Objectives: To determine the feasibility of sentinel lymph node (SLN) mapping in early-stage endometrial cancer and to evaluate the impact of the SLN result on adjuvant therapy prescription. Materials and methods: 140 women with histologically confirmed endometrial cancer, treated with a minimally invasive hysterectomy, bilateral salpingo-oophorectomy and SLN mapping were included. All mapped SLNs were confirmed by histopathology. Where the SLN was negative on H&E staining, ultra-staging with IHC was performed. Results: From January 2017 to May 2019, 122 patients were analysed. The overall and bilateral SLN detection rates were 86% (105/122) and 73% (89/122), respectively. The detection rates were not significantly different between low and high-risk disease. SLN metastasis was found in 15% (3/20) of patients the in high-risk group and 5.7% (5/87) in the low-risk group. Six of the 8 cases were identified by ultra-staging. Fourteen of 103 patients had their adjuvant treatment reduced based on SLN status after ultra-staging. Conclusion: SLN mapping can reliably detect the SLN in low and high-risk disease. The advantage for SLN mapping is in low-risk patients that allowed them to receive appropriate adjuvant therapy. Ultra-staging with IHC increased the detection of positive SLNs and decreased the prescribed adjuvant therapy in 14% of our patients.
Endometrial cancer is the sixth most common cancer in females, worldwide. There were an estimated 382,000 new cases and 90,000 deaths in 2018. In Australia, endometrial cancer is the fifth most common cancer with 3040 new cases and 582 deaths in 2018 . The majority of endometrial cancers are diagnosed as early stage, low grade tumours and have an excellent prognosis with 5-year survival rates exceeding 90% . 5-year survival for node positive advanced stage disease in contrast is 50–58% [3,4], with lymph node status being prognostic for recurrence and survival.
Pre-operative diagnosis is an important step to obtain a cell type and histologic grade and make a decision of treatment plan. Currently, the diagnostic methods of endometrial cancer include dilatation and curettage (D&C), suction biopsy (Pipelle), vacuum aspiration biopsy random essay (Novak curette and Vabra aspirator), hysteroscopic endometrial biopsy, etc. Outpatient endometrial biopsy (Pipelle, Novak curette and Vabra aspirator) is a non-invasive technique comparing with D&C. Although this method has a high overall accuracy in diagnosing endometrial cancer , this is a blinded technique. An inadequate specimen causes a decrease in the diagnostic accuracy. Preoperative hysteroscopic biopsy can provide an adequate tissue. Grasp endometrial biopsy is one of a technique providing more accurate diagnosis of histology type and tumour grade when in presence of endometrioid type tumour compared to blind endometrial biopsy obtained using the Novak curette .
Standard treatment for early-stage endometrial cancer includes extrafascial hysterectomy with bilateral salpingo-oophorectomy . For patients with disease apparently confined to the uterus and cervix, knowledge of pelvic and para-aortic lymph node status is important for accurate surgical staging, and for guiding adjuvant radiation therapy. Two randomized controlled trials have however failed to demonstrate a therapeutic advantage for systematic lymphadenectomy, although neither trial had a consistent policy with respect to the management of the paraaortic lymph nodes and did not utilize nodal status to direct adjuvant therapy [8,9].
Low-risk patients, defined as grade 1 or 2 endometrioid histology,
Studies of systematic pelvic and para-aortic lymphadenectomy have consistently shown that patients with positive pelvic nodes have a 50% incidence of positive para-aortic nodes [11,12]. In those with confirmed stage 3 disease, Mariani and colleagues concluded that both adequacy of pelvic and para-aortic dissection and delivery of adjuvant radiation to nodal beds independently reduced pelvic and paraaortic failures . Hence knowledge of pelvic lymph node status is integral for the appropriate prescription of adjuvant treatment, especially in the node-positive patients, where the addition of systemic chemotherapy to radiation has also demonstrated an improvement in survival [2,14].
Sentinel lymph node (SLN) mapping is an alternative technique that enables assessment of lymph node status and avoids the surgical complications associated with complete pelvic and para-aortic lymphadenectomy such as blood vessel or nerve injury, lymphocyst formation and lymphedema [15-17]. The techniques for lymphatic mapping are colorimetric mapping with coloured dyes, radionuclear mapping with technetium 99 (Tc99) and near-infrared fluorescence (NIRF) imaging with indocyanine green dye (ICG). A systematic review and meta-analysis of SLN mapping in endometrial cancer showed a pooled SLN detection rate of 81%, sensitivity of 96% and negative predictive value (NPV) of 99.7% . The use of ICG with NIRF imaging, intracervical tracer injection, a SLN mapping algorithm and an ultra-staging protocol are all associated with improved detection rates, increased sensitivity to detect node positive patients and improved NPV [18-20].
At Mater Hospital Brisbane, we have been using ICG with NIRF imaging for SLN mapping as a part of surgical staging in all women with clinically uterus-confined endometrial cancer undergoing laparoscopic or robotic surgery since 2017. We conducted this pilot study to determine our detection rate and localization of mapped SLNs, to assess the safety of the technique within our institution as well as to assess the utilization of SLN biopsy results in informing decisions on adjuvant therapy compared to our existing staging and adjuvant therapy protocols.
This retrospective study was approved by Mater Misericordiae Ltd Human Research Ethics Committee (HREC). From January 2017 to May 2019, all patients with histologically confirmed endometrial cancer were consented for laparoscopic or robotic hysterectomy, bilateral salpingo-oophorectomy and SLN mapping with ICG at Mater Hospital Brisbane, Queensland, Australia. The inclusion criteria were all patients with histologically confirmed endometrial cancer and radiologically confirmed FIGO stage I disease. Patients with extra-uterine disease on imaging were excluded. We further excluded any case where ICG injection was omitted or abandoned for any reason and any cases with incomplete medical records.
All surgeons were gynaecologic oncologists with significant experience in
endoscopic surgery including lymphadenectomy and SLN mapping.
KARL STORZ Image1 S OPAL1 for NIR/ICG was used in laparoscopic
surgery and Firefly
A comprehensive pelvic lymph node dissection was performed selectively in cases where SLN mapping failed to detect a SLN in either hemi-pelvic, only in those patients with intermediate and high-intermediate risk uterine features (grade 3 endometrioid, deep myoinvasion or bulky tumour), as per current institutional practice (Supplementary Fig. 1). Low risk patients (grade 1–2 endometrioid with superficial myoinvasion) were not staged further if SLN mapping failed because of a very low risk of nodal metastasis. Patients with deeply invasive high grade or invasive non-endometrioid tumours i.e., serous, clear cell, carcinosarcoma, were also not subjected to side specific systematic lymphadenectomy if SLN mapping failed, as under or institutional protocol these patients received adjuvant therapy with 4 cycles of chemotherapy and external beam pelvic radiation irrespective of nodal dissection. After SLN dissection, routine hysterectomy, bilateral salpingo-oophorectomy (BSO) was performed.
All specimens were analysed by pathologists specialized in gynaecologic cancers.
All SLNs were sectioned and stained with haematoxylin and eosin (H&E).
Ultra-staging was performed if the SLN was negative on initial H&E staining.
Serial sectioning was performed with 250
All statistical analysis was performed using IBM SPSS Statistics for Windows,
Version 22.0. (IBM Corp Armonk, NY, USA). Descriptive data were presented as mean
with standard deviation (SD) for continuous variables and percentage for
categorical variables. A Chi-square test was used to analyse the differences
between two variables. Overall detection rate was defined as the percentage of
patients undergoing SLN mapping in which at least one SLN was pathologically
identified in either hemipelvis. Bilateral detection rate was defined as the
percentage of patients with at least one SLN pathologically identified in each
hemipelvis. A p-value of
From January 2017 to May 2019, 140 patients with histologically confirmed
endometrial cancer were consented for a minimally invasive hysterectomy, BSO and
SLN mapping. ICG injection was cancelled due to patient factors in 9 cases (Fig. 1). Three cases had an extra-uterine disease, 3 cases had some surgical technique
and anatomical problems, 1 case underwent full pelvic lymphadenectomy, 1 case had
a suspicious synchronous vulvar cancer and 1 case did not record any reason. A
further 9 cases were omitted due to incomplete medical records. SLN mapping was
abandoned intra-operatively (despite prior ICG injection) in a further 11 cases
due to morbid obesity (BMI
The characteristics of the remaining 122 patients who were included in the analysis are summarized in Table 1. Eighty-five patients (70%) had a laparoscopic procedure and 37 patients (30%) had robotic surgery. Endometroid adenocarcinoma was the most common cell type diagnosed in pre- and post-operative histologic results.
|Patients, N = 122 (%)|
|Mean age (years)
|Mean BMI (kg/m
|Previous abdominal surgery|
|- No||61 (50.0)|
|- Yes||61 (50.0)|
|Modality of surgery|
|- Laparoscopic surgery||85 (69.7)|
|- Robotic surgery||37 (30.3)|
|Pre-operative histologic result|
|- grade 1||83 (68.0)|
|- grade 2||19 (15.6)|
|- grade 3||9 (7.4)|
|- Serous||6 (4.9)|
|- Clear cell||1 (0.8)|
|- Mucinous||1 (0.8)|
|- Mixed||2 (1.6)|
|- Others||1 (0.8)|
|Post-operative histologic result|
|-Atypical hyperplasia/No residual cancer||15 (12.3)|
|- grade 1||69 (56.6)|
|- grade 2||17 (13.9)|
|- grade 3||9 (6.6)|
|- Serous||10 (8.2)|
|- Carcinosarcoma||1 (0.8)|
|- Mucinous||1 (0.8)|
|- IA||87 (71.3)|
|- IB||21 (17.2)|
|- II||4 (3.3)|
|- IIIA||2 (1.6)|
|- IIIB||2 (1.6)|
|- IIIC1||4 (3.3)|
|- IVB||2 (1.6)|
|- Absent||97 (79.5)|
|- Present||25 (20.5)|
|Depth of myometrial invasion|
|Peritoneal washing cytology|
|- Negative||100 (82.0)|
|- Positive||14 (11.5)|
|SD, standard deviation; BMI, body mass index; LVSI, lymphovascular space
* FIGO 2009 classification.
Of the 122 cases who had ICG injected, SLNs mapped intra-operatively in 103 cases on the right side and 97 cases on the left. Pathologic results confirmed the presence of nodal tissue in 100 cases (82%) on the right and 94 cases (77%) on the left. The overall and bilateral detection rate, based on pathologically confirmed nodal tissue, was 86.1% and 73%, respectively (Table 2). The median number of SLNs removed was one (range 0–6 nodes). External iliac vessels were the most common detection site for the SLN.
|Patients, N = 122 (%)|
|SLN detection (Pathologic detection)|
|- Overall detection||105 (86.1)|
|- Bilateral detection||89 (73.0)|
|- Unilateral detection||16 (13.1)|
|- No detection||17 (13.9)|
|Right hemipelvis||Left hemipelvis|
|Hemipelvic detection||100 (82.0)||94 (77.0)|
|Median number of lymph nodes (range)||1 (0–4)||1 (0–6)|
|Site of SLN detection|
|- External iliac||58 (47.5)||60 (49.2)|
|- Obturator||22 (18.0)||16 (13.1)|
|- Internal iliac||1 (0.8)||9 (7.4)|
|- Common iliac||15 (12.3)||9 (7.4)|
|- Parametrial||1 (0.8)||0 (0)|
|- Infra-mesenteric para-aortic||2 (1.6)||0 (0)|
|- Presacral||1 (0.8)||0 (0)|
|SLN, sentinel lymph node.|
In thirty cases (24.6%), the SLN was mapped to an at uncommon site (a site that is not included as part of routine pelvic lymph node dissection) including the high common iliac vessels, internal iliac vessels, parametria, infra-mesenteric para-aortic and presacral regions. Six cases had non-SLN tissue removed due to suspicious or bulky nodes detected at time of procedure. One case of presumed non-SLN node tissue was not nodal tissue on final histopathology but a deposit of serous carcinoma. The other 5 cases were confirmed as nodal tissue and were all negative for metastasis.
In subgroup analysis of high-risk histology (endometrioid grade 3, serous, clear cell and carcinosarcoma), the overall and bilateral detection rates were 90.9% and 81.8%, respectively. Although the patients with low-risk histology had lower overall and bilateral detection rates (85% and 71%, respectively), there was no significant difference between low and high-risk disease with a p-value = 0.47 for overall detection and a p-value = 0.30 for bilateral detection. Pathologic factors including depth of myometrial invasion, LVSI, cell type, histologic grade, tumor size and peritoneal washing cytology were not predictors of SLN detection based on univariate analysis.
In terms of both overall and bilateral detection, BMI
SLN metastasis was found in 8 out of 122 patients (6.6%) who had ICG injected for the purposes of SLN mapping, or 7.2% of 111 patients who had SLN mapping performed. The characteristics of 8 patients with positive SLNs are shown in Table 3. The most common site of SLN metastasis was the external iliac region. Two positive SLNs were found at the internal iliac and high common iliac regions, areas not routinely dissected in systematic pelvic lymphadenectomy.
|Case NO.||Age (years)||BMI (kg/m
||Positive SLN||Site of positive SLN||Pre-operative histology||Post-operative histology||Stage*||GOG-99 risk||Adjuvant treatment|
|1||70||24||Isolated tumour cells||Internal iliac||Mixed high-grade||Serous||IB||High||CMT/RT|
|2||56||40||Macro-metastasis||External iliac||Endometroid grade 1||Endometroid grade 1||IIIC1||High-intermediate||CMT/RT|
|3||73||35||Isolated tumour cells||External iliac||Mucinous grade 1||Mucinous grade 1||II||Low-intermediate||RT|
|4||62||37||Isolated tumour cells||Common iliac||Endometroid grade 2||Endometroid grade 2||IB||High-intermediate||RT|
|5||55||40||Macro-metastasis||External iliac||Endometroid grade 2||Endometroid grade 3||IIIC1||High-intermediate||CMT/RT|
|6||51||43||Isolated tumour cells||Obturator||Endometroid grade 1||Atypical hyperplasia||IA||Low-intermediate||No|
|7||66||28||Micro-metastasis||External iliac||Endometroid grade 3||Endometroid grade 3||IIIC1||High-intermediate||CMT/RT|
|8||79||46||Micro-metastasis||External iliac||Endometroid grade 1||Endometroid grade 1||IIIC1||Low-intermediate||CMT/RT|
|NO., number; BMI, body mass index; SLN, sentinel lymph node; CMT/RT,
chemotherapy/radiation therapy; RT, radiation therapy. |
* FIGO 2009 classification.
Three of 20 (15%) patients with high-risk histology (grade 3, serous or carcinosarcoma) had positive SLNs involved with metastatic disease, compared with 5 of 87 (5.7%) patients with low risk histology (grade 1 or 2 endometrioid, one case of low grade mucinous). Of the 105 patients who had at least one SLN detected, the ultra-staging protocol with IHC was used in 103 of these (98.1%). 1 of the 5-low risk, SLN positive patients, had a macro-metastasis, while 4 patients had SLN showing micro-metastasis or ITCs which were detected by the SLN ultra-staging protocol. In the three high-risk histology patients with SLN metastasis, one had macro-metastasis, one micro-metastasis and one patient had ITCs. Hence, 6 of the 8 (75%) positive SLNs were detected due to the ultra-staging technique.
There were no intra-operative or post-operative complications associated with
SLN mapping. Two patients had an intra-operative complication which was not
related to SLN mapping. The first case had bladder injury during robotic surgery.
She did not have a history of previous abdominal surgery and her BMI was 43
After surgery, the adjuvant therapy was prescribed based on the adjuvant therapy protocol of Queensland Centre for Gynaecological Cancer (QCGC) (Supplementary Fig. 3). Without knowledge of lymph node status (based on uterine features alone) 37 of 122 patients (30.3%) would receive adjuvant treatment. Using the adjuvant therapy protocol, it was predicted that radiation therapy (RT) would be prescribed in 37 cases (30.3%), with the addition of chemotherapy (CMT/RT) in 27 cases (22.1%), based on high-risk features.
Based on SLN status, predicted adjuvant therapy as per uterine features was altered in 16 out of the 103 patients (15.5%) that underwent successful SLN mapping. This represents 13% of the entire cohort of patients (Fig. 2). Case NO.4 would have been prescribed CMT/RT based on the local protocol, but as only isolated tumor cells were detected in the SLN (considered a negative node at our institution) systemic chemotherapy was withheld. Case NO. 8 had low-risk disease but had micro-metastasis in SLN on final pathology and received CMT/RT. For the remaining 14 patients with negative SLN after ultra-staging, adjuvant treatment was de-escalated from CMT/RT to RT in 5 cases, CMT/RT to observation in 7 cases and RT to observation in 2 cases.
Adjuvant treatment alteration based on sentinel lymph node status.
Lymphadenectomy in endometrial cancer is required for accurate staging and the knowledge of lymph node status determines adjuvant treatment . SLN mapping has been proposed to provide information on lymph node status, without the morbidity of full lymph node dissection. According to National Comprehensive Cancer Network (NCCN) guideline, SLN mapping can be considered for the surgical staging of uterine-confined tumour without metastasis or extra-uterine disease demonstrated by imaging or exploration . The recommended tracers were Tc99, coloured dye (isosulfan blue 1%, methylene blue 1% and patent blue 2.5% sodium) and ICG.
ICG is a small particle tracer detected by NIR. This tracer has been used for lymph node mapping in many cancers include endometrial cancer. ICG is accepted for SLN mapping by many authorities including NCCN  because of the high detection rate, sensitivity and NPV . The other benefit of ICG was reported in endometriosis surgery. ICG with NIR is useful in the evaluation of vascularization in intestinal anastomoses and identifying ureters or ureteric injury after ureterolysis for parametrial deep infiltrating endometriosis .
Our study used ICG as the tracer for SLN mapping in minimally invasive surgery. The cervical submucosa and stroma were chosen as the site of injection as it has been reported to improve detection rates. This protocol provided a high detection rate (86.1% of overall detection rate and 73% of bilateral detection rate) consistent with other studies using this technique. Overall and bilateral SLN detection rates for ICG are reported between 86–100% and 52–88%, respectively [24-31]. This indicates that there is a short learning curve for the technique as SLNs were reliably detected in this early phase of introducing the ICG and NIFR SLN mapping protocol in our institution.
The percentage of SLN detected outside the routine lymphadenectomy zone is between 3–22% [25-28,30]. In our series, 30 patients (24.6%) had SLN detected outside the routine lymphadenectomy zone suggesting that these disease bearing nodes may be missed on standard pelvic lymphadenectomy. 2 of 8 (25%) of SLN metastasis were detected in these aberrant locations.
Our study showed that BMI
Recent literature reports SLN mapping as having a good detection of positive lymph nodes. Fifteen percent (range 10–30%) of all mapped SLNs were positive and 50% of positive SLNs were diagnosed after ultra-staging . In our study, 6.6% of all patients had positive SLN which is consistent with 80% of our participants having a low to moderately differentiated endometroid adenocarcinoma and 70% having disease confined to the inner half of the myometrium, putting this group at low risk of lymph node involvement.
Ultra-staging was required for the diagnosis of metastatic disease (in the form of micro-metastasis or ITCs) in 6 of the 8 patients with positive SLNs (75%). This is relevant as despite a comprehensive pelvic lymphadenectomy, these 6 patients would not have had their LN metastasis detected by standard H&E staining methods, confirming the value of an ultra-staging protocol is confirmed in our series.
In our series 5.7% of low risk patients, who would not have undergone lymph node assessment according to our pre-existing staging algorithm, were found to have positive SLNs and were upstaged. This allowed these patients to have adjuvant therapy to reduce their risk of recurrence.
Our study reported high detection rates (90.9% for overall detection and 81.8% for bilateral detection) for patients with high-risk histological subtypes. Several studies in patients with high-risk histology have confirmed excellent performance of SLN mapping using cervical injection with bilateral detection in the order of 60% and NPV exceeding 98% [32-34]. In this cohort, 21–30% of mapped SLNs are positive, with a low false negative rate (2–5%) [32,33]. In our study 15% of patients with high-risk histology had positive SLNs. This percentage may be an underestimation as our study population only included 20 patients with high-risk histology and we did not perform full lymphadenectomy following SLN mapping in our high-risk patients.
Large retrospective data review from the Surveillance, Epidemiology, and End Results (SEER) Program showed a survival benefit from more extensive lymphadenectomy in the high-risk group . It is likely that the same survival benefits can be achieved from SLN mapping, with SLN status used to prescribe chemotherapy and pelvic +/- para-aortic radiation to patients with positive pelvic nodes.
The limitations of this study are that this is a retrospective study susceptible to biases, including surgical bias to abandon SLN mapping in difficult cases, and bias in prescription of adjuvant therapy based on various patient factors. We did not perform full pelvic lymphadenectomy in patients after SLN mapping and hence cannot provide sensitivity, specificity or false negative rate for our institution. These are the major disadvantage of our study so we cannot conclude that SLN mapping can replace full lymphadenectomy in high-risk group. However, in our unit, prior to SLN mapping, selective pelvic lymphadenectomy was performed in those with intermediate and high intermediate risk features on frozen section and our series does demonstrate that SLN mapping was effectively implemented into the existing staging paradigm as the vast majority of patients in the intermediate and high-risk groups were able to avoid comprehensive staging lymphadenectomy. Further limitations include incomplete medical records which resulted in patient exclusion. An additional limitation is that long-term survival data is not yet available on all participants treated.
The strengths of this study are that it was conducted in a tertiary centre with a high incidence of endometrial cancer. The study has captured the majority of sentinel lymph node mapping cases from the introduction of the technique into our institution’s staging protocol. This study is the first to our knowledge that illustrates the potential impact of SLN status on recommendations for adjuvant therapy in apparent early stage endometrial cancer compared with a protocol that prescribed adjuvant therapy based on uterine features. Long term survival data would be required to validate this approach however our high bilateral SLN detection rates and detection of SLN metastasis are equivocal to published reports indicating reliable detection of node positive patients.
Despite no prior experience with the technique, our detection rates were comparable with those in the literature showing effective implementation of the SLN mapping technique at our institution. We have shown that SLN mapping can be incorporated into the treatment protocol for endometrial cancer without compromising operative safety. Positive nodes located outside the standard lymphadenectomy field may be missed without SLN mapping. Ultra-staging with IHC increased the detection of positive SLNs.
The clear advantage for sentinel node mapping is in low-risk patients, who would not otherwise have a lymphadenectomy. The detection of occult nodal metastasis in 5.7% of these patients in our study allowed them to receive appropriate adjuvant therapy.
Knowledge of the SLN status in our cohort resulted in a reduction in the amount of adjuvant therapy required in a subgroup of patients, hence reducing treatment related morbidity. We await longer follow-up to observe the impact of this on patient recurrence risk and survival. Further studies should be conducted prospectively to evaluate the impact of SLN mapping on prescribed adjuvant therapy, patterns of disease recurrence and disease free and overall survival.
WC collected the data, managed the database and wrote the manuscript. VC and EW collected the data. NC and LP performed the staging surgery and sentinel lymph node mapping. NJ designed the study, performed the staging surgery and sentinel lymph node mapping and edited the manuscript. SB designed the study, and edited the manuscript. All authors read and approved the final manuscript.
This retrospective study was approved by Mater Misericordiae Ltd Human Research Ethics Committee (HREC). Approval number is HREC/MML/46596.
We thank to professor Neville Hacker for his opinion and suggestions during preparation of the manuscript.
This study received no external funding.
The authors declare no conflict of interest.
Supplementary material associated with this article can be found, in the online version, at https://ejgo.imrpress.com/EN/10.31083/j.ejgo4204106.