Introduction
Endometrial cancer (EC) is one of the leading gynecological malignancies in developed countries with an increasing incidence globally [1]. In India, owing to the changing lifestyles and reproductive patterns, an increase in endometrial cancer has been observed, particularly in urban areas. According to data reported as of 2018, the new estimated cases of EC in India was 13,328, with 5,010 estimated deaths [2]. With the escalating trends in EC, accurate staging is crucial for appropriate treatment, planning, and prognosis assessment for these patients. One of the key factors in EC staging is the assessment of lymph node involvement, as it exerts a significant impact due to its prognostic importance in treatment decisions [3-5]. In addition to lymphadenectomy, these women experience comorbid conditions such as hypertension, diabetes, and obesity, further elevating the risk of lower extremity lymphedema. Sentinel lymph node (SLN) mapping has emerged as an alternative approach [6].
The concept behind SLN mapping is that if an SLN is negative for metastasis, the likelihood of finding positive non-SLNs is very low. Additionally, SLNs undergo a rigorous process of ultra-staging that has been demonstrated to identify isolated tumor cells (ITCs) (<0.2 mm) and micro-metastasis (0.2-2 mm), increasing the detection rate of SLN compared to routine pelvic lymph node dissection [7-10].
The primary objectives of this study were to evaluate the incidence of SLN metastasis in patients with presumed low-and intermediate-risk EC and to assess the changes in stage and adjuvant therapy resulting from SLN analysis. Secondary objectives included determining detection rates of SLN using indocyanine green (ICG) dye and complication rates. By examining these outcomes, we further aimed to evaluate the role of SLN mapping in the management of EC and identify areas for improvement in its implementation.
Materials and methods
We obtained data from all patients who underwent minimally invasive surgery (MIS) for presumed low- and intermediate-risk EC using ICG dye for SLN detection between January 2017 and November 2023 in the gynecological oncology department at a tertiary care center in India.
This was a single-center prospective study in which data were collected retrospectively. The inclusion criteria included patients aged 18 years or older with preoperative histologically confirmed grade 1 or 2 endometrioid EC, presumed low- or intermediate-risk EC (classification of low- and intermediate-risk EC was performed according to the ESGO/ESTRO/ESP guidelines for the management of patients with EC), and no evidence of metastasis on magnetic resonance imaging, computed tomography, or positron emission tomography computed tomography who underwent MIS (either robotic or laparoscopic). Exclusion criteria were high-risk endometrial cancer, intermediate-risk with grade 3 tumors, previous pelvic lymph node surgery (e.g., nodal sampling or dissection for any previous malignancy), previous allergy to indocyanine green or iodine, evidence of pelvic/distant metastasis, synchronous malignancy, or any neoadjuvant treatment.
After an adequate pre-operative assessment, the patients were aligned for surgical staging. After the induction of anesthesia, an intracervical ICG (1.25 gm/mL) injection was administered at the 3 and 9 o’clock positions with a 28-gauge needle or a spinal needle. The superficial and deep stroma were infiltrated at 1 mL per injection, totaling 4 mL. Standard port placements were performed after injection, and the retroperitoneal space was opened. This was followed by identification of the infundibulopelvic ligament, ureter, and obliterated umbilical artery. SLNs were visualized by the near-infrared fluorescence camera in either Firefly™ (Intuitive Surgicals Inc., Sunnyvale, CA, USA) fluorescence imaging for da Vinci® Xi™ (Intuitive Surgicals Inc.) or a D-light 4 K camera (Luxonis, Littleton, CO, USA) by detecting the colored tract and node in the fluorescence imaging system. Any lymphatic tract lateral to the obliterated umbilical artery was followed, and this led to identification and dissection of the SLN. If multiple lymphatic tracts were observed, multiple SLNs were dissected and subjected to histopathological analysis. The algorithm described by the Memorial Sloan Kettering Cancer Center [11] was followed, in which all mapped and grossly enlarged nodes were dissected. In the absence of SLN detection, side-specific pelvic lymphadenectomy was performed. All dissected SLNs were sent for ultrastaging analysis and were not frozen. Subsequently, hysterectomy and bilateral salpingo-oophorectomy, or ovarian transposition if desired, were performed by two surgeons.
The histopathological analysis of SLN consisted of an ultrastaging process, in which after formalin fixation, if the initial sections were negative for metastasis, three hematoxylineosin levels that were 50 μm apart are acquired, and one of them is submitted for immunohistochemical (IHC) examination using anti-cytokeratin AE1/AE3 antibody. Macro-metastasis in the lymph nodes was defined as tumor cell infiltration of >2 mm. Micro-metastasis in lymph nodes was defined as a focus of metastatic tumor cells >0.2 mm and <2 mm, whereas ITCs were defined as microscopic clusters and single cells measuring <0.2 mm [12].
1. Sample size calculation
The null hypothesis was that the addition of SLN mapping to the standard treatment for EC (i.e., hysterectomy and bilateral salpingo-oophorectomy) would result in a 10% treatment change in presumed early stage grade 1 and 2 EC. Considering a type I error of 0.05 and a power of 0.8, the sample size calculation was performed using data that included the prevalence of lymph node metastases in presumed low- and intermediate-risk EC being 8-12%, a distribution in preoperative histological grade 1 and 2 EC being 75% and 25%, respectively, an agreement in pre-and postoperative histological grading of 95% [12], and a unilateral detection rate (DR) and bilateral detection rate (BDR) of SLN mapping of 90% and 70% respectively [13]. The presumed loss to follow-up rate was 10%, resulting in a sample size of 153 patients.
Qualitative variables were analyzed using the chi-squared test or Fisher’s exact test. Statistical significance was set at P<0.05. Analyses were performed using the Statistical Package for Social Sciences (IBM SPSS Inc., Armonk, NY, USA).
Results
Between March 2017 and December 2023, a total of 224 patients met the inclusion criteria. Of these, 210 patients qualified for data collection, while the rest had incomplete data. These were patients with presumed low- and intermediate- risk EC (patients with grade 1 or 2 EC with uterine-confined disease) who underwent minimally invasive surgical staging with SLN dissection using ICG. The epidemiological, clinical, surgical, and pathological characteristics of the patients are presented in Table 1.
1. Detection of sentinel lymph node
In total, 412 SLNs were detected in 210 patients. Unilateral SLN detection was performed in 20 patients (9.5%), bilateral SLN detection was performed in 170 patients (80.9%), and no SLN detection was performed in 20 patients (9.5%). After SLN mapping, the mean number of lymph nodes detected was 2.3 per side. Postoperative pathological assessment of the lymph node tissue detected after ICG tracing revealed no lymph node tissue in 18 patients. Of these, in 12 patients (8.5%) with bilateral SLN mapping, only one unilateral node was detected in four patients with unilateral mapping, and no lymph nodes were detected upon pathological examination. Overall, the pathologically confirmed detection rate was greater than 95%. Characteristic features of sentinel node-positive and sentinel node-negative patients are presented in Table 2.
2. Positive sentinel lymph node metastasis
A total of 25 patients (11.9%) exhibited positive sentinel metastasis detection upon pathological and IHC analysis in the form of ITCs and micro-and macro-metastases. Of these, micro- and macro-metastases were present in six (2.9%) and 14 (6.7%) patients, respectively, and ITCs were present in five patients (2.4%).
Upon application of the chi-square test for univariate analysis, post-operative grade (P<0.003), myometrial invasion (P<0.002), and lymphovascular space invasion (P<0.001) were all determined to be statistically significant factors for positive SLN detection.
Robotic hysterectomy was performed in 143 patients, and laparoscopic surgery was performed in 67 patients. Of the 210 patients that were included in the analysis who were presumed low- and intermediate-risk EC, 24 patients (11.4%) were shifted to the high-risk category. The presence of ITCs alone did not affect the change in category to high risk. Of these 24 patients, eight exhibited grade 3 (p53 mutation) and non-endometrioid carcinoma (four were SLN-negative, and four exhibited micro-metastasis). Two of the four patients with micro-metastases experienced concurrent cervical cancer, and the other two harbored ovarian cancer. Sixteen patients with grade 1 and 2 macro-metastases exhibited a change in their stage from 1 to 3.
3. Changes in adjuvant therapy
Of the 20 patients who exhibited SLN metastasis with micro-and macro-metastasis, four patients would have received adjuvant therapy irrespective of their lymph node status, as two patients exhibited ovarian metastasis, and two patients exhibited cervical extension. In the remaining 16 patients, adjuvant therapy was guided by the detection of SLNs. SLN positive metastasis changed the stage to stage III, and therefore, adjuvant therapy in the form of chemotherapy and radiation therapy was administered. A standard protocol of sandwich chemotherapy with paclitaxel and carboplatin three cycles followed by external beam radiation therapy and brachytherapy that was then followed by three more cycles was administered. In patients with ITCs only and no other risk factors (n=3), no adjuvant therapy or stage changes occurred, and routine surveillance was adopted. Overall, 16 patients (7.6%) underwent changes in adjuvant therapy based on SLN mapping alone.
4. Complications
Mild numbness in the lower limbs was the most common postoperative complication, and this improved in 10 patients. Three patients experienced grade 1 lymphedema in the immediate postoperative period, and this was managed with limb elevation and limb physiotherapy. Two patients exhibited a small port-site hematoma that occurred immediately after trocar entry due to small vessel damage and were managed using electrocautery and tamponade. Chylous ascites was observed in one patient and was medically managed with octreotide. All 16 patients with complications were conservatively managed.
Discussion
Of the 210 patients in our study, 186 (88.5%) remained at low and intermediate risk after the final histopathological analysis. The other 24 patients exhibited SLN metastasis, high-grade EC, higher-stage detection, or high risk on molecular profiling. Sixteen patients underwent a change to adjuvant therapy. The SLN detection rate was 95%. Sixteen patients (7.6%) experienced numbness, lymphedema, port site hematoma, and chylous ascites.
The mere presence of grade 1 or 2 is insufficient to label a patient as truly low or intermediate risk. As we have observed in our study, approximately 11-15% of patients are upgraded to high-risk despite exhibiting low-grade uterine-confined disease in the pre-operative investigation. Therefore, undergoing a thorough surgery with SLN dissection, ultra-staging, and proper post-operative pathological analysis is very important for women, as upstaging and change of risk categorization exert an important bearing on the management of these patients.
1. Results in the context of published literature
Of the included presumed low- and intermediate-risk EC patients, 83.8% (in the sentinel lymph node mapping [SLIM] study, 78.9%) were classified in the same category postoperatively, while others exhibited grade 1 and 2 SLN metastases or high-risk EC with or without SLN metastases.
The FIRES study included 385 patients with EC treated by 19 surgeons in 10 institutions. The DR and BDR of SLN biopsies were 86% and 52% [14]. SLN metastases were observed in 10.6% of the patients with presumed pre-operative low-and intermediate-risk EC, and another 2.4% exhibited ITCs. Studies by Koskas et al. [15], Abdullah et al. [16], and Burg et al. [17] have demonstrated similar results. Our BDR was 62.9%. The BDR in the studies by Holub et al. [18], Barranger et al. [19], Ballester et al. [20], and SLIM were 81%, 54.5%, 69%, and 76%, respectively.
Holloway et al. [9] noted that although SLN mapping may only remove two or four lymph nodes at a time with a certain false-negative rate and the risk of missing occult lymph nodes, the overall DR of metastatic lymph nodes was higher than that of conventional lymphadenectomy. Raimond et al. [21] recruited 304 patients and observed that the incidence of lymph node metastasis in patients with SLNs was three-fold higher than in those without SLNs (16.2% vs. 5.1%; respectively). Among SLN-positive patients, 8.1% were detected using ultra-staging.
The results of our study indicate that SLN mapping leads to less undertreatment of patients with low- and intermediate-risk EC if SLN metastases are present, as it leads to disease upstaging. Overtreatment can also be prevented based on limited therapy, with the final histology suggestive of grade 3 EC without SLN metastases.
This study demonstrated that SLN mapping reduced undertreatment and overtreatment in patients with SLN metastases. In our study, 20 patients exhibited micro- and macro-metastases and were administered adjuvant therapy, thus preventing undertreatment. Overtreatment was reduced in four patients who were classified as high-grade and non-endometrioid types with SLN metastases. A second lymphadenectomy was omitted due to the prior known node status from SLN mapping.
This study demonstrated that of the 11.9% of patients with presumed low- and intermediate-risk EC lymph node metastasis, adjuvant therapy was received by 16 patients solely based on SLN involvement. Based on the DR of SLN using 95% ICG dye, we recommend SLN mapping in low- and intermediate-risk patients.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
Print
