	58.0	204/40	244	China	Unlimited	Hepatic resection
Jiyoon Mong, 2020 [9]	57.1a	190/52	242	Korea	≤5 cm	Hepatic resection
Donglk Cha, 2021 [14]	Unavailable	270/79	349	Korea	≤5 cm	RFA
Hyojin Kang, 2021 [15]	57.5a	128/30	158	Korea	≤5 cm	Hepatic resection
Wencui Li, 2022 [16]	Unavailable	358/72	430	China	Unlimited	Hepatic resection
Ruizhi Wang, 2023 [17]	Unavailable	101/103	204	China	≤5 cm	RFA

RFA, radiofrequency ablation.

^aValues were described by mean.

DFS and OS

A total of 7 studies compared DFS between patients with MRI-based rim enhancement and those without MRI-based rim enhancement, and the pooled analysis of these studies showed that patients with MRI-based rim enhancement had decreased DFS compared to those without MRI-based rim enhancement (HR: 2.77, 95% CI: 2.11–3.62) (P < 0.001). Meanwhile, no heterogeneity existed among these studies (I² = 0.0%, P = 0.991) (Fig. 2a). In addition, 2 studies explored OS between patients with MRI-based rim enhancement and those without MRI-based rim enhancement, and there was no heterogeneity among them (I² = 0.0%, P = 0.981). Then, the fixed-effect model showed that patients with MRI-based rim enhancement had a decreased OS compared to those without MRI-based rim enhancement (HR: 5.43, 95% CI: 2.14–13.79) (P < 0.001) (Fig. 2b).

Fig. 2.

Forest plot of survival comparison between patients with and without MRI-based rim enhancement. Pooled analysis of DFS (a) and OS (b).

Publication bias

Funnel plots showed a generally symmetric distribution, indicating no obvious publication bias in DFS (Fig. 3a) and OS (Fig. 3b). Meanwhile, Begg’s and Egger’s tests were also conducted. The data suggested that no publication bias of DFS was discovered (P = 1.000 for Begg’s test and P = 0.968 for Egger’s test) (Fig. 3a). Meanwhile, Begg’s test illustrated that no publication bias of OS was found (P = 1.000), while Egger’s test was not applicable (Fig. 3b).

Fig. 3.

Funnel plot of publication bias. Publication bias of DFS (a) and OS (b).

Quality assessment and sensitivity analysis

The included studies were all cohort studies; thus, Newcastle‒Ottawa Scale criteria were applied to assess the risk of bias in these studies. The total score of these studies ranged from 7 to 9, suggesting a generally low risk of bias (Table 2). Moreover, the sensitivity analysis showed that the significance of DFS and OS did not change by omitting each study, implying the pleasing robustness of the results (Table 3).

Table 2.

Assessment of the risk of bias by Newcastle-Ottawa Scale criteria

Studies	Selection	Comparability	Outcome	Total score
Hyungjin Rhee, 2019	4	1	3	8
Zhouchao Hu, 2020	3	1	3	7
Wencui Li, 2020	3	1	3	7
Jiyoon Mong, 2020	3	2	3	8
Donglk Cha, 2021	3	1	3	7
Hyojin Kang, 2021	4	2	2	8
Wencui Li, 2022	3	2	2	7
Ruizhi Wang, 2023	4	2	3	9

Table 3.

Sensitivity analysis

Study omitted	Estimate (HR)	95% CI
		Lower	Upper
DFS
Hyungjin Rhee, 2019	2.75	2.07	3.65
Zhouchao Hu, 2020	2.77	2.09	3.67
Wencui Li, 2020	2.70	1.98	3.7
Jiyoon Mong, 2020	2.90	2.17	3.87
Donglk Cha, 2021	2.71	2.04	3.60
Wencui Li, 2022	2.76	2.07	3.67
Ruizhi Wang, 2023	2.77	2.05	3.74
Combined	2.77	2.11	3.62
OS
Jiyoon Mong, 2020	5.35	1.12	25.55
Hyojin Kang, 2021	5.48	1.72	17.48
Combined	5.43	2.14	13.79

CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; OS, overall survival.

Subgroup analysis of DFS by maximum tumor size

Among studies with a maximum tumor size ≤5 cm, pooled analysis showed that patients with MRI-based rim enhancement had lower DFS (HR: 2.64, 95% CI: 1.82–3.83) (P < 0.001), while no heterogeneity was discovered (I² = 0.0%, P = 0.874). Regarding studies with unlimited or unclear maximum tumor size, no heterogeneity was discovered among these studies (I² = 0.0%, P = 0.996). The pooled analysis revealed that patients with MRI-based rim enhancement had decreased DFS compared with those without MRI-based rim enhancement (HR: 2.91, 95% CI: 1.97–4.30) (P < 0.001). Overall, heterogeneity did not exist between groups (P = 0.717) (Fig. 4).

Fig. 4.

Forest plot of subgroup analysis for DFS by maximum tumor size (≤5 cm or unlimited/unclear).

Subgroup analysis of DFS by treatment

In studies with RFA treatment, the fixed-effect model showed that patients with MRI-based rim enhancement had lower DFS than those without MRI-based rim enhancement (HR: 2.87, 95% CI: 1.86–4.44) (P < 0.001) without heterogeneity among these studies (I² = 0.0%, P = 0.931). Among studies with hepatic resection, the pooled analysis revealed that patients with MRI-based rim enhancement had decreased DFS compared to those without MRI-based rim enhancement (HR: 2.70, 95% CI: 1.92–3.80) (P < 0.001); in addition, no heterogeneity was found among these studies (I² = 0.0%, P = 0.886). Overall, no heterogeneity was discovered between groups (P = 0.825) (Fig. 5).

Fig. 5.

Forest plot of subgroup analysis for DFS by treatment (hepatic resection or radiofrequency).

Subgroup analysis of DFS by sample size

In terms of studies with sample sizes ≤200, the pooled analysis showed that patients with MRI-based rim enhancement had lower DFS than those without MRI-based rim enhancement (HR: 2.83, 95% CI: 1.49–5.34) (P = 0.001); meanwhile, no heterogeneity was found among these studies (I² = 0.0%, P = 0.893). Among studies with a sample size >200, the fixed-effect model showed that patients with MRI-based rim enhancement had decreased DFS compared to those without MRI-based rim enhancement (HR: 2.75, 95% CI: 2.05–3.71) (P < 0.001), while no heterogeneity was discovered among these studies (I² = 0.0%, P = 0.936). Generally, there was no heterogeneity between groups (P = 0.942) (Fig. 6).

Fig. 6.

Forest plot of subgroup analysis for DFS by sample size (≤200 or >200).

Publication bias in subgroup analyses

The Begg’s and Egger’s tests were adopted to assess the publication bias in subgroup analyses of DFS, which showed that no obvious publication bias was found (all P > 0.050) (Supplementary Table 2, supplemental digital content 2, http://links.lww.com/EJGH/A995).

Discussion

To date, surgical resection and RFA are viewed as radical treatments for HCC [19,20]. Nevertheless, the prognosis of HCC patients undergoing surgical resection or RFA is still unfavorable, with a 5-year survival rate ranging from only 37% to 66.5% [21–23]. To date, several studies have reported that the presence of MRI-based rim enhancement is correlated with poor prognosis among HCC patients [15,17]. However, these studies have only been published in recent years, and the sample sizes are relatively small [9,11–17]. Thus, the application of MRI-based rim enhancement as a prognostic indicator of HCC in clinical settings still needs a more comprehensive assessment. In the current meta-analysis, patients with MRI-based rim enhancement had lower DFS and OS than those without MRI-based rim enhancement. The possible explanations might be that (1) MRI-based rim enhancement indicated low microvascular density and a sinusoid-like microvascular pattern in the tumor, which were related to poor differentiation and microvascular invasion, respectively [11,24]; both of these factors were correlated with poor DFS and OS among HCC patients [25,26]; and (2) MRI-based rim enhancement was also related to a more severe hypoxic and fibrotic tumor microenvironment [11], both of which led to decreased DFS and OS in HCC patients [27,28].

To further explore the prognostic value of MRI-based rim enhancement in HCC patients, subgroup analyses based on maximum tumor size, treatment, and sample size of the included studies were conducted. The data revealed that patients with MRI-based rim enhancement had lower DFS than those without MRI-based rim enhancement regardless of the maximum tumor size, treatment, and sample size of the included studies. The potential reasons might be that (1) the presence of MRI-based rim enhancement was not solely determined by the size of the tumor; rather, MRI-based rim enhancement could reflect the activity and aggressiveness of the tumor and could be present even in small tumors [11]; thus, MRI-based rim enhancement was correlated with lower DFS irrespective of tumor size. (2) MRI-based rim enhancement was thought to be related to the presence of a fibrous capsule surrounding the tumor, which would not affect the treatment choice among patients [29–31]. (3) The sample size of an individual study could affect the precision and accuracy of the estimated effect size, but it might not affect the presence or absence of a relationship between MRI-based rim enhancement and prognosis in HCC [32]; hence, despite the sample size of the included studies, rim enhancement was a negative predictive factor of DFS among HCC patients. The abovementioned subgroup analysis also illustrated that no obvious confounding factors existed in the results of the main analysis.

Nevertheless, there were some limitations in this meta-analysis: (1) among the included studies, only two reported the correlation between MRI-based rim enhancement and OS in HCC; thus, OS could only be compared in the main analysis but not in the subgroup analysis among patients with and without MRI-based rim enhancement. (2) The number of studies and patients enrolled in this study was restricted, which might lead to low statistical power. (3) The included studies were conducted in Asia, which could induce regional bias. (4) Two studies included in the current meta-analysis were conducted by the same author [13,16]. It was hard to confirm whether the population overlaps, hence it was hard to know if the inclusion of the same author in the final meta-analysis had an impact on the actual results. Nevertheless, the sensitivity analysis showed that kicking out the studies on by one could not affect the significance, which meant that the inclusion of the studies performed by the same author might have a weak impact on the actual results.

In conclusion, the presence of MRI-based rim enhancement is correlated with poor survival in HCC patients, indicating that it may serve as a radiological biomarker for stratified management among these patients.

Acknowledgements

This study was supported by Guangxi Zhuang Autonomous Region Bureau of Traditional Chinese Medicine (No. 20210681), Guangxi University of Traditional Chinese Medicine Doctoral Research Initiation Fund Project (No. 2021BS029) and Beijing Medical Award Foundation (No. YXJL-2022-0665-0211).

Conflicts of interest

There are no conflicts of interest.

Supplementary Material

ejgh-36-505-s001.pdf ^{(199.8KB, pdf)}

ejgh-36-505-s002.pdf ^{(243.6KB, pdf)}