Bladder cancer (BLCA) is the second most common urinary tract malignancy worldwide, whose incidence rate is increasing year by year. According to the global cancer statistics, an estimated 573,278 new BLCA cases and almost 212,536 BLCA deaths occurred in 2020 (1). For muscle-invasive nonmetastatic (MIBC) and high-risk non-muscle-invasive BLCA, radical cystectomy (RC) and pelvic lymph node dissection are often recommended (2). Accurate survival prediction after RC is essential, which is instrumental in guiding postoperative therapy and follow-up. As the most common staging system for evaluating tumor prognosis, the eighth edition of the American Joint Committee on Cancer (AJCC) staging system is based on the primary tumor (T) status, regional lymph node (N), and distant metastasis (TNM) stage (3). However, there is a certain degree of inadequacy, such as neglect of the influence of lymph node dissection (LND), which can lead to the different prognosis of patients with the same TNM.

In recent years, many studies have been devoted to exploring the impact of lymph node dissection on tumor prognosis (4–8). A meta-analysis showed that extended pelvic lymph node dissection (ePLND) brought recurrence-free survival (RFS) benefits compared with non-ePLND. Not only did patients with lymph node positive and pT3-4 diseases benefit from ePLND, ePLND also provided better RFS for patients with lymph node negative (9). Wright et al. thought that the increased number of lymph nodes removed (ELNs) during cystectomy was related to the improvement of the survival rate of patients with positive-lymph node cancer (10). Similarly, Wang et al. found that the number of LND may be an independent factor related to the survival of patients receiving RC (11). In addition, Jin et al. believed that LODDS defined as the log ratio between the number of metastatic lymph nodes and the number of negative lymph nodes had a significant prognostic value for MIBC patients (12). However, the lack of information on individualized tumor characteristics were their common limitation.

In fact, the T stage is a powerful risk factor for BLCA and represents the major tumor features. An increasing number of studies have suggested that T stage is closely associated with prognosis and tumor biological features (13–15). T stage can represent the biological characteristics of tumor. Xie et al. used the combination of negative lymph nodes (NLNs) and T stage (log (NLNs+1)/T stage) as a new prognostic factor to reflect the degree of individualized LND in gastric cancer patients (16). However, whether this novel indicator can be applied to bladder cancer remains unknown.

Here, in this study, we obtained the BLCA receiving RC cohort from the Surveillance, Epidemiology and End Results (SEER) database to explore the prognostic value of this new factor (log (NLNs+1)/T stage) in BLCA patients. And Based on this factor, a more accurate prognostic model for BLCA after radical cystectomy was constructed.

Because of the high incidence rate of BLCA, the risk stratification of bladder urothelial carcinoma after RC has essential clinical significance (19). It is conducive to follow-up consultation, postoperative treatment and clinical trials. For BLCA patients receiving RC, the prognosis not only correlates with T stage and biological characteristics (14, 15), but also with the degree of lymph node dissection (5, 11). However, so far, effective and objective indicators to evaluate the impact of individualized lymph node resection are still lacking.

In this study, we defined LONT as the log of the ratio between the NLN counts plus one and the T stage, where NLNs represents the degree of LND and T stage represents tumor characteristics and the disease severity of tumor (16). Compared with the simple application of ELNs (11) and LODDS (12) to represent the degree of LND, LONT took into account the characteristics of individualized tumor. It can be understood as the NLNs adjusted by T stage, representing the relative number of negative lymph nodes removed for postoperative BLCA patients. A higher value of LONT indicates a larger relative number of negative lymph nodes, and a lower value indicates a smaller relative number of negative lymph nodes. The same LONT value may represent the same degree of risk even if the patient’s T stage and the number of negative lymph nodes are different, which was conducive to comparing the individualized degree of LND in patients with different TNM stages. In addition, we further established a simple and effective prognostic model based on LONT. The model was composed of nine prognostic factors, including LONT, age, race, tumor size, histologic.type, T.stage, N.stage, summary.stage and chemotherapy, which were obtained based on univariate and multivariate Cox regression analysis. We also compared our model with the AJCC stage and SEER summary stage on clinical performance, the results of C-index, AUC and DCA proved that our nomogram had a better prediction value. Moreover, we further constructed a risk stratification system to divide patients into low-, middle- and high-risk groups, which was instrumental in the choice of patients’ treatment.

To our knowledge, only one study had explored the role of LONT in the prognosis of postoperative patients with gastric cancer (16). Similar to its research, we found that this new indicator was an independent prognostic factor in postoperative BLCA patients. The result of univariate Cox regression analysis suggested that the HR of NLNs in OS and CSS was 0.983 and 0.984, respectively. Interestingly, when we combined T stage with NLNs, its HR decreased significantly to 0.354 and 0.339. Similar results also occurred in the multivariate Cox regression and validation cohort. At the same time, the prognosis of BLCA patients after RC could be significantly stratified by LONT both in CSS and OS cohorts. The proportion of LONT in our nomogram was also largest. In addition, this prognostic factor had strong clinical availability and can be obtained through a simple calculation of postoperative pathology. All these results indicated the importance of LONT in predicting postoperative bladder cancer, which can further improve the accuracy of prediction.

In recent years, many researchers have been devoted to establishing a predictive model for postoperative bladder cancer (19–23). Although these models had been well validated externally, they may not be universally applicable. Because some included variables were usually unavailable, such as adjuvant radiotherapy and lymphatic vascular invasion, and the calculation is relatively complicated (24). In addition, Yang et al. constructed a prognostic model to assess the cancer-specific survival for BLCA patients after RC (24). The final model consisted of five variables including T stage, marital status, N stage, tumor size and chemotherapy. The C index of our model is significantly higher than them, whether in the primary cohort (0.734 vs 0.718) or validation cohort (0.720 vs 0.707). Compared with the above models, our study may have the following advantages. Firstly, we were the first to introduce a novel and significant factor (LONT) to predict CSS in BLCA patients receiving RC. This variable took full account of the individual LND effect. Secondly, we further developed a risk stratification system according to the nomogram score, which may help clinicians identify high-risk groups in time.

Indeed, some shortcomings should be acknowledged in our study. Firstly, it may be inaccurate for us to only represent the characteristics of tumor by T stage, because the known important biological characteristics of tumor also include pathological type, grade, genotyping, etc. Secondly, some potentially important prognostic factors were not included in our study, such as complications and lymphatic vascular invasion. In addition, the SEER database lacks specific information about surgery and chemotherapy. The sequence of chemotherapy and the choice of surgical methods and chemotherapy drugs may have different effects on the prognosis (25–27). Lastly, even if we carried out external validation, further prospective studies were required to verify our conclusions.

As a novel prognostic indicator, LONT can fully reflect the degree of individualized lymph node dissection in different patients. Based on LONT, a more effective nomogram was developed and validated to predict 3- and 5- CSS probabilities, which is conducive for clinicians to formulate individualized treatment plans.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

This study was approved by the institutional of the First Affiliated Hospital of Nanchang University. All data from SEER was open access.

TC and XZ conceived the study. HW and TC collected and analyzed the data. XZ and MJ drafted the manuscript. TC and LC generated the tables and figures. BF supervised the study. All authors approved the final version. All authors contributed to the article and approved the submitted version.

This study was supported by grants from the National Natural Science Foundation of P.R. China (Grant Nos.81560419).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.