3.4 Prognostic impact of NLNs counts after the propensity-matched analysis
To make a more objective evaluation of the prognostic value of the NLNs, we performed a propensity score matching procedure. As described in the methods section, matching based on patients with >17 NLNs was performed. Eventually, 57 patients with >17 NLNs were matched with 57 patients with ≤17 NLNs. Before PSM, the baseline characteristics of tumor size, T stage of tumor and surgery type were not balanced in 2 groups, this situation was significantly improved after the PSM. After the PSM, the univariate and multivariate analysis demonstrated that there was still a significant improvement in terms of cancer-specific survival for patients with >17 NLNs compared with patients with ≤17 NLNs (Fig. 2B and Table 4).
3.5 Prognostic impact of NLN counts according to the stage of tumors
We performed subgroup analysis to study the prognostic impact of NLNs counts according to the stage of tumors. In patients with stage I tumors, the number of NLNs was evaluated to be associated with cancer-specific survival in the Kaplan–Meier analysis. Patients with >17 NLNs had a significantly better cancer-specific survival than patients with <17 NLNs (P = .010). This result was persistent in the multivariate analysis. There was a significant decrease in terms of cancer-cause specific mortality for patients with >17 NLNs (HR, 0.36; 95% CI, 0.17–0.73), compared with patients with ≤17 NLNs. The similar results were found out in the analysis of patients with stage II tumors. The optimal cut-off number for the NLNs count was 15, which was determined by the X-tile program. The prognostic value of NLNs was evaluated in both univariate and multivariate analysis. Patients with more NLNs had a better cancer-specific survival than patients with less number of NLNs. However, there was no significant difference of survival between the more and less NLNs count group, in patients with stage III tumors (P = .552). Patients with less number of NLNs even had a slightly better cancer-specific survival than patients with more NLNs (HR, 1.21; 95% CI, 0.64–2.28).
3.6 The sub-stratify analysis according to the TLNs extracted
To avoid the potential influence of the TLNs extracted on the prognostic value of NLNs, we performed the sub-stratify analysis according to the TLNs extracted. Patients were stratified into 2 groups, patients with low total number of retrieved LNs (≤15 total retrieved LNs) and patients with high number of retrieved LNs (>15 total retrieved LNs). There was still a significant better prognosis in patients with high NLNs compared with patients with low NLNs. And the cut-off number for NLNs in the above 2 groups (7 for the low TLNs group and 25 for the high TLNs group) were determined by the X-tile program.
Perihilar cholangiocarcinoma is an aggressive disease, and the prognoses of patients with perihilar cholangiocarcinomas are poor. LN status is reportedly a strong predictor of the prognoses of patients with perihilar cholangiocarcinomas.[11,16,17] Patients are classified as N0 patients if they lacked LN metastases and N+ patients if they had an involvement of LNs, according to the AJCC staging system. The N0 patients have a significantly better survival rate than patients with LN metastases. Therefore, adequately retrieved LNs are essential for the avoidance of understaging, and the number of retrieved LNs is regarded as a predictor of patients’ prognoses. The AJCC staging system suggested that patients with perihilar cholangiocarcinomas have at least 15 retrieved LNs; however, this suggestion has yet to be verified. A recent meta-analysis demonstrated that patients who had more than 15 retrieved LNs did not demonstrate an increased survival rate than patients who had fewer retrieved LNs. Furthermore, the prognostic value and optimal number of retrieved LNs are still controversial, and the relevant studies have obtained different conclusions.[11,19,20]
Compared to the TLNs, the number of PNs and the PNR showed convincing prognostic values in several studies of patients with perihilar cholangiocarcinomas. The study of Alfredo et al analyzed a small sample of patients and revealed that a PNR of more than 0.25 was an independent indicator of a worsened survival. Taro et al concluded that the better staging method of nodal status should be based on the number, and not the location, of PNs Felice et al used a better cut-off number (0.2) to study the prognostic value of the PNR and observed that the PNR was the only independent prognostic factor for overall survival in patients with LN metastases.
Although the number of PNs and the PNR were demonstrated to be better indicators of the impact of LN status on survival, there were limitations when these indicators were used in N0 patients. Additionally, the PNR was unavailable in patients who only had positive LNs. Therefore, the concept of the use of NLNs as indicators was proposed to study the interactions of NLNs with the prognoses of patients. Previous studies have demonstrated that the number of NLNs was an important indicator of the prognoses of patients with colon and esophageal cancers.[12,21] For resectable gastric cancer, the number of NLNs could improve the survival prediction of the PNR, although the prognostic value of NLNs was not significant in the multivariate analysis. However, for patients with perihilar cholangiocarcinomas, it has not been studied whether there are any interactions between the number of NLNs and the prognoses of patients.
The present study screened 938 patients with perihilar cholangiocarcinomas from the SEER database. The N0 patients accounted for 53.5% of all patients; therefore, relying only on the number of PNs and the PNR for predicting the prognoses of patients was insufficient. Both the univariate and multivariate survival analyses revealed that the number of NLNs was significantly associated with the cancer-specific survival of patients. Patients with more than 17 NLNs had a significantly better cancer-specific survival rate than patients with fewer NLNs. Subsequently, the subgroup survival analysis demonstrated the independent prognostic value of the number of NLNs in patients with stage I and II tumors. Additionally, there was no significant difference in terms of cancer-specific survival between patients with >15 and ≤15 retrieved LNs.
There were several hypotheses for the mechanisms underlying the impact of the number of NLNs on prognoses in patients. The first hypothesis was that a greater number of NLNs could be deemed as a marker for the adequacies of surgical and pathological care. Additionally, the number of NLNs was regarded as a basic guarantee for R0 resections and sufficient lymphadenectomies in several studies. Regardless of the surgical and pathological care, either R0 resections or lymphadenectomies could affect the treatment outcomes and prognoses of patients. The second hypothesis was that a greater number of NLNs could guarantee the accurate staging of nodal status, which was demonstrated to be beneficial for the prognoses of patients. The micrometastases in LNs are difficult to discover, and there may be micrometastases in unretrieved LNs. A study by Hendrik et al revealed that approximately 12% of patients with perihilar cholangiocarcinomas had micrometastases in the LNs and that patients with micrometastases had worsened prognoses than patients without micrometastases. Therefore, the third hypothesis was that a greater number of negative LNs indicated that more LNs were resected and retrieved, thus indicating fewer potential micrometastases in the remaining LNs. Furthermore, several anatomic studies have demonstrated that a greater number of NLNs could improve the underlying tumor-host interactions and reset the immunological balance to improve survival.
Several limitations should be noted when interpreting these results. First, although a population-based database was used to screen for the patients, the sample size of our study was still not sufficiently large compared with congener studies for other diseases. Second, several factors were not recorded in the SEER database, such as information regarding adjuvant chemotherapy, surgery details, and areas of lymphadenectomy, among others. Third, the information for radiotherapy in the survival analysis did not contain the details of the protocols, and the SEER database did not provide these data. Fourth, disease-free survival could not be calculated because of the lack of information about local recurrences in the SEER database. Fifth, patients who received preoperative radiation treatments were excluded. However, there may be patients who received radiation treatments in some other centers that were not recorded in the SEER database; thus, the downstaging effect of radiation could not be entirely ruled out. Sixth, the AJCC staging system that was used in the present study was the 6th edition, which was not the most commonly used system in the present day (due to the limitations of the SEER database). Seventh, the sample size was small after PSM, which was because too many clinical factors were balanced in PSM procedure. Finally, we could not collect data that referred to the surgical margin status in the SEER database; this was important in that surgical margin status is an important prognostic factor in patients with resected perihilar cholangiocarcinomas.
In conclusion, the number of NLNs was evaluated to be an important independent prognostic factor for the cancer-specific survival of patients with perihilar cholangiocarcinomas. Patients with greater numbers of NLNs had an increased cancer-specific survival rate compared to patients with fewer NLNs.
Conceptualization: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Duke Chen, Wanchun Xiong.
Data curation: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Duke Chen, Wanchun Xiong.
Formal analysis: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Wanchun Xiong.
Funding acquisition: Yunfeng Gao, Dong Xu, Wanchun Xiong.
Investigation: Yunfeng Gao, Wanchun Xiong.
Methodology: Yunfeng Gao, Yu-Shen Wu, Duke Chen, Wanchun Xiong.
Project administration: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Duke Chen, Wanchun Xiong.
Resources: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Wanchun Xiong.
Software: Yunfeng Gao, Wanchun Xiong.
Supervision: Yunfeng Gao, Duke Chen, Wanchun Xiong.
Validation: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Duke Chen, Wanchun Xiong.
Visualization: Yunfeng Gao, Dong Xu, Yu-Shen Wu, Duke Chen, Wanchun Xiong.
Writing – original draft: Yunfeng Gao, Wanchun Xiong.
Writing – review and editing: Yunfeng Gao, Dong Xu, Wanchun Xiong.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
negative lymph node count; perihilar cholangiocarcinoma; SEER; survival analysis