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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Indian J Gynecol Oncol. 2020 Apr 13;18(2):43. doi: 10.1007/s40944-020-00386-8

UPDATE ON SENTINEL LYMPH NODE MAPPING IN ENDOMETRIAL CANCER PATIENTS WITH A HIGH RISK FOR NODAL METASTASIS

Derman Basaran 1, Mario M Leitao Jr 1,2
PMCID: PMC7899161  NIHMSID: NIHMS1626051  PMID: 33628871

Abstract

Surgery is the mainstay of treatment for the majority of patients diagnosed with endometrial carcinoma. Systematic lymphadenectomy has traditionally been considered a standard part of surgical therapy. More recently, however, the value of this has been a subject of much debate.

The sentinel lymph node (SLN) mapping algorithm has emerged as an acceptable alternative to conventional pelvic and para-aortic lymph node dissection in endometrial cancer. Clinical trials have demonstrated the accuracy of SLN mapping in detecting nodal spread in patients with endometrial cancer. However, data regarding the oncological outcomes of this approach, particularly in the setting of endometrial cancer with a high risk of nodal spread, is still lacking. In this review, we provide an overview of SLN mapping in endometrial cancer. We will specifically discuss its use in patients with a high risk for nodal metastasis. Controversies and future directions for research will also be discussed.

INTRODUCTION

Over the past two decades, the gynecologic oncology community has witnessed major practice-changing advances in the surgical management of endometrial carcinoma. Routine lymphadenectomy was challenged by two international randomized controlled trials that showed no survival benefit and increased morbidity in patients assigned to undergo lymphadenectomy [1, 2]. The selective lymphadenectomy algorithm from Mayo Clinic demonstrated that patients with certain favorable uterine factors can be spared lymph node dissection and its associated morbidities, without jeopardizing oncological outcomes [3]. Sentinel lymph node (SLN) assessment has also been proposed as a more precise method than complete systematic nodal dissection [4]. Although SLN mapping has gained broad acceptance, questions remain regarding its use as a standard of care in patients with endometrial cancer. Here, we will address the use of SLN biopsy in the setting of endometrial cancer with a high risk for nodal metastasis.

Evolution from clinical staging to surgical staging

Prior to the mid-1980s, endometrial cancer was staged clinically, and a systematic retroperitoneal nodal dissection was not performed. In 1988, following publication of the Gynecologic Oncology Group (GOG) 33 study--a single arm observational study--the International Federation of Gynecology and Obstetrics (FIGO) changed the staging guidelines for endometrial cancer from clinical to surgical staging [5]. However, the addition of lymph node status to FIGO staging initiated an ongoing controversy. This is because the majority of patients with endometrial cancer present without lymph node metastasis, and lymphadenectomy is associated with major morbidity [6, 7]. There has never been a randomized trial conducted to establish routine lymphadenectomy as a standard of care in patients with newly diagnosed endometrial carcinoma. In fact, the authors of GOG 33 concluded that the intent of their study was to define the incidence and risk factors for lymphatic metastases; the study did not comment on standards for endometrial cancer staging and did not establish lymphadenectomy as a standard approach [5]. Since that time, retrospective studies have suggested that lymphadenectomy may have a therapeutic effect in some select patient groups with endometrial cancer characterized by high-risk features such as deeply infiltrative tumors or high-grade histology [8]. However, a systematic review based on the two international randomized controlled trials described above showed increased adverse events, but no evidence of reduction in death or recurrence, when lymphadenectomy was performed [9]. In the meantime, the Mayo Clinic “low-risk” criteria were used in a prospective observational study, showing that patients with these low-risk features had a less than 1% risk of harboring a positive lymph node, compared to a 16% risk of lymphatic involvement in those who did not meet the low-risk criteria [3]. The classification of patients into low-risk and high-risk categories based on the Mayo Clinic criteria appears to prevent unnecessary lymphadenectomies in low-risk patients by abandoning dissection altogether. However it was also shown that, based on these criteria, many high-risk patients would be exposed to unnecessary lymphadenectomies [10]. Another major drawback of utilizing the selective lymph node algorithm was the necessity of a highly experienced intraoperative gynecologic pathology consultation, which is not readily available even in a majority of tertiary care centers.

Sentinel lymph node mapping concept

The SLN mapping algorithm relies on the orderly progression typical of lymphatic metastases in the setting of solid tumors. First detailed in a 1977 study reporting on a penile lymphangiogram, SLN mapping has since become a standard of care in penile carcinoma, melanoma, and breast cancer [11]. The National Comprehensive Cancer Network (NCCN) guidelines first included the SLN algorithm in 2014. The most recent version states that SLN mapping can be considered for the surgical staging of endometrial cancer, which may also include high-risk histologies (serous carcinoma, clear cell carcinoma, carcinosarcoma) [12].

SLN mapping for gynecologic malignancies first gained acceptance in vulvar cancer. The first report on SLN biopsy in endometrial cancer was published by Burke and colleagues from M.D. Anderson Cancer Center in 1996 [13]. In this feasibility trial, investigators injected isosulfan blue dye into the sub-serosal myometrium of 15 patients with high-risk endometrial cancer. They were able to identify deposition of dye into nodes in 10 of 15 cases (67%). This report was followed by several other observational studies which evaluated SLN mapping in endometrial cancer using either single dyes, combinations of dyes, or Tc-99 radio colloid, and various injection sites including cervical, myometrial and hysteroscopic peritumoral [4].

Although there is no uniform consensus on the ideal injection site, cervix is the preferred site for most surgeons due to its simplicity and high detection rates [14]. A systematic review of dye injection sites in endometrial cancer showed that the overall detection rate of sentinel nodes was 62–100% after cervical injection and 73–95% after uterine corpus injection [15]. Investigators also demonstrated para-aortic SLN detection rates of 39%, 2%, and 17% after uterine, usual cervical, and deep cervical injections, respectively [15]. The limits of SLN mapping associated with the para-aortic region is particularly important for patients with high-risk histologies, in whom isolated para-aortic metastasis are found in up to 16% [3]. Clinicians should consider the potential drawbacks of cervical injections on paraaortic SLN detection in patients with high-risk histology.

In a meta-analysis of 55 studies involving 4915 women, the overall detection rate of SLN mapping was 81% (95% CI 77–84), with a 50% (95% CI, 44–56) rate of bilateral pelvic node detection [16]. The use of indocyanine green (ICG) dye was associated with higher rates of bilateral SLN detection than use of blue dye (75% vs. 51%, p= 0.008). Although combined use of a radiotracer and a dye were associated with higher rates of overall SLN detection, there was no difference in detection rates for bilateral or para-aortic SLN mapping [16]. The results of these observational studies are supported by the findings of the randomized phase III FILM (Fluorescence Imaging for Lymphatic Mapping) study, which accrued patients from the United States and Canada. The investigators used a randomization algorithm that assigns patients to lymphatic mapping with isosulfan blue dye (visualized by white light) followed by ICG (visualized by near-infrared imaging), or ICG followed by isosulfan blue dye. Once mapping with both dyes was complete and documented, all lymph nodes identified with either dye were excised. This study showed that ICG had significantly higher overall (96% vs. 74%) and bilateral (78% vs. 31%) SLN detection rates than blue dye (p<0.0001 in both observations) [17]. A post-hoc analysis for metastatic nodes has also shown that 38% of the involved nodes were detected by ICG dye only and would have been missed with use of blue dye only. ICG dye with near-infrared imaging is now considered the optimal method for SLN detection in patients with endometrial cancer.

After demonstrating the efficacy of SLN mapping in endometrial cancer, the next step was to evaluate its accuracy in detecting metastatic disease compared with conventional lymph node dissection. The most important determinant of the reliability of SLN mapping in detecting nodal metastases is the false negative predictive value (NPV)--in other words, the ability of a negative SLN mapping, in all patients undergoing SLN mapping, to truly reflect the absence of nodal spread. The European SENTI-ENDO trial was the first prospective study to evaluate the accuracy of SLN biopsy using cervical dual injection of technetium and patent blue dye in 125 patients with endometrial cancer [18]. Pelvic lymph node metastases were noted in 20 of 125 patients (16%). SLN detection rates were 77% in the right hemipelvis and 76% in the left hemipelvis, with an overall detection rate of 89%. Among the 111 patients in whom SLNs were detected, 19 (17%) had pelvic lymph node metastases; 16 of these 19 (84.2%) were detected with SLN mapping. Three false-negative cases were found in contralateral pelvic lymphadenectomy in 2 patients, and in para-aortic lymphadenectomy in 1 patient. Considering the right and left hemipelvis as single units (no false-negative cases were found), NPV was 100% and sensitivity 100%; however, at the whole patient level, NPV was 97% (95% CI 91–99) and sensitivity 84%. The recently published FIRES (Fluorescent Imaging for Robotic Endometrial Cancer Sentinel lymph node biopsy) study is a prospective, multi-institutional trial conducted in the United States [19]. This study showed that SLN mapping technique was associated with a sensitivity of 97.2%, NPV of 99.6%, and false-negative rate of 2.8%. Both the FIRES and SENTI-ENDO studies showed limited bilateral nodal mapping rates (52% and 61.6%, respectively); this appears to be a result of including many institutions with varying levels of SLN mapping experience. We speculate that the accuracy of SLN mapping might be even higher in centers with robust experience and high bilateral mapping rates. [20]

The main principle of SLN mapping is removal of the lowest possible amount of nodal tissue from the lymphatic basins; as well, pathological ultrastaging of the harvested nodes is extremely important. The ultrastaging process differs significantly from traditional handling of lymph node specimens by the pathologist and involves bivalving the nodes longitudinally and submitting each side for hematoxylin and eosin (H&E) staining. The Memorial Sloan Kettering Cancer Center (MSKCC) Pathologic Ultrastaging algorithm consists of an initial evaluation by routine H&E; if this evaluation is negative, two adjacent 5-μm sections (one H&E and one cytokeratin AE1/AE3) are cut from each paraffin block at each of two levels 50-μm apart, and evaluated in depth [21]. The results of the SLN mapping studies in endometrial cancer are reported according to the American Joint Committee on Cancer (AJCC) Staging guidelines for the staging of breast cancers: macrometastases are defined as groups of malignant cells >2.0 mm; micrometastases are defined as >0.2 mm and/or >200 cells, but none >2.0 mm. Isolated tumor cell (ITC) clusters are small clusters of cells not >0.2 mm, present as either single tumor cells or clusters of <200 cells; ITCs can be detected by H&E or by IHC alone but must be seen on both [22]. The H&E and IHC tests are conducted simultaneously. If cells are identified only on IHC but not on H&E, they should be considered as cytokeratin-positive (CK+) cells only and not as ITCs. SLN mapping in endometrial cancer, using this pathological ultrastaging algorithm, was able to detect micrometastasis and ITC. These low-volume metastases were identified in 4.5% of patients and would otherwise have gone undetected on routine evaluations [21]. The clinical significance of low-volume metastases is not yet understood, and patients with low-volume metastases have mostly received the same adjuvant treatment protocols as patients with macroscopic nodal disease [23].

Oncological outcomes of SLN mapping

SLN mapping has now proven to be an accurate staging modality. The next question is whether SLN mapping alone has any impact on oncologic outcomes. It is highly unlikely that a lymphadenectomy in patients with negative SLNs will ever improve survival, as the false NPV is very low and the role of lymphadenectomy in patients with disease in SLNs is still debated. At the same time, some clinicians now question whether there is a potential role for therapeutic lymphadenectomy in higher-risk endometrial carcinomas. It is true that the oncological outcomes of SLN mapping in any subtype of endometrial cancer have not been studied in a well-designed, randomized trial; but routine lymphadenectomy has not been studied in that setting either. Therefore, a head-to-head comparison of systematic lymph node dissection with SLN mapping does not exist; our current knowledge is limited to retrospective observational studies. In a retrospective study of 304 patients with presumed low- or intermediate-risk cancer who underwent standard pelvic LND+/−SLN mapping, Raimond et al. showed that SLN mapping detected metastatic lymph nodes in 16.2% of women, compared with a 5.1% detection rate for LND (p=0.03) [24]. Patients with micrometastases detected by SLN mapping received adjuvant radiation. Although SLN mapping demonstrated increased detection of metastasis, and therefore changed decisions regarding adjuvant treatment more often in the SLN group than in the systematic lymphadenectomy group, recurrence-free survival did not differ between the patient cohorts. The lack of standardization of adjuvant treatments, and the retrospective design of this study, prevent firm conclusions.

The oncological outcomes of SLN mapping and selective lymphadenectomy in endometrial cancer were compared in historical cohorts by two tertiary referral centers in the US: Mayo Clinic and MSKCC [25, 26]. In the Mayo Clinic study, complete pelvic and para-aortic lymphadenectomy to the renal veins was performed in select patients who were deemed at risk for nodal metastasis due to grade 3 cancer and/or primary tumor diameter >2 cm (LND cohort); at MSKCC, an institutional SLN mapping algorithm was used (SLN cohort). In the first published report by Eriksson et al., patients with low risk of nodal spread were included [25]. In patients with limited myometrial invasion, the median number of pelvic and para-aortic lymph nodes removed were significantly lower in the SLN cohort compared to the LND cohort (6 vs. 34 and 5 vs. 16, respectively, p<0.001). The detection rate of pelvic nodal metastasis was 5.1% in the SLN cohort and 2.6% in the LND cohort (p=0.03); the detection rate of para-aortic nodal metastasis was 0.8% and 1.0% (p=0.75), respectively. The 3-year disease-free survival rates were similar using both approaches (94.9% in the SLN cohort and 96.8% in the LND cohort) (p=0.35). A sequel report by Ducie et al. investigated the performance of SLN mapping in patients at high-/intermediate-risk for nodal metastasis [26]. Intermediate-risk was defined as endometrioid histology with >50% myometrial invasion, and high-risk was defined as serous or clear cell histology (any myometrial invasion). In the intermediate-risk group, stage IIIC disease was diagnosed in 30/107 (28.0%) (LND), 29/82 (35.4%) (SLN) (p=0.28). In the high-risk group, stage IIIC disease was diagnosed in 20/103 (19.4%) (LND), 26 (21.7%) (SLN) (p=0.68). Para-aortic lymph node assessment was performed significantly more often in intermediate-/high-risk groups in the LND cohort (p<0.001). In the intermediate-risk group, paraaortic lymph node metastases were detected in 20/96 (20.8%) (LND) vs. 3/28 (10.7%) (SLN) (p=0.23). In the high-risk group, paraaortic lymph node metastases were detected in 13/82 (15.9%) (LND) and 10/56 (17.9%) (SLN) (p=0.76). Ducie et al. showed that SLN mapping and LND provide similar detection rates of stage IIIC endometrial cancer; however, survival outcomes were not reported. The results of these historical comparison studies suggested that either method would be a reasonable approach to determine nodal spread.

The summary of studies that reported on the survival of endometrial cancer patients with high risk of nodal metastasis is presented in Table 1. Schiavone et al. reported the outcomes of 136 patients with uterine carcinosarcomas [27]. Of these, 48 had SLN mapping and 88 had routine LND. Of the 67 patients with a documented recurrence, 14/20(70%) in the SLN and 34/47(74%) in the LND group demonstrated a distant/multifocal pattern of recurrence. There was no difference in median progression-free survival between the groups (23 vs. 23.2 months, p=0.7). Schiavone and colleagues reported a similar analysis of patients with uterine serous carcinoma. More than 80% of all patients received adjuvant chemotherapy alone, or chemotherapy with radiation therapy. At a median follow-up of 40 months, the 2-year progression-free survival rates were 77% in the SLN group (N=153) and 71% in the LND group (N=95) (p = 0.3) [28]. These two retrospective studies, with very large patient cohorts, suggested that SLN mapping is safe in evaluating nodal spread in high-risk endometrial cancer. A major caveat to interpreting the results described above, is that many patients in the SLN cohorts also had completion lymphadenectomies (evidenced by the high median numbers of nodes removed in the SLN cohorts). Investigators from the same institution performed another analysis comparing the oncological outcomes in uterine serous carcinoma patients who underwent SLN mapping alone (N=79) versus patients who underwent classic systematic LND (N=166)[29]. In this study, the median total number of removed lymph nodes was only 3 in the SLN cohort (compared to 12 in the SLN cohort reported in the previous analysis). Rates of nodal metastasis were 26.5% and 29.5% in the SLN and LND cohorts, respectively (p=0.6). The 2-year overall survival rates were 89.1% and 83.9% in the SLN and LND cohorts, respectively (p=0.9). The results of the most recent analysis with well-defined study cohorts also showed that the oncological outcomes in patients with uterine serous carcinoma was not affected by SLN mapping [29]

Table 1.

Oncological outcomes of SLN mapping algorithm in endometrial cancer patients with high risk of nodal metastasis

Study Nodal assessment groups Histologic subtypes(N) Lymph node positivity (%) p value DFS p value OS p value
Schiavone [27] SLN Carcinosarcoma (N=48) 17.5% NA 23 months (median) 0.7 NA NA
Lymphadenectomy Carcinosarcoma (N=88) NA 23.2 months (median) NA
Basaran [29] SLN Uterine Serous Carcinoma (N=79) 26.5% 0.6 58.8% (2-year DFS) 0.4 89.1 (2-year OS) 0.8
Lymphadenectomy Uterine Serous Carcinoma (N=166) 29.5% 64.9% (2-year DFS) 83.9 (2-year OS)
Buda [30] SLN Endometrioid* (N=54) Others (N=11) 27.3% 0.3 79.2% (5-year DFS) 0.8 NA NA
SLN & Lymphadenectomy Endometrioid* (N=79) Others (N=26) 32.4% 81.6% (5-year DFS) NA
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DFS, disease-free survival; OS, overall survival; SLN, sentinel lymph node; NA, not available

A European multicenter, retrospective study analyzed 171 women with high-risk endometrial cancer who underwent primary surgical staging. Sixty-six patients were allocated to the SLN cohort, and 56/66 (84.9%) of these had only SLN mapping without lymphadenectomy [30]. One hundred and five patients had SLN mapping as well as lymphadenectomy. More than 75% had endometrioid histology. Consistent with other studies on high-risk histology, the most common site for disease recurrence was distant/peritoneal spread. The 5-year median recurrence-free survival was 79.2% for patients in the SLN cohort, and 81.6% in the LND cohort.

CONCLUSIONS

Evaluation of retroperitoneal nodal spread by SLN mapping has significantly changed the way gynecologic oncologists operate on patients with endometrial cancer. High-quality data from prospective studies has shown that SLN mapping is as accurate as systematic lymphadenectomy. Retrospective analyses have suggested that SLN mapping does not appear to compromise oncologic outcomes, compared to systematic lymphadenectomy. While these studies are limited by their retrospective nature, it is important to remember that lymphadenectomy itself was never established as a standard via a randomized trial, and subsequent randomized trials have failed to support a therapeutic benefit. However, we still lack a head-to-head trial comparing SLN mapping with lymphadenectomy, with respect to survival outcomes.

Controlling distant metastasis is the cornerstone to improving overall survival in patients with advanced/high-risk endometrial cancer. Randomized clinical trials have also shown that treatment with chemotherapy alone is as effective as combined chemotherapy/radiation [31, 32]. In light of published retrospective data suggesting that SLN mapping in high-risk endometrial cancer does not jeopardize oncological outcomes and may even be better in identifying patients who need adjuvant treatment, SLN mapping may prove to be the optimal surgical management of these high-risk patients. Future studies on SLN mapping should focus on oncological outcomes, and the management of micrometastases and ITCs that cannot be identified without ultrastaging.

Acknowledgments

Funding: Funded in part through the NIH/NCI Support Grant P30 CA008748.

Footnotes

CONFLICT OF INTEREST STATEMENT

The corresponding author states that there are no conflicts of interest.

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

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