Comprehensive lymphadenectomy is required for accurate staging in USC patients, but its therapeutic benefits are highly controversial. A large-scale randomized controlled trial in the treatment of endometrial cancer (ASTEC) has shown that systematic PLND offers no therapeutic benefits compared with no lymphadenectomy (22). In contrast, several retrospective studies have demonstrated that comprehensive lymphadenectomy was associated with significant improvements in the survival of both node-negative and node-positive women with USC (21, 23, 25). These studies, however, had the following limitations. First, USC patients were generally underrepresented, thus the conclusion derived might not apply in USC patients. Second, most studies mentioned only the number of removed regional lymph nodes, while few explored the extension of PLND or the number of para-aortic lymph nodes. Our study enrolled 2843 USC patients who had undergone surgery from the SEER database. Among them, 1643 patients underwent PLND + PALND and the number of removed para-aortic lymph nodes was specified and analyzed. In our study, a larger number of removed pelvic lymph nodes was associated with better OS and CSS (Fig. 1A&B, Supplementary Table 1). However, the removal of more para-aortic lymph nodes did not lead to better OS and CSS (all P > 0.1, Fig. 1C&D).
The association between comprehensive PLND and survival can be interpreted in several ways. First, patients with a more extensive PLND may avoid understaging and therefore are more likely to receive adjuvant therapy when truly indicated. Nearly all USC patients after surgery should have received adjuvant chemotherapy ± radiation therapy to further prolong survival (4, 17). However, our results showed that there were no significant differences in either the positive pelvic lymph node rate or the percentage of adjuvant therapy between the ≥ 12 subgroup and < 12 subgroup (both P > 0.05,Supplementary Table 1). Therefore, the survival benefit of comprehensive PLND might not be explained simply by understaging or adjuvant therapy. Second, it may be possible that comprehensive PLND is therapeutic by removing more clinically occult lymph nodes and theoretically reducing the likelihood of lymph node recurrence. A multicenter retrospective cohort analysis in Korea with 476 surgically staged FIGO IB-IIIC2 patients indicated that more lymph nodes removed were associated with more positive lymph nodes detected and concluded that removing as many pelvic lymph nodes as possible improved survival in high-risk patients (18).
In our study, more extensive PALND did not improve OS or CSS (both P > 0.2, Fig. 1C&D). The most likely explanation was the significantly higher complication rate and longer surgical time associated with comprehensive PALND. A population-based analysis from the National Cancer Database indicated that the addition of PALND improved survival in USC patients, however, they did not specify the respective number of pelvic and para-aortic lymph nodes. We believe that the significance of lymph node number from lymphadenectomy outweighs the significance of lymphadenectomy type, and the addition of PALND to PLND does not contribute to survival benefits when the number of removed pelvic lymph nodes is controlled. Therefore, we recommend PALND sampling over extensive PALND dissection, which would likely minimize perioperative morbidity while preserving staging accuracy.
Multiple prognostic factors can affect the survival of USC patients, but to our best knowledge, previous studies have never comprehensively integrated all relevant risk factors, and in particular, the number of removed para-aortic lymph nodes was rarely mentioned. Currently, the FIGO staging system remains the most widely used prognostic tool. However, as patient survival within the same FIGO stage is still heterogenous, we aim to develop a more comprehensive prognostic tool. Nomograms are intuitive statistical tools that can provide comprehensive and individualized survival predictions for cancer patients (30). Thus, in the current study, a nomogram was developed and validated with 2853 USC patients after surgery from the SEER database to predict the 3- and 5-year OS and CSS.
Through univariate log-rank analysis and subsequent multivariate analysis, we identified age, T stage, N stage, tumor size, adjuvant therapy and the number of removed pelvic lymph nodes as independent prognostic factors for the survival of USC patients after surgery. Previously, younger age and adjuvant therapy were shown to be associated with better survival in high-risk endometrial cancer patients (8). In our study, patients older than 60 years had a significantly worse OS and CSS than those younger than 60 years old (P < 0.01, Table 2). Chemotherapy combined with radiotherapy led to better survival outcomes than chemotherapy alone, radiotherapy alone or neither. The FIGO staging system, which emphasizes on tumor invasion depth, lymph node involvement and the extent of tumor spread, has always been the standard survival prediction tool for gynecological cancer patients (16, 17). Similarly, we also identified T stage and N stage as the most important prognostic factors in the final nomogram. In addition, tumor size was found to be one of the key prognostic factors in our study. Generally, tumor size has been regarded as a factor indicating invasive ability without prognostic significance, but tumor size was not included in the current FIGO staging. However, a large National Cancer Database study with 2902 stage IIIC USC patients demonstrated that tumor size was associated with significantly worse survival (P < 0.0005) (19), which was consistent with our findings. We believe that USC patients with smaller tumor sizes are more likely to receive cytoreductive surgery with a higher success rate, which indirectly improves survival. In our study, calibration plots showed optimal consistency between the nomogram prediction and actual observation, which guaranteed the repeatability and reliability of the established nomogram. Excellent discrimination was demonstrated by the significantly higher C-index of the nomogram than that of the FIGO staging system (P < 0.001). To further illustrate the independent discrimination ability of the nomogram, patients were divided into low-risk, intermediate-risk and high-risk subgroups based on the 25th and 75th percentile of the total scores (Table 3). In each FIGO stage, respective KM survival curves of different risk subgroups were plotted, as shown in Supplementary Fig. 2.
However, several limitations should be considered. First, our study is limited by the retrospective nature of the data and selective bias inevitably exists. Second, several recognized prognostic parameters were not available in the SEER database, including the tumor biomarkers CA125. Third, further external validation is warranted to confirm the prognostic utility and expand the application of our nomogram.