The role of the sentinel lymph node mapping in the actual treatment of endometrial cancer

Introduction

In high-income countries, endometrial cancer is perhaps the most prevailing gynecological malignancy, with an incidence rate rising annually with aging and with high obesity rates of the population⁽¹⁾. Surgery is the main element in the management of endometrial cancer, consisting of total hysterectomy associated with bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy⁽²⁾. The lymph node status is an essential element in staging and in determining the prognosis and the need of adjuvant treatment. However, over the years, there have been several controversies regarding the lymph node evaluation technique. Surgical staging usually involved systematic pelvic lymphadenectomy and was often associated with complications such as lymphedema, lymphocysts, cellulitis and local nerve deterioration⁽³⁾. Therefore, sentinel lymph node (SLN) mapping became widely accepted as an eligible alternative of assessing the lymph node status in a less aggressive method, consistent with the principles of personalized medicine⁽³⁾. This article aims to review the current literature concerning SLN mapping in endometrial cancer and to assess the future perspectives of this procedure.

Materials and method

We conducted a descriptive review, analyzing the leading international guidelines regarding the role of sentinel lymph node mapping in endometrial cancer (The National Comprehensive Cancer Network, The Society of Gynecologic Oncology, The European Society of Gynecological Oncology), published between 2018 and 2023. In addition, we reviewed studies from the PubMed database published between May 2011 and October 2023. The search query included a combination of multiple Medical Subject Headings (MeSH) terms such as “endometrial cancer”, “sentinel lymph node”, “ultrastaging” and “lymphadenectomy”.

To assess the eligibility of the reviewed studies, we applied a series of inclusion and exclusion criteria. Thus, we included in our review solely the studies that met the following criteria: (1) studies on endometrial cancer with sentinel lymph node mapping; (2) studies with large sample sizes (a minimal sample size of 100 participants); (3) laparoscopic or robotic approach in SLN detection; (4) studies that used radiolabeled tracers, blue dyes and/or indocyanine green; (5) studies that assessed the accuracy, the safety profile and applicability of the SLN mapping; (6) studies that compare the SLN procedure to the pelvic lymphadenectomy. We excluded from our review: (1) studies published before 2010; (2) open surgery approach in SLN mapping; (3) case reports.

Results

Endometrial cancer staging

In order to properly assess the prognosis and the treatment course in patients with endometrial cancer, healthcare providers need to follow a thorough staging process. In the 1950s, The Federation of International Gynecology and Obstetrics (FIGO) standardized staging for endometrial cancer relying solely on two criteria⁽³⁾. Accordingly, they divided patients with endometrial cancer into either stage 1 or stage 2, using the extent of clinical invasion of the uterus⁽³⁾. A turning point in the staging process happened in 1962 with the introduction of a four-stage system, followed by a shift from medical to surgical staging in 1988⁽⁴⁾.

Over the years, as medicine evolved, FIGO progressively updated the staging guidelines, broadening the understanding of the histopathology of the disease⁽⁴⁾. The staging system became more extensive, including factors such as tumor grade, myometrial invasion depth, locoregional extension, lymph node status and distant metastasis⁽³⁾.

The most notable advancement in the field is represented by the introduction of the molecular classification of endometrial carcinoma⁽⁵⁾. This majorly impacts the ability of the clinician to assess the prognosis and to thoroughly conduct the treatment plan. Probably the most significant molecular classification used nowadays is the one proposed by The Cancer Genome Atlas (TCGA), which defines four major categories, taking into consideration molecular features such as: POLE mutation, microsatellite instability, TP53 mutation, and the grade of somatic copy-number alteration (SCNA)⁽⁵⁾. There are many ramifications emerging from integrating this classification in clinical practice. For instance, as far as POLE mutated tumors are concerned, their prognosis is favorable irrespective of the tumor grade, as opposed to the TP53 mutation, which automatically implies a highly negative impact on the prognosis⁽⁵⁾. Therefore, integrating the histopathological aspect with the molecular architecture of the tumor leads to a broadened perspective on the survival outcome of the patient, with the opportunity to personalize the treatment course accordingly⁽⁵⁾.

One controversial aspect of the staging process of endometrial cancer is represented by defining the lymph node status⁽²⁾. Routine lymphadenectomy was introduced by FIGO in 1987 in the attempt to better characterize the extent of the tumoral process, resulting in upstaging many cases⁽⁴⁾. Nevertheless, lymphatic invasion is not common for all the subcategories of endometrial cancer, as the ones confined to the endometrium uphold a risk of lymphatic metastasis of only 1%^(3,6). Thus, this approach is not favorable in early-stage carcinoma, bearing an increased rate of perioperative morbidity and no significant impact on the oncologic outcomes⁽²⁾. As less invasive surgical procedures became the alternative of choice in many gynecologic oncology centers, sentinel lymph node mapping established its place as an accurate and trustworthy alternative to the classic pelvic lymphadenectomy⁽²⁾.

Sentinel lymph node mapping in endometrial cancer

In regard to the National Comprehensive Cancer Network (NCCN) guidelines, SLN mapping may be taken into consideration for patients with no perceivable extrauterine disease at exploration and no evidence of metastatic disease on preoperative imaging⁽⁷⁾. As far as high-risk pathology is concerned, SLN mapping represents a solid alternative to complete lymphadenectomy⁽⁷⁾.

The Society of Gynecologic Oncology (SGO) encourages the use of SLN mapping in the surgical staging process for low and intermediate-risk endometrial cancer, whereas for the intermediate-high and high-risk categories it only represents a feasible option as long as the para-aortic lymphatic stations are inspected^(2,3).

SLN biopsy is considered appropriate for staging purposes in low and intermediate-risk patients, as The European Society of Gynecological Oncology (ESGO) states, but it can be omitted in patients with no invasion of the myometrium⁽¹⁾. Pelvic lymphadenectomy is not recommended in these cases⁽¹⁾. For the high-risk group, SLN mapping is an acceptable alternative to lymphadenectomy, even though the radical approach is the desirable option⁽¹⁾.

SLN algorithm and technique

The main goal of SLN sampling is to evaluate the lymph nodes that are most at risk of tumoral invasion, so we can avoid the systematic pelvic lymphadenectomy and its associated complications⁽³⁾. In 2018, NCCN proposed an algorithm to guide healthcare providers and to ensure the highest level of accuracy of the procedure⁽⁸⁾. Therefore, SLN mapping requires a thorough inspection of the peritoneal cavity beforehand to assess the tumoral extension.

The preferred tracer injection site is considered to be the cervix, even though the uterine fundus, deeper myometrium and hysteroscopically guided tumor injections have been studied^(9,10). Superficial (1-3 mm) and deep (1-2 cm) cervical injections are to be used to acquire efficient dye delivery to the layers of the lymphatic drainage system origins (superficial subserosal, intermediate stromal and deep submucosal)⁽²⁾. There are three alternative techniques of cervical injection, as follows: 3 and 9 o’clock; 2, 5, 7 and 10 o’clock; 3, 6, 9 and 12 o’clock⁽²⁾. The deeper cervical injections may facilitate para-aortic lymph nodes evaluation by reaching the lymphatics in the infundibulo-pelvic ligaments⁽³⁾.

Regarding gynecologic cancers, three methods of SLN mapping have been used over time⁽³⁾. The colorimetric method implies visualizing the lymphatic nodes using colored dyes in white light⁽³⁾. It is the most applicable method as it requires the least complex equipment. Typically, isosulfan blue and methylene blue are the dyes of choice; 3-5 ml of a 1% solution of isosulfan blue can be utilized, taking into account the risk of allergic reaction (anaphylaxis) in 1.1% of the cases and the possibility of low detection rates^(11,12). Methylene blue is used off-label as 2-4 ml of a 1% solution and has a low detection rate in case of obesity⁽²⁾. However, it is associated with paradoxical methemoglobinemia and serotonin syndrome⁽¹³⁾.

One of the first methods of SLN mapping is represented by the radionuclide method, that requires the injection of radiolabeled colloid technetium 99 (Tc99) and identification of the SLN using nuclear imaging⁽¹⁴⁾. Usually, it is associated with the use of blue dyes or indocyanine green (ICG)⁽³⁾. Following the injection of 1 ml of 1 mCi of Tc99, gamma-detecting probes are used to identify the tracer signal during surgery⁽¹⁵⁾. Its advantages rest in the ability to successfully perform SLN sampling in patients with excess weight and in cases of atypical lymphatic drainage⁽²⁾.

Furthermore, the method with highest detection rate is considered to be the near-infrared method which utilizes indocyanine green (ICG)^(3,16). For optimal usage, ICG must be diluted 0.5-1.25 mg/ml using sterile water and 2-4 ml of the solution must be injected⁽¹⁷⁾. The use of near-infrared light allows the surgeon to visualize the lymphatic channels and nodes in real time during dissection⁽³⁾. Thus, this method is considered superior for obese patients compared to the blue dye tracers^(16,18).

Regardless of the SLN sampling, if any suspicious lymph nodes are visualized, they should be removed, sometimes requiring the completion of the pelvic lymphadenectomy⁽⁸⁾. In the unfortunate case of SLN failure, consisting in the lack of tracer penetration to the targeted lymph nodes, lymphadenectomy should be performed either bilaterally or side-specific⁽⁸⁾.

Ultrastaging versus frozen sections

In order to assess the grade of tumoral invasion of the sampled lymph nodes, pathologists review multiple sections of the SLN as hematoxylin and eosin (HE) stained slides⁽²⁾. In addition to the HE staining, immunohistochemistry comes in good use as NCCN suggests⁽⁷⁾. The protocol proposed by Memorial Sloan Kettering standardizes the procedure⁽¹⁹⁾. This way, in case of negative initial HE evaluation, two more cuts are to be assessed, one in HE staining and the other analyzing cytokeratin AE1/AE3⁽¹⁹⁾.

Moreover, SGO developed three more protocols, each proposing different sectioning intervals, and one of them describing a cytologic smear out of the dissected node⁽³⁾.

Ultrastaging is an essential pathological technique which allows the detection of small lymphatic metastases (micrometases and isolated tumor cells) which could be missed in a routine evaluation⁽²⁾. Micrometastases are defined as more than 0.2 mm and/or more than 200 cells, with a limit of 2 mm, whereas the isolated tumor cells are characterize by a small cell cluster not greater than 0.2 mm or the presence of less than 200 cells⁽²⁰⁾. 

According to NCCN and SGO, frozen sections are to be used only in special conditions, as their sensitivity is considered to be low and it can alter the future ultrastaging process^(3,8). They suggest that any suspicious lymph nodes found at inspection should be sent for frozen sections, the result influencing the decision of evaluating the aortic lymph nodes⁽²⁾.

Discussion

Having compared the international guidelines on SLN mapping in endometrial cancer, it is agreed that it is the leading procedure for assessing the lymph node status for surgical staging purposes, allowing the healthcare provider to adopt a tailored adjuvant treatment course.

As far as accuracy of the procedure is concerned, several retrospective studies have analyzed the problem, revealing a 91-98% sensitivity rate of SLN mapping in endometrial carcinoma and a rate of detection over 90%, highly reliant on both the surgical technique and the surgeon’s experience^(21,22).

A study of reference in the field is the SENTI-ENDO trial, the first prospective study to assess the accuracy of SLN mapping in endometrial cancer⁽¹⁵⁾. All patients enrolled followed a strict SLN sampling protocol followed by systematic pelvic lymphadenectomy⁽¹⁵⁾. The trial revealed a detection rate of 89% and a sensitivity rate of 84% for SLN mapping, perhaps due to the use of Tc99 as a tracer⁽¹⁵⁾. Its results might have been different if indocyanine green was used, perhaps leading to an increased sensitivity rate⁽¹⁵⁾.

Furthermore, studies have been conducted to compare SLN mapping to lymphadenectomy, the most notable one being the FIRES trial⁽²³⁾. In this large multicentric prospective trial, SLN sampling using ICG was evaluated and compared to complete lymphadenectomy in stage I endometrial cancer⁽²³⁾. The study reported a detection rate of 86% and a sensitivity rate of 97.2% for SLN sampling, therefore supporting SLN mapping in the surgical staging process⁽²³⁾.

The SHREC trial was designed to analyze the accuracy of the SLN mapping procedure in high-risk endometrial cancer⁽²⁴⁾. Patients with stage I/II endometrial carcinoma were selected for this study, after strict inclusion criteria⁽²⁴⁾. A high-grade histology, deep invasion of the myometrium, cervical stromal invasion and non-diploid cytometry were the criteria for high-risk patients⁽²²⁾. The trial revealed a 98% sensitivity rate and a 95% detection rate for bilateral SLN mapping, encouraging the use of SLN sampling in gynecologic oncology practice⁽²⁴⁾.

Previously, many studies focused solely on the low-grade group, but no data on the outcomes of SLN sampling in high-grade endometrial carcinoma were available. Thus, Cusimano developed a study which aimed to assess SLN mapping in high-grade endometrial cancer⁽²⁵⁾. The SENTOR study excluded all low-grade cases, analyzing a total of 146 patients who underwent the SLN procedure followed by pelvic and sometimes para-aortic lymphadenectomy⁽²⁵⁾. The reported results were encouraging, with a 97.4% detection rate and a 96% sensitivity rate for the SLN sampling, this way implementing the concept of SLN mapping in high-grade endometrial carcinoma as an eligible alternative to lymphadenectomy⁽²⁵⁾.

Conclusions

The surgical management of endometrial cancer has evolved over the years, leading to advancements such as the use of SLN mapping in the surgical staging process. Its rapid adoption in the clinical practice of many gynecologic oncology centers around the world resides perhaps in the high sensitivity and the low morbidity rates associated with the procedure. Thus, even though complete lymphadenectomy has been considered the preferred method used for staging purposes, in this era of less invasive surgery, SLN mapping is soon to become the gold standard procedure, adhering to the principles of tailored medicine, without jeopardizing the oncologic outcome. 

 

Conflict of interest: none declared  
Financial support: none declared
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