Objective To assess the long term outcomes and prognosis of sentinel lymph node sampling compared with full lymph node dissection in endometrial cancer patients.
Methods We used the Surveillance, Epidemiology, and End Results (SEER) database for information on women diagnosed with endometrial cancer from 2010 to 2019. We conducted a comparison including overall survival between patients who had undergone sentinel lymph node sampling only and patients who had undergone formal lymph node dissection. Propensity score matching was performed according to the patient’s age, type of endometrial cancer, grade and stage of disease, and adjuvant therapy. Subgroup analyses were performed according to type and grade of endometrial cancer.
Results 41411 endometrial cancer patients were identified through the database. After matching, 6019 patients each were included in the sentinel lymph node and lymph node dissection groups. Median (interquartile range (IQR)) follow-up time was 16 (7-31) months in both groups. One year survival rates were longer in the sentinel lymph node group compared with the lymph node dissection group (hazard ratio (HR) 1.61 (95% confidence interval (CI) 1.17 to 2.21); p=0.004). Subgroups analysis according to grade of disease showed that 1 year survival rates were longer in the sentinel lymph node group in patients with endometrioid-type grade 1–2 endometrial cancer (HR 1.70 (95% CI 1.31 to 2.56); p=0.01), while no difference in survival was found between the sentinel lymph node and lymph node dissection groups in the subgroup of patients with high grade endometrial cancer (HR 1.40 (95%CI 0.94 to 2.24); p=0.17). In patients with low grade endometrial cancer included in the sentinel lymph node group, only 7% had lymph nodes positive for malignancy compared with 17% in the high grade group.
Conclusion Survival rates were not compromised in endometrial cancer patients undergoing sentinel lymph node sampling versus full lymph node dissection for all grades of disease.
- SLN and Lympadenectomy
- Uterine Cancer
- Endometrial Neoplasms
Data availability statement
Data are available in a public, open access repository.
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What is already known on this topic
Retrospective studies have mostly confirmed the long term oncological safety of sentinel lymph node evaluation in low grade endometrial carcinoma and recently also in high grade carcinoma.
Studies were mostly single centered and large studies with comprehensive databases have not been conducted.
What this study adds
Our large national database study, reflecting the outcomes and prognosis of patients with endometrial cancer, showed that for low and high grade cancer, sentinel lymph node dissection was safe.
How this study might affect research, practice or policy
Randomized trials are needed for further data on referral of low, intermediate, and high grade endometrial cancer patients to either sentinel lymph node dissection or full lymph node dissection.
In the future, decisions for adjuvant treatment in endometrial cancer patients could be based on sentinel lymph node sampling results, and on the molecular signature of the tumor.
Endometrial carcinoma is the most common gynecological malignancy in developed countries.1 In most endometrial cancer cases, treatment consists of diagnostic and therapeutic surgery and, according to surgical staging, adjuvant radiotherapy or chemotherapy is considered.2 3 In recent years, the tumor molecular profiling by cancer genome atlas strategy has been added to the decision making process on adjuvant treatment, and hopefully in the future will improve overall survival in endometrial cancer patients.4 5
The standard surgical procedure for endometrial cancer patients is total extrafascial hysterectomy, and bilateral salpingo-oopherectomy with pelvic and para-aortic lymph node evaluation. The rate of lymph node metastases varies with tumor stage and grade, from 3–5% in minimally invasive low grade tumors to >20% in high grade deep myometrial invasive tumors.6 Women who do not have lymph node evaluation are incompletely staged and thus information guiding further treatment is lacking. Some believe that the morbidity associated with lymph node dissection outweighs its benefits, specifically in cases where the likelihood of nodal involvement is low.7 The sentinel lymph node is defined as the first lymph node to which cancer cells from a primary tumor metastasize. In recent years, the approach to lymph node evaluation in endometrial cancer patients has consisted of an injection of tracer to the uterine cervix which identifies sentinel nodes. If there is no metastasis to the sentinel lymph nodes, it is extrapolated that the rest of the lymph nodes are free of metastasis and therefore full lymphadenectomy can be omitted.
The Memorial Sloan Kettering protocol is the accepted method for sentinel lymph node evaluation.8 Advantages of the sentinel lymph node method include reduction of potential complications and morbidity, such as vessel injury, lymphedema, lymphocele, and associated cellulitis, and reduction of the operation time compared with full lymphadenectomy. Moreover, the sentinel lymph node method enables accurate detection of sentinel lymph nodes in each hemipelvis and the ultrastaging of the lymph nodes in histological processing, which allows detection of low volume metastasis and further guides treatment.9 10 Some have also advocated that the addition of sentinel lymph node sampling to the ultrastaging procedure might improve clinical outcomes, due to enhanced detection of positive lymph nodes with micrometastases, and thus selection of the appropriate treatment.11–13
Studies have confirmed the accuracy and long term oncological safety of the sentinel lymph node evaluation in low grade endometrial cancer.10 14 15 Recently, some studies have also showed its feasibility in high grade endometrial cancer patients.16 17 However, large studies with comprehensive databases are still missing, and most studies reflected a single institute experience. The objective of this study was to assess the long term outcomes of the sentinel lymph node procedure compared with full lymph node dissection in endometrial cancer patients.
Study Participants and Follow-up
With permission of the Surveillance, Epidemiology, and End Results (SEER) program, clinicopathological and prognosis data of women diagnosed with endometrial cancer were collected and analyzed. Patients were selected and collected in tabular format in the case listing option of the SEER Stat software.18 Included were endometrial cancer patients diagnosed between January 1, 2010, and December 31, 2019, who were reported in the SEER plus 17 registries, with a record of either sentinel node or lymph node dissection and a known grade of disease. Excluded were patients diagnosed with uterine sarcoma, patients diagnosed with endometrial cancer aged <20 years, and patients with neoadjuvant treatment or an unknown sequence of systemic therapy and surgery. The recorded data included age and year at diagnosis, endometrial carcinoma histology, type of endometrial cancer, stage and grade of disease, summary of lymph node dissection, number of positive lymph nodes, peritoneal cytology, adjuvant therapy, cause of death, and overall survival.
A comparison between patients who had undergone sentinel biopsy only and patients who had undergone pelvic lymph node dissection was conducted. The sentinel lymph node procedure is defined in the SEER data. Of the remaining non-sentinel lymph node cases, patients in whom four or more lymph nodes were removed were included in the lymph node dissection group. Survival was calculated as the number of months from a diagnosis of endometrial cancer to death or the last follow-up.
Propensity score matching with a ratio of 1:1 was performed according to the patient’s age, type of endometrial cancer, grade and stage of disease, adjuvant therapy, and year of diagnosis for similar follow-up time.
Subgroup analysis of survival rates were conducted:
in patients diagnosed with endometrioid-type grade 1–2 endometrial cancer, according to the type of lymph node evaluation; and
in patients diagnosed with non-endometrioid-type (excluding rare types such as clear cell and mixed cell carcinoma)/endometrioid-type grade 3 endometrial cancer according to the type of lymph node evaluation.
Data were extracted as case listing tables and further analyzed with SPSS software (SPSS, Chicago, Illinois, USA). Categorical variables are presented as number (%), continuous variables with normal distribution as mean (standard deviation (SD)), or otherwise as median (interquartile range (IQR), 25 and 75 percentiles). Patient characteristics were compared with Pearson’s χ2 and Fisher’s exact tests. Kaplan–Meier and log rank tests were used to estimate survival and compare differences between groups, respectively. Cox regression was applied for investigating the effect of several variables on survival. P<0.05 was considered statistically significant.
Overall, between 2010 and 2019, 41 411 patients were diagnosed with endometrial cancer, had a record of either sentinel lymph node sampling or lymph node dissection, and matched our inclusion criteria. After propensity score matching, 6019 patients were included in each group. The clinical and histological characteristics of each group are detailed in Table 1. Despite propensity score matching, in the lymph node dissection group, more patients with positive lymph nodes were observed (p=0.03), but when looking at the numbers, the differences were clinically minimal, with only a 1% difference between the groups. Median follow-up time was 16 (IQR 7-31) months in both groups.
A survival analysis comparing sentinel lymph node and lymph node dissection patients was conducted (Figure 1). The 1 year survival rate of patients in the sentinel lymph node group was 98.7% (±standard error (SE) 0.2%), while in the lymph node dissection group the 1 year survival rate was 98.0% (±0.2%) (hazard ratio (HR) 1.61 (95% confidence interval (CI) 1.17 to 2.21); p=0.004).
To adjust for the effect of the positive lymph node rate, which was found to be significantly different between the groups, a multivariate model of survival was conducted. Both type of lymph node dissection (HR 1.45, 95% CI 1.23 to 1.72, p<0.001) and metastatic lymph node status (HR 4.28, 95% CI 3.54 to 5.18, p<0.001) were found to be significant variables that negatively influenced survival.
Subgroup Analyses: Endometrioid-type Grade 1–2 Endometrial Cancer
In a subgroup analysis of patients with endometrioid-type grade 1–2 endometrial cancer, 10036 patients were included: 5012 patients in the sentinel lymph node group and 5024 patients in the lymph node dissection group. The characteristics of each group are detailed in Table 2. In the selected grade 1 patients (n=3296) that had undergone sentinel lymph node, the percentage of metastatic lymph nodes was 5% (n=150). Median (IQR) follow-up time was 16 (7-30) months in both the sentinel lymph node and lymph node dissection groups.
Survival analysis comparing sentinel lymph node and lymph node dissection patients was conducted (figure 2). The 1 year survival rate of patients in the sentinel lymph node group was 99.1% (±SE 0.2%), while in the lymph node dissection group the 1 year survival rate was 98.5% (±0.2%) (HR 1.70 (95% CI 1.31 to 2.56); p=0.01).
To adjust for the effect of stage of disease and positive lymph node rate, which were found to be significantly different between the groups, a multivariate model of survival was conducted. Both type of lymph node dissection (HR 1.64, 95% CI 1.29 to 2.07; p<0.001) and stage of disease (HR 2.40, 95% CI 1.93 to 2.94; p<0.001) were found to be significant variables that negatively influenced survival, while metastatic lymph node status (HR 1.84, 95% CI 0.74 to 4.55, p=0.19) was not significant.
High Grade Endometrial Cancer (Non-endometrioid-type/Endometrioid-type Grade 3)
In a subgroup analysis of patients with high grade endometrial cancer, 2002 patients were identified: 1007 patients in the sentinel lymph node group and 995 patients in the lymph node dissection group. The characteristics of each group are detailed in Table 3. No differences in demographics or clinical characteristics were found. Median follow-up time was 18 (IQR 8-37) months in the sentinel lymph node group and 17 (8-34) months in the lymph node dissection group.
Survival analysis comparing sentinel lymph node and lymph node dissection patients was conducted (online supplemental figure S1). The 1 year survival rate of patients in the sentinel lymph node group was 96.4% (±SE 0.7%), while in the lymph node dissection group the 1 year survival rate was 94.8%(±0.8%) (HR 1.40 (95 %CI 0.94 to 2.24); p=0.17).
Summary of Main Results
This study explored the SEER database, a large multicenter database for patients with endometrial cancer, to determine if patients who had undergone sentinel lymph node evaluation had significantly longer survival compared with those who had a full lymph node dissection, irrespective of age, stage, grade, histology, or adjuvant therapy. With a median follow-up time of 16–18 months, 1 year survival rates were calculated in the subgroup analyses according to grade of disease. While in the low grade group longer survival rates were observed in the sentinel lymph node group, no differences in survival between the sentinel lymph node and lymph node dissection groups were found in the subgroup of high grade patients.
Results in the Context of Published Literature
Surgical treatment has been revolutionized with the introduction of the sentinel lymph node. In endometrial cancer, sentinel lymph node evaluation was first introduced in 1996 in a study of 15 patients who underwent laparotomy for moderate risk to high risk endometrial cancer.19 Years later, Abu-Rustum and colleagues introduced their protocol for sentinel lymph node evaluation, and later retrospective studies, prospective studies, and a Cochrane review showed that the false negative rate had decreased from 15% to 2%.15 20–22 Albite, a key factor in decision making when planning for endometrial cancer surgery, is still the histologic subtype. In a retrospective comparison of low grade, low stage endometrial cancer, comparing full lymphadenectomy, no lymphadenectomy, and sentinel lymph node sampling, no significant difference was seen between the extent of lymphadenectomy and the risk of recurrence.14 In line with previous studies, we also showed in the sentinel lymph node group a low incidence of positive lymph nodes in low grade endometrial cancer patients and specifically in grade 1. When full lymphadenectomy is performed, the risk of lymph node involvement was reported to be <5% in low grade endometrial cancer. These rates are comparable with the rates observed in the sentinel lymph node group.
Our study showed increased survival in the sentinel lymph node group of patients compared with patients who had a full lymphadenectomy. This finding is in line with Kogan et al who showed in their single institute retrospective trial improved survival outcomes for the addition of sentinel lymph node evaluation to lymph node dissection, with decreased recurrence.11 A systemic review and meta-analysis by Bogani et al included 3536 patients: 1249 (35.3%) undergoing sentinel lymph node evaluation and 2287 (64.7%) undergoing lymphadenectomy. No differences in overall recurrence rates and nodal specific recurrence were found.23 In the specific group of low grade/low risk endometrial cancer, the improved survival rates were also consistent with comparable survival between the two methods.24 Recently, Matsuo et al25 explored the SEER database for stage II endometrial cancer patients from 2010 to 2018 and showed a 45% yearly increase in sentinel lymph node biopsy utilization, with a concurrent decrease in the number of lymph nodes per sentinel lymph node procedure, and no difference in overall survival between the sentinel lymph node and lymph node dissection groups, consistent with results of our study.
In studies including patients diagnosed with high grade endometrial cancer, the risk of lymph node metastases was much higher (20–30%). Preliminary retrospective studies in high grade endometrial cancer analyzing the accuracy of sentinel lymph node evaluation compared with back up full lymphadenectomy, demonstrated that backup full lymphadenectomy identified an additional 1% of patients with nodal disease. No differences in recurrence or survival were observed between the groups.17 Altin el al published their retrospective experience with high grade deep invasive endometrial cancer in which 240 patients underwent sentinel lymph node sampling followed by full pelvic and para-aortic lymphadenectomy. Using the sentinel lymph node algorithm for grade 3, sensitivity was 97% with a negative predictive value of 98%.16
Other studies which included high risk patients with lymph node metastasis and specific high grade histologies confirmed the oncologic safety of sentinel lymph node evaluation compared with lymph node dissection.26 27 A meta-analysis of 17 original studies involving 1322 women confirmed a sensitivity of 88% and negative predictive value of 96%.28 Moreover, among 510 patients with non-invasive International Federation of Gynaecology and Obstetrics (FIGO) grade 1–2 endometrioid carcinoma, no positive sentinel lymph nodes were detected, but as previously demonstrated with full lymphadenectomy, in the group of patients with higher grade and deeper invasion, the rates of positive sentinel lymph nodes increased with increased myometrial invasion and grade to 24% in outer half invasion grade 3.29 However, the National Comprehensive Cancer Network (NCCN) guidelines state that sentinel lymph node mapping can be considered for the surgical staging of apparent uterine confined malignancy when there is no metastasis demonstrated by imaging studies or no obvious extrauterine disease at exploration of low grade cases.30
Even though the studies were retrospective, the NCCN still states that sentinel lymph node evaluation may also be used in high risk histologies.30 The SEER database includes about 50% of the US population and therefore might show trends in the surgical management of endometrial cancer. Our study confirms the guidelines and shows that in recent years, most sentinel lymph node biopsies are in low grade cases compared with high grade cases.
Strengths and Weaknesses
Our study had some limitations. First, the retrospective nature of our study may increase sources of bias. Second, one of the limitations of the SEER database is the lack of information on back up lymphadenectomy, although we assumed that less than four lymph nodes implied no systemic lymphadenectomy performed. Although the SEER database records if a sentinel lymph node procedure was performed, it does not have information on which specific protocol was used. Also, if an ultrastaging procedure was performed on lymph nodes, which surgical approach (open vs minimally invasive) was used is not reported, or the incidence of recurrence and type of recurrence. Due to the relatively new approach of sentinel lymph node evaluation in endometrial cancer patients, the median follow-up time of this group and matching controls were limited.
Implications for Practice and Future Research
An open label randomized trial was recently started for accrual of intermediate and high risk endometrial cancer patients with full lymph node dissection or sentinel lymph node evaluation. The results of this trial are anticipated in 2027.31 Until this time, we can base our practice on retrospective data, such as our study, that have confirmed the oncologic safety of the sentinel lymph node procedure in this specific population. We believe that in the future, decisions about adjuvant treatment in endometrial cancer patients will be based on sentinel lymph node results, and on the molecular signature of the tumor.
Our analysis suggests that survival was not compromised in endometrial cancer patients undergoing sentinel lymph node sampling compared with full lymph node dissection. Due to the small number of positive lymph nodes in low grade endometrial cancer patients, future studies should consider omitting lymph node evaluation completely in this selected population.
Data availability statement
Data are available in a public, open access repository.
Patient consent for publication
This study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) Program, following author authorization for using the database. This public population based cancer database is supported by the NCI ethics program and approval of all participants in this database are managed by the SEER program.
We are grateful to Ms Nili Stein from the Department of Community Medicine and Epidemiology, the Lady Davis Carmel Medical Center, for her help in the matching and for assistance in the statistical section of the study.
Contributors CN: data collection, statistical analysis, writing-original draft, methodology, and investigation, guarantor. YK: conceptualization, writing-review and editing, validation, and review. LO: validation and review. OL: writing-review and editing, validation, and review. YS: conceptualization, writing- review and editing, methodology, investigation, supervision and guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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