Endometrial cancer is one of the most common gynecologic cancers with a rising incidence (1). It was estimated that 417,000 women were diagnosed, and 97,300 women died of this disease in 2020 (2). According to the International Federation of Gynecology and Obstetrics (FIGO), the lymph node metastasis (LNM) status of patients with endometrial cancer (EC) is an essential reference for assigning a pathological stage, guiding adjuvant treatment, and determining prognostic value (3). The 5-year overall survival (OS) rate of patients with either pelvic lymph node metastasis (PLN+) or para-aortic lymph node metastasis (PAN+) is roughly 57–66% (4).

The FIGO 2009 Staging stratified Stage IIIC into Stage IIIC1 (PLN+) and Stage IIIC2 (PAN+ ± PLN+) by the presence of para-aortic lymph node metastasis, indicating a worse prognosis with PAN involvement (5–7). The most common LNM patterns are well-recognized as PLN+PAN- and PLN+PAN+, since the reported incidence of isolated para-aortic lymph node metastasis (PLN-PAN+) is merely around 1–3% in EC (8, 9). With the further investigation on LNM patterns in EC, the incidence of PLN-PAN+ among patients with LNM differs widely in recent studies, varying from 6 to 46.2% (5, 10–23). The adequacy and extent of lymphadenectomy in EC remain controversial worldwide, dominantly on the extent of para-aortic lymph node dissection (24, 25). The increasing incidence of PLN-PAN+ would partially strengthen the insight for para-aortic lymph node dissection. Also, the prognostic impact of PLN-PAN+ among patients with LNM remains unclear. Thus, a large sample size of EC cases is urgent to obtain the objective incidence and prognostic implications of PLN-PAN+.

It is well-acknowledged that myometrial invasion, degree of differentiation, histological type, tumor size, and tumor site are used as references for guiding surgical planning (26–29). Also, the National Comprehensive Cancer Network (NCCN) guidelines make recommendations regarding sentinel lymph nodes (SLNs) in EC. It is worth exploring further whether these clinical features and detective techniques could play a role in evaluating PAN+(30), especially PLN-PAN+.

In this study, we aim to describe the incidence and characteristics of PLN-PAN+ in a large-scale sample of patients with EC from multicenter across China and seek to evaluate the prognostic impact of PLN-PAN+ on recurrence and disease-specific survival. Moreover, the accuracy of the current methods used to identify techniques for predicting PAN+ would be tested.

With an extensive collection of medical records from 30 centers, we comprehensively analyzed LNM patterns in 4,001 individuals who had undergone simultaneous PLN and PAN dissection. In this study, we demonstrated the non-negligible incidence and terrible prognostic impact of PLN-PAN+ among patients with EC.

The overall LNM rate was 10.8% among the patients who underwent both PLN and PAN dissection, which was similar to the rate of 9.9–21.6% derived from the previous study (5, 10–23). In our cohort, the incidence of PLN-PAN+ was 2.8%, which was in close agreement with 3% in the research of Kumar et al. (9) and 2.8% in Todo et al. (5). Moreover, regarding the distribution of LNM sites, our findings show that metastasis occurs most frequently in PAN+, 6.6%. The prevalence distribution is consistent with another study by Odagiri et al. (15). Together, these results indicate that PLN-PAN+, a key site in a postoperative stage in EC, is critical for solving postoperative personalized adjuvant treatment.

Unexpectedly, we uncovered that over one-fourth (26.5%, 114/431) of individuals with positive LNM showed PLN-PAN+ in this large-sample study. For comparison, we further calculated the incidence of PLN-PAN+ from other research studies, which were all based on a small sample size, and found that it varied from 6 to 46.2%, (5, 10–23). Over the past decade, the widely used Mayo criteria (18) have provided well-recognized risk factors for LNM in EC. According to their protocol, lymphadenectomy is not recommended for the low-risk group. However, in our study, 1.9% of patients in the low-risk group identified by Mayo criteria, which is not small probability events, were PLN-PAN+. Therefore, PLN-PAN+ with low-risk patients is rare but may occur. These results make us rethink the high-risk factors for LNM in EC.

Delaying recurrence and improving the prognosis of ECs are the primary concerns of patients and gynecologic oncologists. In this study, we discussed the value of PLN-PAN+ in recurrence and prognosis. Referring to non-LNM, LNM demonstrated sharp decreases in both RFS and DSS. Although PLN+PAN+ showed a worse prognostic trend, no statistically significant differences were laid on clinical outcomes among the different patterns of metastasis: PLN-PAN+, PLN+PAN-, and PLN+PAN+. These results were consistent with the study of Guo et al. (23), indicating that relapse and prognosis are strongly associated with all the LNM patterns. During our postoperative follow-up, we found that para-aortic lymph node recurrence occurred in seven patients. Notably, six of the seven patients did not undergo PAN dissection, and the other one patient did not undergo systematic lymph node dissection, indicating that PAN is a high-risk location for tumor metastasis. Thus, PLN-PAN+ is also an important issue that deserves further attention from gynecologic oncologists. Moreover, the “jumping metastasis” in the lymphatic drainage pathway makes LNM status more difficult to predict in EC.

The pre- and intraoperative identification of patients at high risk for PLN-PAN+ is challenging (18). The current intraoperative assessment of LNM status mainly uses high-risk factors, gross LNs, or cervical tracer-labeled SLNs (32). Our findings demonstrated the limitations of using LVSI and intraoperative gross LNs in the assessment of PAN+. According to the Sentinel Lymph Node Biopsy vs. Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging (33) prospective cohort study, SLN biopsy had an acceptable diagnostic accuracy of positive LN in high-grade EC with a high risk of LNM. However, the potential risk of missing PLN-PAN+ remains one of the main concerns and criticisms (30, 34), because SLN labeling on cervical tracer injection may not adequately map the PAN area (35). Then, additional fundal site injections of SLN labeling are needed to improve the assessment of PANs (36, 37). Multinu et al. found that ultrastaging and pathologic review can identify occult pelvic lymph node metastases and reduce the prevalence of true PLN-PAN+ (38). Clinicopathological and intraoperative observations might not be enough to predict PLN-PAN+ in the pre- and intraoperative stages. New biomarkers may be urgently needed for identifying PLN-PAN+ pre-operatively, which will be fulfilled along with the developing understanding of EC on the molecular level.

Our study has both limitations and strengths. First, this retrospective study led to a selection bias. Second, the molecular classification of EC could play a role in prognosis and lymph node metastasis patterns, but due to national conditions in China, the lack of such data prevents us from making a more adequate assessment. The strength mainly lies in the large population from multiple superior hospitals with standardized diagnosis and therapy procedures. To the best of our knowledge, this study represents the largest series reporting PLN-PAN+ cases.

In this nationwide, a large number and retrospective study, the PLN-PAN+ pattern was comparable to the other two metastasis patterns (PLN+PAN- and PLN+PAN+) in terms of incidence rate and prognostic impact. Clinical methods and molecular biomarkers are urgently needed to identify patients at high risk for PLN-PAN+ in the following studies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

GC, CS, and BW worked on the design of the study. Data collection was conducted by YS, CZ, SY, CX, MX, GL, JihL, BL, JW, WZ, JieZ, WC, HG, RG, FX, XW, LH, XZ, XL, PZ, JiaZ, JM, QY, YFa, and KL. XY, YD, ZW, and JinL were responsible for the cohort follow-up. WL, YFu, and JJ performed data extraction and analysis and wrote the manuscript. BK and XC supervised the whole study. All authors contributed to the article and approved the submitted version.

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.

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