This study is considered significant considering that centrality, which is defined as the vascular proximity of liver metastasis, was proven to be another morphologic factor in deciding the resectability of CRLM. During the resection of liver metastasis, how to optimally solve two conflicting issues of preserving maximum liver function and securing sufficient resection margin after hepatectomy should be significantly considered. Traditionally, volumetric parameters such as tumor size and number of CRLM have been shown to be significant factors associated with resectability and prognosis after resection [7, 8]. However, the concept of resectability of CRLM has been changed over the last decade with the introduction of several treatments. Surgical techniques, such as portal vein embolism (PVE) or two-stage hepatectomy (TSH) are proven to be safe and curative in selective cases of advanced CRLM with inadequate future liver remnant (FLR) or underlying liver diseases [9, 10]. Combined resection with IORFA is beneficial in preserving FLR with favorable oncologic outcomes [11, 12]. Additionally, NAC with a target agent and rescue surgery for unresectable CRLM results in tumor downsizing with survival benefits . Considering that the benefits of these treatments have been proven, active resections have been widely performed, and the criteria for resectability have focused on how to perform R0 resection with sufficient liver function . Thus, factors associated with positive resection margin should be comprehensively studied to define the resectability of CRLM.
Although the standard width of the resection margin of CRLM remains unknown, traditionally, resection margin of 1 cm has been accepted as a minimal margin to obtain favorable oncologic outcomes . Certainly, R1 resection, i.e., microscopic identification of malignant cells on the resection margin, is a negative factor for survival after resection based on previous reports . However, other studies reported that the width of surgical margin, even < 1 cm, does not affect survival in patients with R0 resection . Thus, hepatic resection tends to be actively performed even when the length of the resection margin is < 1 cm on imaging modality. However, in this study, when the centrality was high (< 1.5 cm), the rate of R0 resection was low. Additionally, OS was also worse in patients with high centrality than in patients with low centrality.
Daisuke et al. suggested several factors in indicating hepatectomy, such as previous hepatectomy, disease type (hepatocellular carcinoma, benign or metastatic lesion), liver function, and tumor size and number . They also reported that performing hepatectomy is highly difficult when the tumor is located in deeper layers or proximal to the branch of the Glissonean tree. As the tumor is closer to the primary branch of the Glissonean tree, the hilar dissection or anatomical resection is required to completely resect the tumor. The centrality in this study was at the bifurcation of the primary Glissonean branch; thus, we could assume that the centrality was a factor indicating the difficulty of hepatectomy to secure sufficient resection margin near the center of the liver.
Subsequently, how should we approach CRLM with high centrality? Attempts to secure sufficient resection margin at the central side of the liver, such as anatomical resections, should be made to achieve favorable oncologic outcomes. Additionally, treatments to increase or preserve hepatic reserve (such as PVE or TSH) should be considered to compensate largely reduced liver volume after resection. Volume-saving therapy, such as IORFA, may also be a promising treatment option for lesions observed at the opposite lobe of the liver. Additionally, recent studies reported a greater conversion rate of initially unresectable CRLM after NAC with regimens of oxaliplatin, irinotecan, and other target agents . Thus, NAC should be considered in patients with high centrality, so that hepatectomy can be performed after securing sufficient resection margin at the central side. However, prolonged chemotherapy may also have a detrimental effect on the hepatic parenchyma due to oxaliplatin-induced sinusoidal obstruction or irinotecan-induced steatosis [19, 20]. Hence, liver function and remnant liver volume should be carefully monitored during chemotherapy. Taken together, various treatment tools should be considered when establishing appropriate strategies for CRLM with high centrality, and treatments should be customized based on patient’s condition.
This study has several limitations. First, the definition of the center of the liver, bifurcation of the portal vein at the first branch of the Glissonean tree, was subjective and did not include other important structures in the liver. For example, proximity to the inferior vena cava is an important factor in deciding treatment strategy of CRLM, but it was not considered in this study. Second, the factor of centrality ≤ 1.5 cm was selected empirically according to the opinion of hepatobiliary surgeons in our MDT team. According to the ROC curve analysis, the specificity for positive resection margin of centrality ≤ 1.5 cm was 91.0%. However, the sensitivity was only 31.4%, suggesting that factors other than centrality should be considered when deciding the positive resection margin of CRLM. Third, this study was retrospectively conducted based on previous pathologic reports, which contained only the shortest length of resection margin of specimens and did not indicate whether the resection margin was of the central side. Fourth, the result of a subgroup analysis in Fig. 5 might not be sufficient to support the idea that NAC was effective in Z2 due to the small volume of subgroups. Although the OS of the subgroup in Z2 was statistically different, additional large-scale studies are required to confirm the association between NAC and centrality.