The findings of this meta-analysis revealed that surgical margins correlate with the prognosis of HCC patients; besides, a wide surgical margin (≥1 cm) could improve long-term prognosis compared to a narrow surgical margin (<1 cm). This is in line with the results reported in previous articles [39, 40]. Through subgroups analyses, we found that the above outcome showed a similar phenomenon in different subgroups except for studies from Western countries. In this analysis, a wide surgical margin did not prolong the OS of patients compared to a narrow surgical margin. This is potentially attributed to the inclusion of a few studies (five articles).
No consensus has been reached in academia on whether gender is an independent risk factor for the prognosis of HCC patients after hepatectomy [45]. Although there is no direct evidence that gender is a risk factor for HCC prognosis, men have higher smoking rates, alcohol consumption rates, and tumor burden than women [46]. A different study found that women have a better long-term prognosis than men, but without statistical difference among patients with HCC lesions maximum size<3 cm or with solitary HCC [47].
Notably, regional factors were also considered in subgroup analysis. The etiology of HCC in different regions is remarkably different. Asian countries, specifically East Asia are dominated by viral hepatitis, whereas HCC etiology in Western countries is mostly related to alcohol [48]. Subgroup analyses revealed that despite HCC patients with/without hepatitis B virus (HBV) and liver cirrhosis, a wide surgical margin prolonged the prognosis of patients than a narrow surgical margin. HBV-liver cirrhosis-HCC progression is a vital approach for HCC occurrence. High HBsAg level, lack of antiviral treatment, severe liver cirrhosis are risk factors affecting this process [49–51]. Despite in single or multiple HCC populations, the wide surgical margin group could still yield a better prognosis than narrow surgical margin group. Nevertheless, a study on a single HCC revealed that a wide surgical margin was not a prognostic factor, however, after propensity score matching (PSM), a wide surgical margin could still prolong the prognosis of patients [44]. This is possibly because PSM could reduce the confounding bias of OBS and improve the research efficacy by omitting the unmatched study subjects.
Microvascular invasion (MVI) is the presence of tumor emboli in vascular spaces rowed by endothelial cells from the tumor capsule into the liver parenchyma (either hepatic vein or portal vein branches) [52]. Research confirms that MVI is an independent risk factor for postoperative recurrence and metastasis of HCC, this significantly affects the long-term prognosis of patients [53, 54]. Based on the distribution and number of MVI, MVI is classified into the following grades, M0: no MVI; M1 (low risk): MVI <5 and the distance from adjacent liver tissues ≤1 cm; and M2 (high risk): MVI >5 or the distance from adjacent liver tissues >1 cm [55]. Researchers attempted to develop a preoperative model integrating laboratory examinations and imaging examinations to predict MVI. However, its accuracy requires additional validation by large-scale prospective multi-center studies [56]. At present, MVI can only be diagnosed by postoperative histopathological examination; this significantly limits the application of MVI in guiding diagnosis and treatment. From MVI to macrovascular invasion, the malignant degree of HCC cells gradually increases and destroys the surrounding tissues; the chance of radical surgery is lost if a macrovascular invasion is formed [57]. Therefore, effective surgical plans and postoperative adjuvant treatment can be adopted if timely interventions are implemented at the MVI stage of HCC. This thus minimizes metastasis and HCC recurrence as well as significantly improves the prognosis of patients.
To survive and metastasize, cancer cells must evade the immune system. After cancer cells invade the bloodstream, the classic hematological mechanism believes that platelets, leukocytes, and endothelial cells mediate the related process of metastasis and recurrence [58]. New research indicates that MVI provides another path for HCC recurrence and metastasis; besides, HCC cell clusters obtain endothelial coating by protruding the vessels, this enables evasion of the immune surveillance mechanism and thereby preventing the activation of the coagulation cascade [59–62]. Thus, if a liver resection with a narrower surgical margin is performed on patients, theoretically, the residual micrometastasis increases the risk of recurrence [37]. Besides, 90% of MVI occurs in the range less than 1cm from the edge of the tumor. If a wider margin is achieved, the incidence of MVI can be reduced, hence significantly preventing tumor recurrence and metastasis [63]. However, due to data unavailability, we were unable to analyze the influence of MVI on the results in subgroup analysis.
The surgical margin should however not be blindly enlarged for preventing the recurrence and metastasis of HCC after surgery. Due to the excessively wide surgical margin, more normal liver parenchyma will be removed, causing serious postoperative complications including liver failure, and eventually death [8, 9, 11, 12]. Poon et al. [12] revealed that the relatively healthy liver parenchyma should not be sacrificed for obtaining the wider margin, particularly in cirrhotic patients with limited hepatic functional reserves. Another study [25] showed that a wide surgical margin could not improve the OS of patients compared to a narrow surgical margin. This was because of different baselines of the experimental group and the control group; this was largely reflected in liver cirrhosis, large and multiple tumors.
Previous research evaluated the relationship between surgical margins and prognosis by systematic review and meta-analysis [64, 65]. The findings [64] are inconsistent with ours and suggested that prognostic benefit was not achieved in patients receiving a resection margin≥1 cm. A few articles (5 articles) included is a potential reason. This study lacked sensitivity analysis, therefore, the reliability and stability of its findings are uncertain.
Zhong et al. [65] results are consistent with our findings, however, this study has limitations. First, although the number of included studies is more than that of previous studies, it is still a few compared to our study (37 articles versus 7 articles). Besides, subgroup analysis was not performed. It, therefore, remains unknown whether this conclusion (the prognostic benefit of a wide margin) will be interfered with by other factors.
Our study has worth-mentioning limitations. First, due to limited related studies, we could not perform a comprehensive analysis of different resection margin lengths. Secondly, the study population is from Asia, therefore the results cannot be directly applied to the population in Western countries. Thirdly, most of the included literature is retrospective, thereby hinting a possibility of the potential risk of information bias. Fourthly, due to the unavailability of relevant data, we did not perform additional subgroup analyses including MVI.