This study is considered significant considering that centrality, which is defined as the proximity with the liver hilum at the portal bifurcation 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, all hepatectomy for CRLM should be performed with efforts to achieve sufficient resection margin length even for the centrally-located tumors.
Troisi et al. suggested several factors in affecting the difficulty of 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? Per et al. demonstrated that associating liver partition and portal vein ligation (ALPPS) made major resections possible with improved resection rates compared with conventional TSH . They also reported the rate of severe complications and negative resection margins were comparable with TSH. Enhanced one-stage hepatectomy (E-OSH) is another technique that makes major hepatectomy possible especially for deep-located nodules [19, 20]. E-OSH utilizes the intraoperative ultrasound and vascular manipulations to achieve complete vascular control and detachment of liver metastasis from intrahepatic vascular structures. This approach was reported to be helpful to overcome the disease progression between the two hepatectomies which was a major drawback of TSH and also showed a comparable survival with ALPPS. These approaches, ALPPS and E-OSH, should be considered for advanced liver metastasis with high centrality. 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 [22, 23]. 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. For example, proximity to the inferior vena cava is an important factor in deciding adequate vascular outflow, 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 91.9%. However, the sensitivity was only 30.6%, 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, although the difference was not statistically significant, the difference of the long-term overall survival between of - NAC group in Z1 and that of + NAC group in Z1 was relatively significant. This might be caused by the small volume of subgroups of Z1 (number of NAC- in Z1 = 13 and number of NAC+ in Z1 = 22). Fifth, the reason why the centrality is related with a worse survival was not definite. More major hepatectomy were performed in the high centrality group and major hepatectomy is related with post-hepatic liver failure . We carefully assumed that the liver function of the high centrality group might be deteriorated due to complications after major hepatectomy such as liver cirrhosis or biliary fistula in the mid or long term period of follow-up and treatments such as repeat resections for recurrent hepatic metastasis or compliance to the chemotherapy might be affected to survival of patients. However, the tumor burden of the high centrality group seemed to be higher than that of the low centrality group, thus the heterogeneity in tumor burden might affect the results of survival of patients with high centrality.