ICC is a malignant disease with a poor prognosis. The goal of surgery is complete (R0) resection. The prevalence of LNM in ICC is as high as 17%-39.1%[15, 16], and LND is considered as part of R0 resection. Many surgeons believe that LND improves ICC survival. However, some researchers found that LND is only a staging operation and has little effect on prognosis[4, 17]. In our study, the initial analysis showed a poorer prognosis in the LND group, which might be explained by the incongruity of the baseline characteristics. Variables were better adjusted using IPTW than propensity score matching (PSM); there was no significant difference in OS between the groups. This is not consistent with the findings of some prior studies. Yoh et al. compared the effect of LND on prognosis in patients with no suspected LNM before surgery[15]. This indicated that LND improved both DFS and OS in the nLND group. Only 112 patients were included, and some deviations in preoperative imaging assessment may exist. Ma et al.[18] found that patients who underwent extensive LND in the R0 resection group and group without distant metastases had a better prognosis, even after PSM. However, there was no difference in the whole cohort. Kim et al. obtained a results in the LND ≥ 6 and nLND groups, the former’s OS is better[19]. However, the sample size was only 68, and the OS in this study was much longer than those in other studies. We also verified this conclusion using IPTW. Unlike OS, DFS was better in the nLND group. LNM status was unknown in the nLND group; therefore, we could not include it in any match. Although many possible variables were included in IPTW to address this problem, it could not completely balance the LNM situations of the two groups. Generally, our research supported the hypothesis that LND has no prognostic benefit, but it may be related to DFS in ICC.
However, this does not render LND unmeaningful. The prevalence of LNM in ICC is high (approximately 31.9. -58.0%)[20, 21]. Since LNM is a predictor of poor prognosis in ICC, LND should be performed routinely as it is the only means to assess the LN status. The best approach for LND is controversial. The 8th edition of the AJCC cancer staging system suggests routine LND and removal of at least 6 LNs. This system also clearly defines regional LNs[22]. In addition to hilar nodes (common bile duct, hepatic artery, portal vein, and cystic duct nodes), regional LNs include the inferior phrenic and gastrohepatic lymph nodes in the left liver lobe. The right lobe covers the periduodenal and peripancreatic LN areas. Extraregional LNM like distant metastases are contraindications to surgery according to the NCCN guideline. [23]. Although the NCCN guidelines recommend only the dissection of the hilar area[24], the LND extent is insufficient. In our data, 75.2% underwent LND, and 35.5% had a sufficient number of dissected lymph nodes, of which 61.4% were hilar lymph nodes. This indicates that the N stage of more than half of the patients may not be exact, and the assessments in some patients with LNM are incorrect because LND is not performed or poorly done. However, some improvements in these rates have been observed. The proportion of qualified LND is increasing, though it is still not satisfactory[25]. The large difference in baseline data also showed that many surgeons perform LND, which is consistent with previous studies[14, 26, 27]. Generally, the tumors of the LND group were more malignant, with higher tumor marker levels, T stage, vascular invasion, and nerve invasion. Surgery was indicated in these patients because the surgeons suspected that they would have more LNMs; this was confirmed by the LND subgroup analysis (LN-positive vs. LN-negative). Unfortunately, this did not change the fact that LND could not improve the prognosis. Given that LND rendered surgery more challenging, caution should be taken when selecting this procedure in some patients.
Another question was the best number and area of LND. In a large multicenter study published by Zhang et al., the dissection of 6 lymph nodes was the best for obtaining a better overall survival[13]. This was not confirmed in our data. In fact, we did not find a significant cutoff LND number for survival using X-tile software. This requires further study. Concurrently, the LND area was not significantly different in our study. From our findings, LND did not improve survival; further studies should preferably focus more on the relationship between LND and LNM detection rate, than on that between LND and OS. To obtain very accurate results, LND should be routine and standardized, instead of just removing the LNs which were probed intraoperatively. Although this has been recommended by the AJCC, there is still need for further research.
The current N staging system seems to be a little simplistic. A cutoff of 1 (i.e., LNM-positive and negative) has been shown to effectively differentiate the patients’ prognoses[9, 11, 18, 28–31]. Zhang et al. put forward a new N stage model: N0 (LNM 0), N1 (LNM 1–2), and N2 (LNM > 2); they found that their model performed better in patients with at least 6 dissected lymph nodes[13]. In our study, we grouped patients with LNM 1–3 and LNM ≥ 3, and found a difference (14 months vs. 9 months); however, the difference was not statistically significant, regardless of the cutoff value. There was no significant difference in the LND ≥ 6 subgroup. We tried to correct this result using IPTW but failed, because the sample size was not large enough. Further studies focusing on a better N staging system should be conducted.
This study had some limitations. First, the sample size was small. Data was collected by many people and may have produced incorrect results. LND was recorded only by the surgeon who performed the operation, which may make it less objective. The analysis methods in this study could not eliminate the differences between groups. Despite these limitations, we provide researchers with reference data for ICC surgery, prognostic model, and staging system, through in-depth data analysis.