Sentinel lymph node mapping in endometrial cancer: time for a change

Since the publication of the results of the clinic-pathological study GOG #33, staging for endometrial cancer changed from clinical to surgical and required a pelvic and para-aortic lymphadenectomy (1,2). Since then, the role of the pelvic and para-aortic lymphadenectomy has been widely debated. In patients with non-bulky lymph nodes, the lymphadenectomy plays a staging role. Since the risk of lymph nodal metastases varies in endometrial cancer patients and is particularly low in patients with small, well differentiated and superficially invasive lesions, several authors believe that the routine performance of a full pelvic and para-aortic lymphadenectomy is not useful and should be avoided in a specific subgroup of endometrial cancer patients (3).

A widespread approach to this problem is the performance of the full lymphadenectomy based on the identification of intrauterine risk factor at frozen section analysis. However, the performance of this strategy varies widely among institutions and depends on the threshold set for the indication to a full lymphadenectomy (4-8).

In the last few years, the sentinel lymph node (SLN) mapping has been widely adopted as an alternative to a conventional surgical staging. This approach may offer several advantages over a systematic lymphadenectomy, not only by reducing the surgical morbidity but also by increasing the precision of the lymph nodal information obtained. When talking about the SLN mapping in endometrial cancer it has to be kept in mind that this procedure is accepted as an alternative to a full lymphadenectomy only by part of the international guidelines (9,10).

Here, we will present three manuscripts that will help us discuss the clinical applicability of the SLN mapping in endometrial cancer first and the technical aspects of the mapping next. In the first manuscript, How et al. analysed the anatomic distribution of the SLNs in early stage endometrial cancer patients (11). In their series, 7.9% of the SLNs found in 13.1% of the cases were detected in areas, such as the parametria, the internal iliac vein and the pre-sacral area, that are not routinely included in the landmarks of a systematic lymphadenectomy. These results are consistent with those of other series in this setting (12,13). Anatomic studies have shown that the lymphatic drainage of the uterus is relatively complex. Two lymphatic pathways have been described: the first one, called upper paracervical pathway, drains to the lymph nodes located in the obturator fossa and the external iliac vessels, and a second one, called lower paracervical pathway, that drains to the pre-sacral lymph nodes (14). Whereas the lymph nodes draining the first pathway are included in the landmarks that define a systematic pelvic lymphadenectomy, the second ones are not. Hence, through a systematic lymphadenectomy, we systematically omit to sample relevant lymph nodes. Interestingly, Persson et al. were able to show that in order to identify both lymphatic pathways bilaterally, a higher dose of tracer is needed (14). The definition of the optimal dose of tracer to be injected and the optimal number of SLNs that need to be retrieved is a still debated issue (15,16). Overall, the SLN mapping in endometrial cancer has proven to be reliable with a reasonable false negative rate, especially if the SLN mapping algorithm as proposed by the Memorial Sloan Kettering Cancer Center is applied (17).

In addition to the fact that the SLNs represent a targeted sampling, they also undergo a more thorough pathological analysis, the ultrastaging, that enables to identify small metastases that might have otherwise been missed. Through the SLN mapping we transition from a labour intense surgical procedure to a target surgical procedure and a labour intense pathological analysis.

The second manuscript addresses the impact of the SLN mapping on recurrence patterns in endometrial cancer (18). In a large retrospective study, How et al. compare disease free survival as well as pattern of recurrences in endometrial cancer patients treated with hysterectomy, bilateral salpingo-oophorectomy and systematic lymphadenectomy or SLN mapping followed by systematic lymphadenectomy. The authors could not find any differences in terms of disease-free survival at 48 months of follow-up but were able to show that in the group undergoing SLN mapping followed by systematic lymphadenectomy the pelvic side wall recurrences accounted for a significantly less common. The authors conclude that this may be the result of a more efficient detection of the SLNs enabling for a more meticulous removal of affected lymph nodes.

Other institutions have compared disease free and overall survival among patients undergoing a systematic lymphadenectomy or a SLN mapping further proving the oncological safety of the SLN mapping as compared to a full lymphadenectomy both in low risk and in high risk endometrial cancer patients (19-21). In high intermediate risk endometrial cancer patients, overall survival is negatively affected if pathological lymph nodal data are lacking (22). Both patients with pathologically non-affected and affected lymph nodes have better survival curves as compared to patients who had not been surgically staged (22). These data clearly show that the prognostic value of the pathological lymph nodal status, at least in this subgroup of patients, is of great importance and helps directing appropriate adjuvant treatments.

Finally, we want to discuss the technical aspects of the SLN mapping. When performing a SLN mapping various tracers with different performances can be adopted: Tc-99m, blue dyes and indocyanine green (ICG) (23). In a prospective trial, How et al. injected 100 endometrial cancer patients intracervically with the three tracers and evaluated the performance of the tracers in terms of detection rates (24). In their analysis, the use of blue dye did not seem to increase the detection rates of the cocktail of traces and the authors recommend to use a combination of Tc-99m and ICG only. Since its application as a tracer for SLN mapping, ICG has become the preferred tracer because of its safety profile and user friendliness (22). Nowadays, ICG is mostly used alone and not in combination with other tracers, since it has repeatedly demonstrated to yield higher detection rates as compared to the conventional tracers (25,26).

Despite controversial indications of different international guidelines, SLN mapping is rapidly gaining acceptance in clinical practice. SLN mapping not only allows to reduce the surgical trauma and therefore the surgical morbidity but is a more precise and efficient method as compared to a systematic lymphadenectomy in identifying the most representative lymph nodes to be analysed under the microscope.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.org/article/view/10.21037/gpm.2018.10.01/coif). AP serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from Jun 2018 to May 2020. MLG serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from Sep 2018 to Aug 2020. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60:2035-41. [Crossref] [PubMed]
2. FIGO. (International Federation of Gynecology and Obstetrics) FIGO stages, 1988 revision. Gynecol Oncol 1989;35:125-7.
3. Mariani A, Webb MJ, Keeney GL, et al. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000;182:1506-19. [Crossref] [PubMed]
4. Kumar S, Medeiros F, Dowdy SC, et al. A prospective assessment of the reliability of frozen section to direct intraoperative decision making in endometrial cancer. Gynecol Oncol 2012;127:525-31. [Crossref] [PubMed]
5. Laufer J, Scasso S, Papadia A, et al. Association between tumor diameter and lymphovascular space invasion among women with early-stage endometrial cancer. Int J Gynaecol Obstet 2013;123:142-5. [Crossref] [PubMed]
6. Morotti M, Menada MV, Moioli M, et al. Frozen section pathology at time of hysterectomy accurately predicts endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia. Gynecol Oncol 2012;125:536-40. [Crossref] [PubMed]
7. Papadia A, Azioni G, Brusacà B, et al. Frozen section underestimates the need for surgical staging in endometrial cancer patients. Int J Gynecol Cancer 2009;19:1570-3. [Crossref] [PubMed]
8. Sala P, Morotti M, Menada MV, et al. Intraoperative frozen section risk assessment accurately tailors the surgical staging in patients affected by early-stage endometrial cancer: the application of 2 different risk algorithms. Int J Gynecol Cancer 2014;24:1021-6. [Crossref] [PubMed]
9. NCCN Clinical Practice Guidelines in Oncology. Uterine Neoplasms. Version 2.2018. Available online: http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
10. Colombo N, Creutzberg C, Amant F, et al. ESMOESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol 2016;27:16-41. [Crossref] [PubMed]
11. How J, Boldeanu I, Lau S, et al. Unexpected locations of sentinel lymph nodes in endometrial cancer. Gynecol Oncol 2017;147:18-23. [Crossref] [PubMed]
12. Papadia A, Imboden S, Siegenthaler F, et al. Laparoscopic Indocyanine Green Sentinel Lymph Node Mapping in Endometrial Cancer. Ann Surg Oncol 2016;23:2206-11. [Crossref] [PubMed]
13. Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol 2017;18:384-92. [Crossref] [PubMed]
14. Persson J, Geppert B, Lönnerfors C, et al. Description of a reproducible anatomically based surgical algorithm for detection of pelvic sentinel lymph nodes in endometrial cancer. Gynecol Oncol 2017;147:120-5. [Crossref] [PubMed]
15. Papadia A, Buda A, Gasparri ML, et al. The impact of different doses of indocyanine green on the sentinel lymph-node mapping in early stage endometrial cancer. J Cancer Res Clin Oncol 2018. [Epub ahead of print] Erratum in: J Cancer Res Clin Oncol 2018.
16. Papadia A, Imboden S, Gasparri ML, et al. Endometrial and cervical cancer patients with multiple sentinel lymph nodes at laparoscopic ICG mapping: How many are enough? J Cancer Res Clin Oncol 2016;142:1831-6. [Crossref] [PubMed]
17. Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125:531-5. [Crossref] [PubMed]
18. How J, Gauthier C, Abitbol J, et al. Impact of sentinel lymph node mapping on recurrence patterns in endometrial cancer. Gynecol Oncol 2017;144:503-9. [Crossref] [PubMed]
19. Ducie JA, Eriksson AGZ, Ali N, et al. Comparison of a sentinel lymph node mapping algorithm and comprehensive lymphadenectomy in the detection of stage IIIC endometrial carcinoma at higher risk for nodal disease. Gynecol Oncol 2017;147:541-8. [Crossref] [PubMed]
20. Buda A, Gasparri ML, Puppo A, et al. Lymph node evaluation in high-risk early stage endometrial cancer: A multi-institutional retrospective analysis comparing the sentinel lymph node (SLN) algorithm and SLN with selective lymphadenectomy. Gynecol Oncol 2018;150:261-6. [Crossref] [PubMed]
21. Schlappe BA, Weaver AL, Ducie JA, et al. Multicenter study comparing oncologic outcomes between two nodal assessment methods in patients with deeply invasive endometrioid endometrial carcinoma: A sentinel lymph node algorithm versus a comprehensive pelvic and paraaortic lymphadenectomy. Gynecol Oncol 2018; [Epub ahead of print]. [Crossref] [PubMed]
22. Ouldamer L, Bendifallah S, Body G, et al. Groupe de Recherche FRANCOGYN. Call for Surgical Nodal Staging in Women with ESMO/ESGO/ESTRO High-Intermediate Risk Endometrial Cancer: A Multicentre Cohort Analysis from the FRANCOGYN Study Group. Ann Surg Oncol 2017;24:1660-6. [Crossref] [PubMed]
23. Papadia A, Gasparri ML, Buda A, et al. Sentinel lymph node mapping in endometrial cancer: comparison of fluorescence dye with traditional radiocolloid and blue. J Cancer Res Clin Oncol 2017;143:2039-48. [Crossref] [PubMed]
24. How J, Gotlieb WH, Press JZ, et al. Comparing indocyanine green, technetium and blue dye for sentinel lymph node mapping in endometrial cancer. Gynecol Oncol 2015;137:436-42. [Crossref] [PubMed]
25. Ruscito I, Gasparri ML, Braicu EI, et al. Sentinel Node Mapping in Cervical and Endometrial Cancer: Indocyanine Green Versus Other Conventional Dyes-A Meta-Analysis. Ann Surg Oncol 2016;23:3749-56. [Crossref] [PubMed]
26. Frumovitz M, Plante M, Lee PS, et al. Near-infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers (FILM): a randomised, phase 3, multicentre, non-inferiority trial. Lancet Oncol 2018;19:1394-403. [Crossref] [PubMed]