Clinical Features Related to Lymphatic Metastasis in Grade 3 Endometrioid Endometrial Cancer: A Retrospective Cross-Sectional Study
Endometrial cancer (EC) is one of the most common gynecological malignancies, with an increasing prevalence worldwide. In the United States, the number of EC patients is projected to reach 42.13 per 100,000 persons by 2030. In China, the incidence of EC has also been on the rise for decades. Approximately 75% of EC patients are diagnosed at an early stage, defined as stage I or II by the Federation of Gynecology and Obstetrics (FIGO). These patients can be treated promptly, resulting in a relatively good 5-year overall survival (OS) rate ranging from 74% to 91%. The primary treatment for EC is standard surgery, which includes hysterectomy, bilateral salpingo-oophorectomy, and evaluation of lymph node metastasis. Risk factors for EC are often considered when determining the extent of surgery.
Grade 3 (G3) endometrioid endometrial cancer (EEC) is classified as a high-risk factor for comprehensive surgery, such as pelvic or para-aortic lymphadenectomy (LND), according to Mayo Clinic standards. However, there is ongoing debate about whether systemic LND is necessary for all G3 EEC patients. Some researchers suggest that exclusive LND is unnecessary, as two randomized trials showed no survival benefit for the LND arm among early-stage EC patients. To minimize the side effects of LND, sentinel lymph node (SLN) biopsy has been utilized in high-risk EC cases. However, this technique is not widely available, especially in regions with limited medical resources. Additionally, there is the issue of pathological upgrading to G3 after surgery, making it challenging to decide on the surgical scope preoperatively to achieve maximal lesion resection with minimal injury.
This retrospective cross-sectional study aimed to evaluate the factors related to lymphatic metastasis (LM) in G3 EEC patients and determine the necessity of lymphadenectomy. The study included 3,751 EC patients admitted to the Obstetrics and Gynecology Hospital of Fudan University from January 2009 to April 2019. Clinical characteristics such as age, grade, stage, and pathological features were analyzed. A total of 1,235 EEC patients were included in the multivariable analysis, with 381 patients involved in the survival analysis due to sufficient follow-up information. Kaplan-Meier curves and log-rank tests were used to analyze survival rates.
Among the 1,235 EEC patients, 181 (14.7%) were categorized as G3, and 1,054 (85.3%) were grade 1 to grade 2 (G1-2). Multivariate analysis demonstrated that lymphovascular space invasion (LVSI), adnexal involvement (AI), and cervical stroma involvement (CSI) were independent risk factors for LM in the G3 cohort, with odds ratios of 3.4, 5.8, and 8.9, respectively. The LM rates increased from 3.3% (3/92) to 75% (9/12) for the G3 EEC cohort as the number of related risk factors increased from one to three. There were no significant differences in overall survival (OS) and progression-free survival (PFS) between the G3 and G1-2 EEC cohorts. Additionally, no survival advantage was observed for G3 EEC patients at an early stage with different adjuvant treatment plans.
The study found that for G3 EEC patients without other pathological positive factors, the LM rate was lower than those with other pathological positive factors. Survival analysis showed no difference between the G3 cohort and the G1-2 cohort. Different adjuvant treatments also had no impact on the overall survival for G3 EEC patients. These findings suggest that lymphadenectomy may not be necessary for G3 EEC patients without additional risk factors, while those with one or more risk factors may benefit from lymph node evaluation.
The study also highlighted the importance of LVSI, AI, and CSI as independent risk factors for LM in G3 EEC patients. LVSI was associated with a more than three-fold increase in LM rates, while AI and CSI were associated with five-fold and nine-fold increases, respectively. The combination of these risk factors further increased the likelihood of LM, with patients having all three risk factors showing a 75% LM rate. These results emphasize the need for careful preoperative evaluation and risk stratification to guide surgical decisions and avoid overtreatment.
In terms of survival, the study found no significant differences in OS and PFS between the G3 and G1-2 EEC cohorts. The 5-year OS was 100%, and the 5-year PFS was 98.2% for the entire cohort. Kaplan-Meier curves illustrated that the OS and PFS of the G3 group were not significantly shorter than those of the G1-2 group. In G3 EEC patients at stage I or II, there was no distinct difference in OS and PFS between subgroups receiving different adjuvant treatments or lymphadenectomy procedures. These findings suggest that less traumatic treatment options, such as pelvic LND alone, may be considered for G3 EEC patients at an early stage, as combined pelvic and para-aortic LND did not show a survival advantage.
The study also discussed the challenges in determining the depth of myometrial invasion (MI) and tumor size (TS) preoperatively. While deep MI (greater than 50%) is a known risk factor for LM, accurate evaluation before surgery is difficult. The NCCN guidelines recommend pelvic enhanced magnetic resonance imaging (MRI) to assess myometrial invasion, but the accuracy of MRI is only about 68% for T2-weighted imaging. Similarly, TS is a controversial risk factor, with different guidelines providing inconsistent recommendations. The latest NCCN guidelines have removed TS as a risk factor due to the difficulty in accurately measuring irregularly shaped lesions.
Age was another factor considered in the study, with higher age generally associated with a higher risk of LM. However, the age cut-off remains inconsistent, with the latest NCCN guidelines using “age ≥60” as a cut-off, while the study found that “≥70 years old” had a significant impact on LM rates. These discrepancies highlight the need for standardized criteria and further research to refine risk stratification models.
The study’s strengths include its long follow-up duration of nearly ten years and the robustness of the identified high-risk factors to adjustments. The findings provide clinically relevant data that can help guide surgical decisions, particularly in regions with limited medical resources. However, the study also has limitations, including its retrospective design, which may introduce selection bias. Additionally, only 30.9% of patients had complete follow-up data, which could affect the accuracy of survival analysis. Nevertheless, the study’s results are consistent with previous research and provide valuable insights into the management of G3 EEC patients.
In conclusion, this study highlights the importance of risk stratification in guiding surgical decisions for G3 EEC patients. LVSI, AI, and CSI are independent risk factors for LM, and their presence should be carefully evaluated preoperatively. For G3 EEC patients without additional risk factors, lymphadenectomy may not be necessary, while those with one or more risk factors may benefit from lymph node evaluation. The study also found no significant differences in survival between G3 and G1-2 EEC patients, suggesting that less traumatic treatment options may be considered for early-stage G3 EEC patients. These findings contribute to the ongoing debate about the necessity of lymphadenectomy in G3 EEC and provide evidence-based recommendations for clinical practice.
doi.org/10.1097/CM9.0000000000001749
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