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Abstract
Objective To achieve the full potential of sentinel lymph node (SLN) detection in endometrial cancer, both presumed low- and high-risk groups should be included. Perioperative resource use and complications should be minimized. Knowledge on distribution and common anatomical sites for metastatic SLNs may contribute to optimizing the concept while maintaining sensitivity. Proceeding from previous studies, simplified algorithms based on histology and lymphatic anatomy are proposed.
Methods Data on mapping rates and locations of pelvic SLNs (metastatic and non-metastatic) from two previous prospective SLN studies in women with endometrial cancer were retrieved. Cervically injected indocyanine green was used as a tracer and an ipsilateral re-injection was performed in case of non-display of the upper and/or lower paracervical pathways. A systematic surgical algorithm was followed with clearly defined SLNs depicted on an anatomical chart. In high-risk endometrial cancer patients, removal of SLNs was followed by a pelvic and para-aortic lymphadenectomy.
Results 423 study records were analyzed. The bilateral mapping rates of the upper and lower paracervical pathways were 88.9% and 39.7%, respectively. 72% of all SLNs were typically positioned along the upper paracervical pathway (interiliac and/or proximal obturator fossa) and 71 of 75 (94.6%) of pelvic node positive women had at least one metastatic SLN at either of these positions. Women with grade 1–2 endometroid cancers (n=275) had no isolated metastases along the lower paracervical pathway compared with two women with high-risk histologies (n=148).
Conclusion SLNs along the upper paracervical pathway should be identified in all endometrial cancer histological subtypes; removal of nodes at defined typical positions along the upper paracervical pathway may replace a site-specific lymphadenectomy in case of non-mapping despite tracer re-injection. Detection of SLNs along the lower paracervical pathway can be restricted to high-risk histologies and a full pre-sacral lymphadenectomy should be performed in case of non-display.
- endometrial neoplasms
- lymphatic system
- lymphatic vessels
- SLN and lympadenectomy
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HIGHLIGHTS
A histology only based risk grouping simplifies preoperative workout and SLN algorithms in endometrial cancer.
Removal of lymph nodes at typical anatomical positions may replace a site wize lymphadenectomy in case of non mapping.
Detection of presacral SLNs is recommended in high risk histology endometrial cancer.
Introduction
Sentinel lymph node (SLN) mapping in women with endometrial cancer has been increasingly recognized during the last decade.1–5 An optimal SLN concept requires a high bilateral mapping rate and a high sensitivity for detecting lymph node metastases. The best outcome has been demonstrated following cervical injection of indocyanine green (Pulsion Medical Systems, PICG0025SE, Feldkirchen, Germany).6 The detection rate of lymph node metastases is further increased by performing histopathological ultrastaging and immunohistochemistry on resected SLNs.7 8 To reduce the false negative rate, Barlin et al. suggested an SLN concept including the resection of macroscopically suspicious lymph nodes regardless of mapping and a site-specific lymphadenectomy in case of no mapping/macroscopically suspect nodes.9
In more than one fifth of endometrial cancer patients, the preoperative risk group will be altered by the final pathology report, most commonly due to discrepancy in preoperative and postoperative evaluation of myometrial depth invasion. For an SLN concept to achieve its full potential, including avoiding the consequences of an erroneous preoperative risk group allocation, endometrial cancer patients in both assumed high and low risk groups should therefore be included.2 10 11 Including both low and high risk patients may therefore make preoperative myometrial invasion measurements unnecessary, simplifying and reducing costs for preoperative workout. The rate of lymph node metastases in true low risk endometrial cancer patients is approximately 5–7%, and an SLN concept including these women would guide adjuvant treatment in women with otherwize undetected metastatic disease and could potentially improve survival.2 11 12 However, for an SLN concept to be acceptable in women with low risk endometrial cancer, the SLN procedure per se should entail acceptable additional surgical time and carry a low risk of complications. Therefore, the principle of a full site-specific lymphadenectomy in case of non-mapping may be questioned from a morbidity perspective, particularly in low risk endometrial cancer patients. The additional 30 min required in the Pelvic SLN detection in the High-Risk Endometrial Cancer (SHREC) study for the SLN procedure, where dissection along both the upper and lower paracervical pathways were performed, is likely too time-consuming to motivate a similar SLN algorithm in presumed low-risk patients, taking into account that surgeries were performed by a few well experienced surgeons.2 11 13 On the other hand, in the SHREC study no complications associated with the SLN procedure were observed, indicating the importance of surgical experience. Another study performed at our institution showed a 13-fold decrease in symptomatic lower limb lymphedema (18.1% compared with 1.3%) and a 5-fold decrease in the incidence of pelvic lymphoceles (13.3% compared with 2.6%) after SLN only compared with a full pelvic lymph node dissection, demonstrating the potential of the SLN concept in decreasing postoperative lymphatic complications.2 11 13 14
The aim of this study was to investigate the prerequisites for simplified and diversified SLN algorithms based on lymphatic anatomy and distribution of SLNs in women with endometrial cancer based on histological risk groups only (International Federation of Gynecology and Obstetrics (FIGO) grade 1–2 endometrioid and FIGO grade 3/non-endometriod types, respectively), minimizing SLN associated operating room (OR) time and complications and alleviating the need for myometrial invasion measurements.
Methods
Data were retrieved from two prospective studies on SLNs in women with presumed low- and high-risk endometrial cancer.2 13 14 Mapping rates per the upper and lower paracervical pathways and anatomical positions of pelvic SLNs (metastatic and non-metastatic) were investigated. In the SHREC study women with presumed high-risk endometrial cancer underwent an SLN procedure followed by a full pelvic and para-aortic lymphadenectomy.13 In the SLN-only study women with presumed low-risk cancers or comorbid women with high-risk cancers were included and not subjected to lymph node dissection beyond the SLN procedure.2 14 All women had a preoperative evaluation that included CT and either an expert vaginal ultrasonography or an MRI to evaluate the extent of myometrial and/or cervical invasion as well as the presence of locally advanced disease. Preoperative histological diagnosis and grade was decided on specimens obtained from either endometrial biopsy, curettage or hysteroscopy.
The SHREC study was conducted at two Swedish tertiary referrals centers, Skåne University Hospital, Lund (June 2014 to May 2018) and Karolinska University Hospital, Stockholm (May 2017 to May 2018), whereas the SLN only study was conducted at Skåne University Hospital, Lund in parallel with the SHREC study.2 13 14 Both institutions are highly experienced robotic centers with an annual caseload of 180–250 endometrial cancer procedures. The number of participating surgeons was limited to five high volume robotic surgeons who partook in case observation and local audit performed by the principal investigator (JP) to eliminate protocol violations. All women were planned for a robotic procedure using a da Vinci Si or Xi Surgical System (Intuitive Surgical, Sunnyvale, CA, USA).
The SLN procedures in both studies were identically performed according to a defined anatomically based surgical algorithm.11 Cervical injection of 1 mL of a 2.5 mg/mL sterile water solution of indocyanine green as tracer was performed with 0.25 mL injected in all four quadrants. Half the volume was injected submucosally, and the remaining half was injected into the cervical stroma. A compression-free fornix presenter without an intracervical device was used. The FireFly mode was utilized for identification of the upper and lower paracervical pathways.2 The avascular presacral, paravesical and pararectal planes were developed, keeping the lymphatic vessels intact. In case of non-display in any pathway after 10 min, an ipsilateral re-injection at 3 or 9 o’clock of 0.25 mL of the tracer was performed. SLN type 1 was defined as the juxta-uterine indocyanine-positive node with an afferent indocyanine-positive lymph vessel in the upper and lower paracervical pathways, respectively, with possible parallel lymphatics in the upper pathway to the external iliac, common iliac and obturator areas. In case of an indocyanine-positive pathway with no indocyanine-positive nodes, the node draining the indocyaninen-positive lymphatic channel was defined as SLN type 2. Nodes macroscopically suspect of metastatic disease were defined as SLN-macro regardless of indocyanine uptake. In this study, all SLN subtypes defined by indocyanine green were pooled together. The upper paracervical parametria were removed separately and treated as SLN tissue. In case of non-mapping and no SLN macro, a pathway-wise site-specific lymphadenectomy was performed unless surgically contraindicated in a small minority of comorbid non-mapping women selected for SLN only, in whom a more restricted sampling was performed along the non-mapped pathway. The positions and types of SLNs were drawn on an anatomical chart. A copy of this standardized depictive chart of defined dissected lymph node stations with corresponding anatomical positions and numbers on pre-labeled jars was also used for the pathology report.13
All SLN tissue was embedded and bisected if the minimum thickness exceeded 3 mm. Ultrastaging using hematoxylin and eosin staining was performed in five sections at three different levels, 200 µm apart, if the maximum diameter of the sentinel node tissue exceeded 1 mm. Immunohistochemistry with staining for pan-cytokeratin and cytokeratin MNF 116 was performed.
Non-SLNs with a thickness <3 mm were embedded entirely and for nodes >3 mm at least half the node was embedded. Non-SLNs were stained for hematoxylin and eosin but were not subjected to immunohistochemistry or ultrastaging. Metastatic disease was classified according to a modification of the American Joint Committee on Cancer staging definitions for axillary nodes in breast cancer (macro-metastases=tumor >2.0 mm in diameter; micro-metastases=tumor cell aggregates between 0.2 and 2.0 mm in diameter; isolated tumor cells=individual tumor cells or aggregates <0.2 mm in diameter and <200 cells).15 The pathologists were not blinded to the results of SLNs and non-SLNs when performing their assessment.
All intraoperative adverse events occurring following injection of indocyanine green and during the SLN procedure as such were separately registered.
To mimic a clinical situation where no preoperative myometrial invasion estimations are used, the included women were subdivided into two groups based on preoperative histology: women with endometrial adenocarcinoma FIGO grade 1–2 (group A); and women with endometrial adenocarcinoma FIGO grade 3 or non-endometrioid histology (group B).
Written informed consent was obtained from all enrolled women. The studies were approved by the respective Institutional Review Boards (Skåne University Hospital, Dnr 2013/163, Karolinska University Hospital Dnr Ö 7–2017) and registered at Clinical Trials.gov (NCT02690259).
Results
Data were retrieved from 423 women, 257 from the SHREC study and 166 from the SLN only study. Demographic and clinical data are presented in Table 1. The bilateral indocyanine green defined mapping rate of the upper paracervical pathway was 88.9%, but this rate was as low as 39.7% in the lower paracervical pathway with only a small increase after re-injection. Seventy-five women with pelvic lymph node metastases had a total of 151 metastatic SLNs in addition to six lymph node metastases along an unmapped lower paracervical pathway, the latter being included in the analyses on distribution of metastatic SLNs.
Demographic and clinical data from 423 women with endometrial cancer included in two prospective studies on detection of sentinel lymph nodes
Of the 275 women in group A (FIGO grade 1–2 endometrioid cancer), 32 (11.6%) had pelvic lymph node metastases, and all had at least one metastatic SLN along the upper paracervical pathway. One woman (0.4%) had an isolated metastatic SLN in the parametrium, constituting 3% of women with lymph node metastases in group A. In six women (2.2%) lymph node metastases were identified along the lower paracervical pathway, neither of which were isolated.
The 148 women in group B (FIGO grade 3 endometrioid and non-endometrioid cancers), 43 (29.1%) had pelvic lymph node metastases, and all were identified through metastatic SLNs. One woman (0.6%) had an isolated metastatic SLN in the parametrium, constituting 2.3% of women with lymph node metastases in group B. Metastatic SLNs or lymph node metastases in women who did not map along the lower paracervical pathway was seen in 16 women (10.8%), and two of these women had isolated presacral metastatic lymph nodes. This constituted 4.7% of the women with pelvic lymph node metastases in group B.
Regardless of histology, the anatomical positions of the SLNs (metastatic and non-metastatic) along the upper paracervical pathway were relatively constant, most commonly the interiliac site (81.8%) and/or the obturator fossa just distal of the bifurcation of the hypogastric vessel ventral to the obturator nerve (61.7%). Parallel lymphatics with simultaneous presence of SLNs in both these compartments were common (Figure 1 and Table 2).
Typical positions and distributions of SLNs (all = ICG pos SLN, and metastatic = SLN+) in 423 women with a preoperatively presumed uterine stage I–II, FIGO grade 1–2 endometrioid, (n=275) or FIGO grade 3 endometrioid and non-endometrioid (n=148) histology following a cervical injection of ICG as tracer. Percentage of metastatic SLN refers to the total number of metastatic SLNs (n=157) all histologies including non-SLN metastases in women with no mapping along the LPP. **All parametria treated as SLN tissue due to difficulty in distinguishing separate ICG positive SLNs due to high background ICG. FIGO, International Federation of Gynecology and Obstetrics; ICG, indocyanine green; LPP, lower paracervical pathway; SLN, sentinel lymph nodes; UPP, upper paracervical pathway.
Distribution of metastatic sentinel lymph nodes in 423 women with preoperatively presumed FIGO grade 1–2 endometroid (group A, n=275, 11.6% node positive) or FIGO grade 3 and non-endometrioid (group B, n=148, 29.1% node positive) endometrial cancers following a cervical injection of ICG.
The anatomical positions of SLNs along the lower paracervical pathway were more variable, either located medial of the internal iliac vessels ventral to the promontory or more cranial presacrally lateral to the hypogastric nerve bundle medial to the common iliac arteries. Crossover of lymphatics between the left and right lower paracervical pathways at the level of the promontory was frequently observed. The positions and distribution of SLNs and metastatic SLNs are shown in Figure 1 and Table 2.
In 160 women (37.8%) SLNs were identified in the upper lymphovascular parametria. Ten women had metastatic SLNs in the parametria (2.4% of all included women and 6.4% of metastatic SLNs). Two women had isolated metastatic SLNs in the parametrium.
Based on these anatomic findings simplified histology-based algorithms are proposed (Figures 2 and 3).
Proposed algorithm for FIGO grade 1–2 endometrioid endometrial cancer. FIGO, International Federation of Gynecology and Obstetrics; ICG, indocyanine green.
Proposed algorithm for FIGO grade 3 endometrioid and non-endometrioid endometrial cancer. FIGO, International Federation of Gynecology and Obstetrics; ICG, indocyanine green.
No adverse reactions related to the injection of indocyanine green were observed. No intraoperative complications associated with the SLN procedure were seen.
Discussion
SLNs along the upper paracervical pathway should be identified in all endometrial cancer subtypes with an ipsilateral re-injection of tracer in case of lack of display. If mapping along the upper pathway is not achieved following re-injection, we propose that nodes at defined typical positions for the SLNs (interiliac and proximal obturator) should be removed instead of a site-specific full lymphadenectomy. SLNs along the lower paracervical pathway should only be identified in patients with high-risk histology cancers and, due to more variable anatomic positions of SLNs along this pathway, replaced by a full presacral lymphadenectomy in case of non-display after primary tracer injection. Macroscopically suspect nodes should be removed regardless of tracer display.
Importantly, for the SLN concept to reach its full potential, women with presumed low-risk endometrial cancer should be included. We believe the proposed simplified algorithm optimizes the detection rate of metastatic disease while minimizing the additional surgical time and intraoperative complications associated with a procedure that will not benefit approximately 90% of women with a histology-only based low-risk group allocation.2 11 12 The reduction in time and complications is achieved by abstaining from dissection along the lower paracervical pathway and avoiding a site-specific lymphadenectomy in case of non-mapping in the upper paracervical pathway, the latter being particularly important in presumed low risk endometrial cancer patients where the acceptance of potential lymphatic complications is low.
In women with high-risk endometrial cancer, an optimal SLN concept retains the detection rate of metastatic disease while reducing the risk of pre- and postoperative complications. Adhering to a defined surgical algorithm including a clear definition of SLNs and maintaining a high level of surgical proficiency is key to preserving high bilateral mapping rates and a high negative predictive value.11 13 By excluding depth invasion the algorithm reduces the effect of erroneous preoperative risk group allocation and alleviates the need for presurgical evaluation of the myometrium, thereby simplifying the preoperative workout. Neither do we believe that intraoperative myometrial invasion estimations will add value to a generally implemented SLN concept; rather add to operating room time, costs and logistically complicate an optimal use of operating room resources.
Contrary to erroneous risk group allocation due to differences in preoperative and postoperative evaluation of depth of myometrial invasion, the risk of upgrading from FIGO grade 1 to grade 3 or non-endometroid histology was found by Leitao et al. and Garcia et al. to be 1.9% and 2.3%, respectively.16 17 Upgrading from FIGO grade 2 to grade 3 occurred in 16%.17 The distribution between FIGO grades 1, 2, and 3 is described to be 50%, 35%, and 15%, respectively.18 Hence, approximately 9% of preoperatively estimated FIGO grade 1–2 cancers may be upgraded to either FIGO grade 3 or non-endometrioid histologies, compared with approximately 20% where the preoperative evaluation of the extent of myometrial invasion is erroneous. The proposed algorithms based on histology only thereby compensate for most consequences of discrepancy between pre- and postoperative staging, and allows for all endometrial cancer patients to be included in an SLN concept in a better way than if a myometrial invasion measurement is used in addition to histology.16 19
Regardless of histology, SLNs along the upper paracervical pathway should be identified, if necessary, after the re-injection of tracer or by removal of anatomical equivalent nodes (interiliac and proximal obturator) in case of non-mapping. The interiliac node is easily attainable whereas the obturator node is usually less accessible, especially in obese women or in women with tortuous iliac vessels, due to its deep location and close proximity to the obturator nerve and internal iliac and obturator vessels. This location is, however, the most frequent position for pelvic lymph node metastases, emphasizing the need for meticulous evaluation of the compartment and a need for surgical proficiency.
Detection of SLNs along the lower paracervical pathway is more time consuming mainly due to slower uptake of tracer, often with a need to wait 10 min or more to evaluate the display. In FIGO grade 1–2 cancers the low risk of metastases along the lower paracervical pathway cannot motivate the additional surgical time or the theoretical increased risk of complications associated with a presacral dissection. In FIGO grade 3 or non-endometroid cancers lymph node metastases along the lower paracervical pathway were detected in 10.8% of women and isolated metastases occurred. Removal of SLNs or in case of non-mapping following primary tracer injection, a full presacral lymphadenectomy should be performed. The latter is due to a more varied location of SLNs along the lower paracervical pathway as well as the diminutive difference in the extent of the lymph node dissection between SLN removal and a full presacral lymphadenectomy. Furthermore, abstaining from re-injection due to non-display of the lower paracervical pathway will prevent overdosing of indocyanine green along the upper paracervical pathway. Adherence to the surgical algorithm with a consistent dissection along the lower paracervical pathway is likely the explanation for a higher mapping and detection of metastases compared with other studies.
Nodes in the upper paracervical tissue/parametrium were identified in almost 40% of women. Although theoretically the most juxta-uterine node, isolated parametrial lymph node metastases occurred in <1% of women. Although further investigation is needed, we believe removal of the upper parametrium is not indicated as part of an SLN procedure at this point.
A weakness of the study is that in the SLN-only study we cannot exclude that SLNs were false negative as a complementary lymphadenectomy was not performed. However, the SHREC study demonstrated a 98% sensitivity of the SLN-indocyanine algorithm and a 100% sensitivity of the overall SLN algorithm (including SLN macro) to detect pelvic lymph node metastases. As we applied the same strict surgical algorithm and both studies were performed in parallel by the same highly experienced surgeons, and that the rate of metastatic SLN was higher than expected in the SLN only group, we believe the results are likely to be accurate.
Further management of women with metastatic pelvic SLNs is under debate. The impact of low volume metastases in SLNs needs further investigation. Depending on adjuvant treatment principles para-aortic nodal status may be of interest. Surgical restaging or postoperative positron emission tomography-CT (PET-CT) can be used. Although suggested, preoperative PET-CT is in our opinion not in line with a less costly, simplified preoperative evaluation and should not be used routinely.
Whether an SLN concept is oncologically safe compared with upfront full lymphadenectomy in high risk cancers remains to be further investigated. To date, no sufficiently powered studies exist and if undertaken would require uniform subgroups and adjuvant treatment principles in a poly-institutional study setting over a long period of time. We do believe that the high negative predictive value of the SLN concept demonstrated in quality studies and the reduction of peri- and postoperative complication rates motivate an SLN concept if implemented in a high volume setting under quality control.
In conclusion, we believe the proposed simplified anatomically based algorithms, differentiated by preoperative histological risk groups only, will in the hands of experienced surgeons, safely and accurately identify women with pelvic lymph nodes metastases while minimizing preoperative workout, SLN associated surgical time and the rate of complications. A prospective evaluation of the algorithms is presently being performed at our institution.
Footnotes
Editor's note This paper will feature in a special issue on sentinel lymph node mapping in 2020.
Contributors The study was designed by JP, MB, BG and CL who also performed the data analyses. All authors contributed to data acquisition and interpretation, writing and revising of the draft and the final approval of the manuscript. The corresponding author confirms he had full access to all data in the study and has the final responsibility for the decision to submit the manuscript. All authors have given their written permission to publish the manuscript in the present form.
Funding The study was funded by Skåne County Councils’s Research and Development Foundation (Grant number REGSKANE 353601 and REGSKANE 632231), Skåne University Hospital donation funds (Grant number 95230) and Radiumhemmets Forskningsfonder (Grant number 174102).
Competing interests JP and CL have received honoraria from Intuitive Surgical for proctoring and lectures in robot assisted surgery, and HF has received honoraria from Intuitive Surgical and Medtronics for similar services.
Patient consent for publication Not required.
Ethics approval The study was approved by the respective Institutional Review Boards (Skåne University Hospital, Dnr 2013/163, Karolinska University Hospital Dnr Ö 7-2017).
Provenance and peer review Commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request providing potentially needed and approved amendments of ethical approvals.