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Abstract
Objective The prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients.
Methods Patients with SLNs–isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan–Meier methods.
Results 494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs–isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1–3.0) and 2.6 years (IQR 0.6–4.2) in the SLN–isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN–isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion.
Conclusions Patients with SLNs–isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs–isolated tumor cells was not associated with worse overall survival.
- Endometrial Neoplasms
- Sentinel Lymph Node
- Lymphatic Metastasis
- Lymph Nodes
- Uterine Cancer
Data availability statement
Data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Isolated tumor cells detected in sentinel lymph nodes (SLNs) do not affect International Federation of Obstetrics and Gynecology (FIGO) endometrial cancer staging.
Limited data exist comparing patients with SLNs–isolated tumor cells with those with node negative disease after stratification by risk factors and adjuvant treatment.
The prognostic value of isolated tumor cells in SLNs still needs to be determined.
WHAT THIS STUDY ADDS
Our study shows that recurrence free survival among patients with low risk endometrial cancer and no adjuvant treatment was significantly worse in patients with SLNs–isolated tumor cells compared with negative nodes.
However, we did not observe any significant difference in overall survival.
Lymphovascular space invasion and FIGO grade 2 were associated with a higher risk of recurrence.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
Future research could focus on the subset of patients with low risk endometrial cancer and SLNs–isolated tumor cells who forgo adjuvant treatment, in order to standardize follow-up and assess the role of adjuvant treatment.
Incorporation of endometrial cancer molecular classification may provide additional guidance in defining prognosis.
Introduction
Endometrial cancer is the most common gynecologic malignancy in developed countries.1 2 Since lymph node status represents one of the most important prognostic factors, standard treatment includes surgical lymph node staging.3 The introduction of sentinel lymph node (SLN) mapping, as an alternative to lymphadenectomy, improved the detection of nodal extrauterine disease, especially in patients with high grade tumors or myometrial invasion.4 5 Ultrastaging of SLNs allows for the identification of low volume metastasis: micrometastasis (>0.2 to ≤2.0 mm) and isolated tumor cells (≤0.2 mm).6 Low volume metastasis is estimated to be approximately 50% of nodal disease of SLNs,7 8 and endometrial cancer patients with low grade endometrioid histology are more likely to be diagnosed with low volume metastasis than other patients with high grade endometrioid or non-endometrioid histotypes.9–11 The presence of isolated tumor cells in ultrastaged SLNs does not change the International Federation of Obstetrics and Gynecology (FIGO) stage grouping, either in the 2009 or 2023 guidelines.12 13 The American Joint Committee on Cancer (eighth edition update 2018) included pN0(i+), a new category for SLNs–isolated tumor cells,14 but the prognostic value of isolated tumor cells in endometrial cancer is still unclear.
In a multi-institutional, international study, we showed that patients with isolated tumor cells and uterine risk factors, such as non-endometrioid histology, lymphovascular space invasion, or uterine serosal involvement, had a poor prognosis, regardless of adjuvant therapy.10 To appropriately triage patients with SLNs–isolated tumor cells, there is a need to identify a low risk group who can forgo adjuvant therapy with a favorable prognosis. A recent study, including only endometrioid early stage endometrial cancer patients with SLNs–isolated tumor cells, showed no benefit of adjuvant therapy, and the risk of recurrence was low regardless of treatment type.15 Further data from studies on endometrial cancer and low volume metastasis have reported excellent outcomes among the few patients with SLNs–isolated tumor cells and no additional uterine risk factors who received no adjuvant treatment or vaginal brachytherapy alone.10 16 17
The prognostic significance of SLNs–isolated tumor cells in patients with otherwise low risk disease remains uncertain, and there is limited information available about patients who did not receive adjuvant treatment. Comparison between patients with isolated tumor cells and negative nodes is further complicated by heterogeneity in study design, including variations in adjuvant therapy, presence of high risk uterine factors, and lack of distinction between different types of low volume metastasis.16 18–20 Conducting analyses focusing on similar risk factors and adjuvant treatment strategies among those with isolated tumor cells and negative nodes could increase clarity. In low risk endometrial cancer patients who did not have adjuvant treatment, this study aimed to assess the prognostic value of SLNs–isolated tumor cells compared with patients with a similar risk profile and negative SLNs.
Methods
This multi-institutional international retrospective cohort study was conducted after institutional review board (Mayo Clinic Rochester) approval, and data sharing agreements were in place for each participating center. Surgically staged patients who had FIGO stage IA endometrial cancer with low risk features (grade 1 or 2 endometrioid histology), no adjuvant treatment, and SLNs–isolated tumor cells or negative nodes on SLN biopsy were included. Exclusion criteria included patients with invasive synchronous cancer, neoadjuvant therapy, non-endometrioid or grade 3 histology, FIGO stage IB or greater disease, unknown adjuvant therapy, or receipt of adjuvant treatment of any kind (vaginal brachytherapy, external beam radiation therapy, or chemotherapy).
Collection was restricted to patients undergoing surgery before December 31, 2019, to allow time for follow-up. Patients with isolated tumor cells were collected from all centers between March 1, 2013 and December 31, 2019, and those with negative SLNs from the primary site (Mayo Clinic Rochester) between October 1, 2013 and December 31, 2018. SLNs–isolated tumor cells was defined as clusters of cells ≤0.2 mm in greatest diameter in a single section. Lymphovascular space invasion was classified as present or absent. The study population was grouped according to SLN status in patients with SLNs–isolated tumor cells versus patients who were node negative. Further comparative analysis between the two cohorts was carried out after excluding patients with lymphovascular space invasion, according to the most recent European Congress on Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology definition of low risk endometrial cancer.21 Primary outcomes were recurrence free survival (event=first recurrence at any site), non-vaginal recurrence free survival (event=first recurrence is non-vaginal), and overall survival (event=death). Additional details regarding surgery, data collection, and statistical methods are available in the appendix (online supplemental file 1).
Supplemental material
In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected editorial team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.
Results
We identified 177 patients with isolated tumor cells from 21 centers, and 694 node negative patients from the primary center (Mayo Clinic Rochester). After exclusion criteria, 494 patients from 15 centers with FIGO stage IA, low grade endometrioid endometrial cancer, who did not receive adjuvant treatment, were included in the final analysis. The study flowchart is shown in Figure 1.
Patient flowchart of inclusion and exclusion criteria for the (A) node negative cohort and (B) sentinel lymph node (SLN)–isolated tumor cell cohort. EC, endometrial cancer.
Baseline Characteristics
Of 494 patients, 452 (91.5%) were node negative and 42 (8.5%) had isolated tumor cells, based on the SLN biopsy ultrastaging. There were no significant differences in clinicopathologic characteristics between the two cohorts, except for the presence of lymphovascular space invasion: 16.7% (n=7) in isolated tumor cell versus 1.5% (n=7) in node negative cohorts (p<0.01) (Table 1).
Clinicopathologic characteristics of patients in the two cohorts*
Of the 42 isolated tumor cell patients, 35 (83.3%) had SLN biopsy alone while 6 (14.3%) underwent SLN biopsy and pelvic lymphadenectomy, and 1 (2.4%) had SLN biopsy and pelvic and para-aortic lymphadenectomy. Regarding the node negative cohort, 379 (83.8%) patients received staging with SLN biopsy alone, 70 (15.5%) had SLN biopsy and pelvic lymphadenectomy, and 3 (0.7%) had SLN biopsy and pelvic and para-aortic lymphadenectomy. No additional metastases were observed in the pelvic and para-aortic lymph nodes in both groups (online supplemental Table 1).
Recurrence Free Survival and Predictors of Recurrence
Recurrence within 5 years was documented in 21 (4.3%) patients (5 SLNs–isolated tumor cells, 16 node negative); vaginal recurrence occurred in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). The isolated tumor cell patient with isolated vaginal recurrence received chemotherapy combined with radiotherapy as salvage treatment and was alive at 32 months of follow-up. Among the four non-vaginal recurrences within the isolated tumor cell patients, one was in the pelvic lymph nodes only. This patient did not receive treatment for the relapse because of a personal decision and was alive at 26.1 months of follow-up. Two patients with non-vaginal recurrence, one with a peritoneal pattern and one with a distant lymphatic pattern (inguinofemoral and pelvic), were subsequently treated with systemic treatment and were alive at 59.9 and 48.5 months of follow-up, respectively. The patient with hematogenous recurrence had an unknown status for the treatment at the time of recurrence and died of other causes. Details of patients with recurrence are summarized in online supplemental Table 2.
Median time to recurrence was 1.0 years (interquartile range (IQR) 0.5-1.2) and 2.4 years (IQR 1.6–4.0) for the SLN–isolated tumor cell patients and node negative patients, respectively. Among the remaining 473 patients without a documented recurrence (37 SLNs–isolated tumor cells, 436 node negative), median duration of follow-up was 2.3 years (IQR 1.1–3.0) and 2.6 years (IQR 0.6–4.2) in the SLN–isolated tumor cell and node negative patients, respectively. SLN–isolated tumor cell patients had worse recurrence free survival (log rank p<0.01) compared with node negative patients (Figure 2A). The 5 year recurrence free survival rates were 85.1% (95% confidence interval (CI) 73.8 to 98.2) and 90.2% (95% CI 84.9 to 95.8) among the SLN–isolated tumor cell and node-negative patients, respectively. In a subset analysis, we excluded 14 patients with the presence of lymphovascular space invasion (n=7 SLNs–isolated tumor cells, n=7 node negative). In this subset without lymphovascular space invasion, SLN–isolated tumor cell patients still had worse recurrence free survival (log rank p=0.05) compared with node negative patients (Figure 2B), but this was not statistically significant. The 5 year recurrence free survival rates were 89.5% (95% CI 78.8 to 100) and 91.1% (95% CI 86.0 to 96.6) among the SLN–isolated tumor cell and node negative patients, respectively.
In addition to worse recurrence free survival, SLN–isolated tumor cell patients had worse non-vaginal recurrence free survival than node negative patients; this was true in the overall cohort and in the subset of patients without lymphovascular space invasion (log rank p<0.01 for both; Figure 2C,D). Non-vaginal recurrence free survival estimates at year 5 were close and had overlapping 95% CIs for SLN–isolated tumor cell and node negative patients (88.2% (95% CI 77.8 to 100) vs 91.9% (95% CI 86.7 to 97.4), respectively). This was similar in the subset of patients without lymphovascular space invasion.
Kaplan–Meier curves estimating survival by node status. (A) Recurrence free survival in the whole population. (B) Recurrence free survival in the population without lymphovascular space invasion. (C) Non-vaginal recurrence free survival in the whole population. (D) Non-vaginal recurrence free survival in the population without lymphovascular space invasion. (E) Overall survival in the whole population. (F) Overall survival in the population without lymphovascular space invasion. ITC, isolated tumor cells.
In univariate analysis (Table 2), SLNs–isolated tumor cells versus node negative, presence of lymphovascular space invasion versus absence, and FIGO grade 2 versus 1 were significantly associated with both recurrence events (any recurrence and non-vaginal). Limited by numbers, we kept multivariable analyses simple considering our covariate of interest, SLN–isolated tumor cell versus node negative cohorts, in one model, with lymphovascular space invasion and FIGO grade in another (Table 3). For any recurrence and non-vaginal recurrence, along with SLN node status, both the presence of lymphovascular space invasion and FIGO grade 2 maintained statistical significance. In the subset without lymphovascular invasion, FIGO grade 2 versus 1 (hazard ratio (HR) 3.15; 95% CI 1.21 to 8.17; p<0.01) was significantly associated with recurrence. After considering the covariate of interest, the association for FIGO grade 2 remained statistically significant (adjusted HR 3.04; 95% CI 1.17 to 7.91; p=0.02) (Table 3). Similar results were found when considering non-vaginal recurrence.
Univariate analysis for predictors of any recurrence and non-vaginal recurrence
Adjusted models for predictors of any recurrence and non-vaginal recurrence within 5 years
Death Information and Overall Survival
Of the 494 patients, 17 patients died within the first 5 years after surgery (1 SLNs–isolated tumor cells, 16 node negative). Two of the 16 node negative patients died of recurrent disease, 13 of other causes, and 1 of unknown cause, while the 1 SLN–isolated tumor cell patient died of other causes. Time to death was 2.0 years for the one SLN–isolated tumor cell patient and 2.7 years (IQR 2.1–4.0) for the 16 node negative patients. Among the remaining 477 patients who were alive (41 SLN–isolated tumor cell, 436 node negative), median duration of follow-up was 2.5 years (IQR 1.9–3.2) and 4.5 years (IQR 3.1–5.0) in the SLN–isolated tumor cell and node negative patients, respectively. The 5 year overall survival rates were 96.8% (95% CI 90.8 to 100) and 94.9% (95% CI 92.3 to 97.5) for the SLN–isolated tumor cell and node negative patients, respectively.
Overall survival was not different between the groups (log rank p=0.80) (Figure 2E). In the subset analysis of patients without lymphovascular space invasion, overall survival remained similar between SLN–isolated tumor cell and node negative patients (log rank p=0.72) (Figure 2F). Death within 5 years was not associated with SLN node status (HR 1.29; 95% CI 0.17 to 9.88; p=0.80).
Discussion
Summary of Main Results
Our multi-institutional international study is the first to investigate the prognostic significance of isolated tumor cells in patients with low risk endometrial carcinoma who did not undergo adjuvant therapy. We compared outcomes of SLN–isolated tumor cell with SLN node negative patients who had similar low risk uterine profiles. SLN–isolated tumor cell patients had worse recurrence free survival compared with SLN node-negative patients with low risk primary tumors, even after excluding those with lymphovascular space invasion. However, overall survival was not different between the two cohorts, for the full sample and the subset excluding patients with lymphovascular space invasion.
Results in the Context of Published Literature
Our findings regarding recurrence free survival in SLN–isolated tumor cell patients with low risk endometrial cancer contrast with previous investigations. Plante et al reported on 31 cases of isolated tumor cells, compared with 43 macrometastasis, 11 micrometastasis, and 434 node negative patients.16 They concluded that patients with isolated tumor cells have an excellent outcome, comparable with node negative patients (3 year progression free survival rates for isolated tumor cell vs node negative patients, 95.5% vs 87.6%). Notably, none of the patients (0/10) with isolated tumor cells who received no adjuvant therapy or vaginal brachytherapy only recurred. However, only 2 of the 31 isolated tumor cell patients had a low risk tumor and observation only, making the comparison with our study population challenging.
In another study, Backes et al15 examined 175 patients with early stage endometrioid endometrial cancer and isolated tumor cells. More than half (99; 57%) received external beam radiotherapy and/or chemotherapy. Interestingly, omission of adjuvant therapy did not impact progression free survival in this population. Focusing on a group more similar to ours, they included 47 patients with FIGO stage IA disease who received observation or vaginal brachytherapy only. Among this specific subgroup, only three recurrences occurred (n=3/47, 6.4%). Of note, in our SLN–isolated tumor cell group, we observed four non-vaginal relapses (n=4/42, 9.5%). This slight difference in the recurrence rates could be explained by the small sample size of this subset of SLN–isolated tumor cell patients. Goebel and colleagues studied 11 endometrial cancer patients with isolated tumor cells and no adjuvant therapy, reporting no recurrence after a median follow-up of 32.6 (range 2–84.4) months.17 All 11 patients from this retrospective study were grade 1, while three had lymphovascular space invasion. In our series, only one of the 29 SLN–isolated tumor cell patients with grade 1 disease had evidence of non-vaginal recurrence after 23.1 months.
Given these studies, SLN–isolated tumor cell patients with endometrioid grade 1 disease (without lymphovascular space invasion) appear to have a very low risk of recurrence. However, data from a meta-analysis on the oncologic impact of micrometastasis/isolated tumor cells suggest an increased relative risk of relapse among low volume metastasis patients compared with node negative patients (relative risk 1.34; 95% CI 1.07 to 1.67), even after adjuvant treatment.19
It is generally suggested that the need for adjuvant therapy is tailored to the presence of other uterine risk factors. Based on our results, this still appears valid, even in cases of early stage, low grade, endometrioid endometrial cancer with isolated tumor cells. In fact, in our series, after adjusting for SLN node status, patients with grade 2 disease had almost three times the risk of non-vaginal recurrence compared with those with grade 1 (HR 2.99; 95% CI 1.08 to 8.29; p=0.03), while the presence of lymphovascular space invasion increased the risk of recurrence by six (HR 6.75; 95% CI 1.32 to 34.46; p=0.02).
Nevertheless, we did not observe a difference of SLNs–isolated tumor cells on overall survival for the whole cohort or the subset without lymphovascular space invasion. In line with previous reports,15 20 these findings leave open the question of the need for adjuvant treatment in this subset of SLN–isolated tumor cell patients. We need more data and follow-up to better answer the question of whether these patients may be most effectively treated at the time of recurrence.
Although lymphovascular space invasion is an established risk factor among endometrial cancer patients with node negative and node positive disease,21 22 its role in the setting of patients with SLNs–isolated tumor cells needs to be better clarified. Whether the detection of lymphovascular space invasion among SLN–isolated tumor cell patients is always correlated with clinical significance (worse prognosis) or just with a spread pathway of isolated tumor cells will be an important question to answer.
Strengths and Weaknesses
The strengths of our study include the use of a multi-institutional international collaborative registry with a large cohort of patients with SLNs–isolated tumor cells. In addition, we restricted the analysis to low risk patients who did not receive adjuvant therapy (observation only) to minimize any confounding treatment effect. Our cohort of untreated SLN–isolated tumor cell patients with low risk disease is the largest known to date. Also, our study is the first to exclusively compare SLN–isolated tumor cell patients with node negative patients with similar risk factors and treatment.
The main limitations of our study are the retrospective nature of the investigation and the relatively small sample size and short duration of follow-up, especially regarding the SLN–isolated tumor cell cohort. In this sense, we should interpret the 5 year survival analysis cautiously. Although recurrence free survival between the two cohorts was significantly different, for the 5 year recurrence free survival rates for SLN isolated tumor cells versus node-negative, the estimates were similar, with overlapping 95% confidence intervals. One explanation could be the small number of SLN–isolated tumor cell patients toward the fifth year of follow-up. It is also important to acknowledge that patients in the node negative cohort were exclusively from the primary center (Mayo Clinic Rochester) whereas the SLN–isolated tumor cell patients came from 15 centers worldwide. The study also lacked a centralized pathology review, and the protocol for SLN ultrastaging was not uniform at all participating centers. Finally, data regarding lymphovascular space invasion status was limited only to present versus absent, and the subclassification of isolated tumor cells, as detected by hematoxylin and eosin or by immunohistochemistry alone, was not available in all centers.
Implications for Practice and Future Research
Given the association with an increased risk of recurrence among SLN–isolated tumor cell patients, our findings are thought provoking regarding the need to standardize follow-up for this subset of patients. Moreover, the clinical implication of the worse prognosis of SLN–isolated tumor cell patients remains unclear. To answer these questions, our group is designing a prospective, multi-institutional, cohort study to investigate the role of SLNs–isolated tumor cells in low risk endometrial cancer and to evaluate standardized follow-up of these patients. The management of patients with isolated tumor cells remains controversial, and we anticipate that stratification of risk subgroups among SLN–isolated tumor cell patients will be further refined using molecular tumor profiling.23
Finally, the SLN ultrastaging protocol is not universally standardized and there are no uniform diagnostic criteria worldwide. In this regard, a recent method in the diagnosis of low volume metastases is the one step nucleic acid amplification assay.24 This molecular based system represents a reliable methodology in the SLN analysis and could be a valid alternative with a standardized analysis and reduced risk of protocol heterogeneity.25
Conclusions
The results of this study represent preliminary data on the specific population of low risk endometrial cancer patients with isolated tumor cells in SLNs who had no adjuvant therapy. We observed worse recurrence free survival among SLN–isolated tumor cell patients compared with node negative patients, while there was no difference in overall survival. However, these findings should be carefully interpreted, and call for additional studies on low risk endometrial cancer patients with SLNs–isolated tumor cells. In fact, we cannot draw definitive conclusions regarding the best treatment strategy to adopt in cases with SLNs–isolated tumor cells in patients with an otherwise indolent endometrial cancer risk profile.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the leading center (IRB Mayo Clinic ID: 19-004650). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The results of this work were presented as a poster presentation at the 23rd International Meeting of the European Congress on Gynaecological Oncology (ESGO 2022), 27-30 October 2022, Berlin, Germany.
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @Cucinella_G, @glaucobaiocchi, @Quique_ChC, @TommasoGrassi3, @Fmultinu, @LuigiDEvitis, @KhaledGhoniemMD
Contributors Conception of the study: AM, GG, and GC. Methodology and investigation: AM, GG, and GC. Dataset preparations (software) and variables revision: GC, GS, MM, and AJF. Data collection and interpretation individually by each center (resources): GC, GS, XCZ, KM, MA, AJ-P, SW, BL, CW, AC, GB, LDB, NT, CT, FR, AB, CP, TG, FL, VZ, FM, LADV, IZ, AH, NJ, RG, SM, AG, MP, ML, EC, JDG, AP, EL-F, AF, CCN, VC, and KG. Data validation and curation: GC and MM. Formal statistical analysis: MM and AJF. Writing-original draft: GC, GG, AM, MEM, and AJF. Writing-review and editing: all authors. Supervision: AM and GG. Project administration: all authors. Final approval of manuscript: all authors. Guarantor: AM and GG.
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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