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Abstract
Objectives Laparoscopy is commonly used for endometrial cancer treatment, and sentinel lymph node (SLN) mapping has become the standard procedure for nodal assessment. Despite the standardization of the technique, there is no definitive data regarding its failure rate. The objective of this study is to identify factors associated with unsuccessful SLN mapping in endometrial cancer patients undergoing laparoscopic SLN mapping after intracervical indocyanine green (ICG) injection.
Methods We retrospectively evaluated a consecutive series of endometrial cancer patients who underwent laparoscopic SLN mapping with intracervical ICG injection, in four oncological referral centers from January 2016 to July 2019. Inclusion criteria were biopsy-proven endometrial cancer, total laparoscopic approach, and intracervical ICG injection. Exclusion criteria were evidence of lymph node involvement or extrauterine disease at pre-operative imaging, synchronous invasive cancer, the use of tracers different from ICG, and the use of neoadjuvant treatment. Bilateral and failed bilateral SLN mapping groups were compared for clinical and pathological features. In patients with an unsuccessful procedure, side-specific lymphadenectomy was performed. Logistic regression was used to identify predictors of failure.
Results A total of 376 patients were included in the study. The overall bilateral and unilateral SLN detection rates were 96.3%, 76.3%, and 20.0% respectively. The failed bilateral mapping detection rate was 23.7%. The median number of sentinel nodes removed was 2.2 (range, 0–5). After multivariate analysis, lymph vascular space involvement [OR 2.4 (1.04–1.12), P=0.003], non-endometrioid histology [OR 3.0 (1.43–6.29), P=0.004], and intraoperative finding of enlarged lymph node [OR 2.3 (1.01–5.31), P=0.045] were identified as independent predictors of failure of SLN mapping.
Conclusion Lymph vascular space involvement, non-endometrioid histology, and intra-operative finding of enlarged lymph nodes were identified as independent risk factors for unsuccessful mapping in patients undergoing laparoscopic SLN mapping.
- SLN and lympadenectomy
- sentinel lymph node
- endometrial neoplasms
- uterine cancer
- uterine neoplasms
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HIGHLIGHTS
Identification of predictors of failed SLN mapping could improve surgical strategy
Lymphovascular space invasion, non-endometrioid histology, and enlarged lymph nodes are independent predictors of mapping failure
The identification of possible predictors of failed SLN mapping could improve detection rate
Introduction
Endometrial cancer is the most common gynecologic cancer in developed countries.1 The standard treatment for it is hysterectomy, bilateral salpingo-oophorectomy, and lymph node assessment, including pelvic and/or paraaortic lymphadenectomy.2 However, the role of lymphadenectomy is a matter of debate, and two randomized studies evaluating this specific issue, showed no benefit in terms of disease-free and overall survival.3 4 Despite these findings, lymph nodal status remains crucial to establish the stage of disease, prognosis, and indication for adjuvant therapies.5 6 In this context, the use of sentinel lymph node (SLN) mapping has been proposed as a compromise, allowing the assessment of nodal status while reducing complications related to lymphadenectomy.7 Supporting this theory, prospective studies have demonstrated a high sensitivity, low false negative rate, and a favorable negative predictive value for SLN mapping.8–10 Moreover, the use of SLN mapping combined with ultra-staging allows the detection of micrometastasis and isolated tumor cells while maximizing overall identification of nodal spread.11
For this reason, since 2015 SLN mapping has been included as a surgical option for nodal assessment in the National Comprehensive Cancer Network (NCCN) guidelines for endometrial cancer, and a comprehensive surgical algorithm has been proposed to reduce the risk of undertreatment, including side-specific lymphadenectomy in patients who have failed mapping and removal of all suspicious lymph nodes.12 Previous studies have investigated the factors associated with failure of mapping, but the variety of surgical routes (robotic, laparoscopic, laparotomic, or vaginal), the different tracers used, and the variable site of tracer injection have not allowed for consistent and definitive data regarding mechanisms associated with unsuccessful mapping.13–15 The aim of this study is to analyze patients with clinical early-stage endometrial cancer, undergoing laparoscopic SLN mapping after intracervical indocyanine green (ICG) injection, with the objective of identifying clinical, surgical, or pathological factors associated with SLN mapping failure.
Methods
Data of patients who underwent laparoscopic SLN mapping after ICG injection for clinical early- stage endometrial cancer from January 2016 to July 2019 were retrospectively retrieved from the oncological databases of the Department of Gynecologic Oncology, University of Palermo, Italy; Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore of Rome, Italy; the Department of Obstetrics and Gynecology, Ospedale degli Infermi, Biella, Italy; and the Department of Gynecology and Obstetrics, University of Parma, Italy. These databases represent research-quality datasets that are prospectively and regularly updated by trained residents under the direct supervision of consultants. Informed consent was obtained from all patients for the anonymized insertion of the data regarding their treatment and oncologic outcome in our research databases. In all participating centers, institutional review board approval was not required because the study involved the analysis of existing data. The Ethics Committee at each institution approved the collection of data for research purposes.
Inclusion criteria were biopsy-proven endometrial cancer, the total laparoscopic approach, and intracervical ICG injection. Exclusion criteria were evidence of lymph node involvement or extrauterine disease at pre-operative imaging, synchronous invasive cancer, the use of tracers different from ICG, and the use of neoadjuvant treatment. At each institution, all patients underwent a pre-operative transvaginal ultrasound, chest-abdomen CT scan, and pelvis MRI: images were reviewed by a dedicated radiologist expert in gynecological tumors prior to surgery. Surgical staging included laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and SLN mapping. According to the NCCN algorithm, side-specific lymphadenectomy was performed in patients with unsuccessful SLN identification, and in the case of intraoperative finding of enlarged lymph nodes, selective nodal debulking was performed.12 Para-aortic lymphadenectomy was performed in patients with an intraoperative finding of enlarged para-aortic nodes, or in those with failed mapping and high-risk cancer.
From a technical point of view, preliminary diagnostic laparoscopy, with lysis of any adhesions, was performed, taking particular care to avoid entering the retroperitoneal structures, in order to prevent inadvertent damage to the lymphatic vessels. After that, the cervix was injected with 25 mg of ICG powder dissolved in 20 mL of sterile water. Superficial (1–3 mm) injection was performed into the cervix at the 3 o'clock and 9 o'clock positions with 2 mL at each site, with a small-caliber needle (22 gage). Cervical grasping before injection and placement of the uterine manipulator immediately after injection were at the surgeon’s discretion. The lymphatic drainage was observed for at least 15 min through an intact peritoneum, then the avascular planes of the paravesical and pararectal spaces were opened. During the retroperitoneal dissection, the near infrared mode was used intermittently to avoid division of the lymphatic vessels and to allow for a second evaluation of the lymphatic anatomy. The SLN was defined as the first juxtauterine ICG mapped node with a clear afferent lymphatic vessel.16
A successful procedure was defined as mapping of at least one SLN in both hemipelvis, while a failed bilateral mapping was defined as a unilateral mapping or a bilateral mapping failure. SLNs were processed by dedicated pathologists according to a standardized ultrastaging protocol. After formalin fixation and paraffin embedding, 3 haematoxylin-eosin levels 50 µm apart were acquired, and one of them was subjected to immunohistochemical examination using anti-cytokeratin AE1/AE3 antibody. Macrometastases were defined as tumor clusters>2 mm; micrometastases were defined as tumor clusters between 0.2 and 2 mm; and isolated tumor cells were defined as single tumor cells or small tumor clusters≤0.2 mm.17 Bulky lymph nodes were defined as lymph nodes>2 cm at surgical exploration. The stage of disease was defined according to the International Federation of Gynecology and Obstetrics (FIGO) staging system.18
Statistical analysis
Statistical analysis was performed using Stata software version 11.0 (Stata Corp, College Station, TX). Predicting factors of SLN mapping failure were evaluated using univariate and multivariable models. Multivariable analysis was built modeling the bilateral mapping (YES/NO) as the dependent variable and all possible factors which were found statistically significant (P<0.05) or with a trend to significance at the univariate analysis (P<0.10) as independent variables. ORs and 95% CIs were calculated. All P-values were two-sided, and significance was defined as P<0.05.
Results
During the study period, 376 patients met the inclusion criteria and were analyzed. The demographic characteristics and clinical-pathological data are reported in Table 1. Median age was 62.6 years (range, 26–90), and mean body mass index was 29.3 kg/m2 (range, 17–52). Three-hundred and twenty-five patients (86.4%) had type 1 (endometrioid) endometrial cancer, while 51 (13.6%) patients had type 2 (non-endometrioid) endometrial cancer. Median tumor size was 27.2 mm (range, 1–110). Cervical invasion was detected in 16 patients (4.2%), and the final tumorous grading was G1 in 88 cases (23.4%), G2 in 211 (56.1%), and G3 in the remaining 77 (20.5 %). Lymphovascular space invasion was identified in 108 patients (28.7%), while myometrial infiltration was absent in 72 patients (19.1%),<50% in 179 (47.6%) patients, and >50% in the remaining 125 (33.2%) patients. The final FIGO staging was as follows: IA in 211 (56.1%) patients, IB in 84 (22.3%) patients, II in 16 (4.3%) patients, IIIA in seven (1.9%) patients, IIIB in three (0.8%) patients, IIIC1 in 48 (12.8%) patients, IIIC2 in five (1.3%) patients, and IVB in the remaining two(0.5%) patients.
Distribution of patients’ clinical-pathological characteristics
Surgical and post-surgical details are described in Table 2. Overall, 287 (76.3%) successful procedures with bilateral SLN mapping were performed, while in 75 (20.0%) patients only unilateral SLN mapping was recorded, and in the remaining 14 patients no SLN mapping (3.7%) was registered. Cervical grasping before injection was performed in 324 (86.2%) patients and the uterine manipulator was placed immediately after injection in 163 (43.4%) patients. Lysis of adhesions was performed in 51 women (13.6%), and intraoperative finding of enlarged lymph nodes was recorded in 32 (8.5%) patients.
Surgical details
SLNs details are shown in Table 3. Finally, 724 SLNs were removed, with a median number of SLNs removed per patient of 2.2 (range, 0–5). SLN location was external iliac in 429 (59.3%) SLNs, obturator in 181 (25.0%), common iliac in 84 (11.7%), internal iliac in 28 (3.9%), and para-aortic in the remaining two (0.1%). At final histology, 638 SLNs (88.1%) were negative, 10 (1.4%) had isolated tumor cells, 46 (6.3%) were positive for micrometastasis, and 18 (2.5%) for macrometastasis, while empty nodes, defined as the absence of lymphatic tissue in presumed sentinel node, were detected in 12 cases (1.7%). Figure 1 shows the SLN detection rate according to the study period. All the operations have been performed by expert surgeons, and, excluding the first year, in which only 10 procedures were performed, in the remaining period, the rate of successful procedures was constant. Logistic regression used to identify predictors of SLN mapping failure is reported in Table 4. At univariate analysis, age >65 years, the presence of myomas, non-endometrioid histology, grade, lymph vascular space invasion, and intraoperative finding of bulky lymph nodes were associated with failed mapping. On the other hand, the presence of adenomyosis and the rate of lymph nodal positivity at final histology were higher in women with a failed procedure, but the difference did not reach statistical significance. Multivariable logistic regression models revealed that only non-endometrioid histological type [OR 3.0 (1.42–6.29), P=0.004], the presence of lymph vascular space invasion [OR 2.4 (1.34–4.28), P=0.003], and intraoperative finding of bulky lymph nodes [OR 2.3 (1.01–5.31), P=0.045] were independent predictors of SLN mapping failure.
Sentinel node detection rate according to the study period.
Sentinel lymph nodes details
Univariate and multivariate analysis of clinico-pathological parameters and treatment details as predictors of bilateral mapping sentinel node failure
Discussion
Our study showed that non-endometrioid histology, lymphovascular space invasion, and the presence of bulky nodes are independent predictors of failure of bilateral sentinel lymph node mapping. Lymph nodal status remains crucial in the management of endometrial cancer patients, and SLN mapping has become a viable surgical option for its assessment. The introduction of ICG and the standardization of the injection technique, has allowed for a significant increase in the overall SLN detection rate, however, the improving bilateral detection rates remains crucial.19 Previous publications have reported on potential predictors of unsuccessful mapping, but due to the variety of surgical routes, the multitude of tracers used, and the different sites of the injection, it has been challenging to obtain definitive data regarding possible mechanisms associated with mapping failure.13–15
From our data the overall, bilateral, and unilateral SLN detection rates were 96.3%, 76.3%, and 20.0%, respectively, and these rates compare with the available literature.8 14–17 Regarding clinical features, the association between older age as well as increased body mass index and SLN mapping failure, had been previously reported.14 15 20 From our data, older age was associated with a reduced SLN detection at univariate analysis: when correcting for possible confounders, this correlation was not confirmed at multivariate analysis. On the other hand, increased body mass index was not correlated with failed mapping; we hypothesize that the use of ICG could overcome the adverse impact of obesity on SLN detection.17 Among surgical details, the potential influence of grasping the cervix before ICG injection or of uterine manipulator placement immediately after the injection was not previously investigated. In our analysis, these did not impact SLN detection. Tortorella et al,14 reported a decreased mapping rate when lysis of adhesions was required: these data were not confirmed in our series, likely due to caution in avoiding retroperitoneal damage, and to delaying of tracer injection after the completion of the adhesiolysis.
Among pathological characteristics, at univariate analysis, we found a significant correlation between failed mapping and non-endometrioid histology, tumor grade, lymphovascular space invasion, intraoperative identification of bulky lymph nodes, and nodal positivity at final histology. However, after multivariable analysis, only non-endometrioid histology, lymphovascular space invasion, and intraoperative identification of bulky lymph nodes were significantly associated with failed SLN mapping. Regarding the impact of histologic subtype, our data is consistent with other studies that show the overall SLN detection rate is lower, with a higher false negative rate in women with non-endometrioid histology.21 22 The association between intraoperative finding of bulky lymph nodes and a lower success of SLN mapping was previously reported, and this could be explained by the blocked lymphatic flow and presence of tumorous thrombi, as can occur with high-volume lymphatic metastases.14 15 An interesting finding emerging from our analysis is the association between lymphovascular space invasion and mapping failure. Two previous manuscripts had shown this correlation, however, in the first study patients underwent robotic surgery using blue dye as tracer, currently no longer considered the gold standard, and in the second report, the study was conducted only in patients with high-risk tumors.23 24 Therefore, this is the first study showing a significant correlation between unsuccessful mapping and lymphovascular space invasion in a homogenous endometrial cancer population undergoing laparoscopic SLN mapping using ICG.
Understanding the reasons for failed mapping could potentially improve the overall success of SLN mapping. First, a histologic review by a dedicated pathologist prior to surgery will accurately define the histologic type. This is important in patients who have undergone polypectomy, and this will also detect lymphovascular space involvement. Moreover, when lymphovascular spaces status is not documented on the biopsy specimen, a recently proposed scoring system seems to predict the risk of lymphovascular space invasion.25 Second, an imaging review, by a dedicated radiologist, should be performed to reduce the rate of unexpected enlarged nodes. This will potentially identify those patients at risk for failed mapping, this could modify pre-operative counseling, anticipating a higher possibility of undergoing full lymphadenectomy, and could allow for a better planning of the operating times and surgical expertise.
The principal strength of our study is that, to our knowledge, this is the largest cohort of endometrial cancer patients, where the risk factors that might lead to failed mapping is explored. However, we have to underline that the retrospective nature of the study cannot exclude reporting bias, although the presence of a systematic pre-operative imaging, the detailed and systematic collection of data, and the high standardization of the surgical technique allowed us to collect a homogeneous, well-defined population, with high-quality data.
In conclusion, we found that non-endometrioid histology, lymphovascular space invasion, and the presence of bulky nodes are independent predictors of the failure of bilateral sentinel lymph node mapping and thus should be considered important elements when discussing and planning for a surgical approach. Further studies, investigating the impact of cervical size and vaginal anatomy would be of interest to integrate into the results from this study.
References
Footnotes
Twitter @frafanfani
Contributors GS, FF, RB and VC: conception and design of the study. GS, FF, SU, NB and VC: manuscript preparation. GS, VAC, SU, NB, MD, GM, SR, IC and GDN: data collection. GS, VAC, SU, NB, VG, MD, GM, SR, IC and GDN: patient recruitment. GS, FF, RB, GiSc and VC: data analysis and interpretation. GS and VG: statistical analysis. GS, FF, RB, SU, GiSc and VC: responsible surgeon. GiSc: conception and design of the study.
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.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.