Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics

doi:10.1016/j.ajog.2021.05.034

American Journal of Obstetrics and Gynecology

Volume 225, Issue 4, October 2021, Pages 367.e1-367.e39

https://doi.org/10.1016/j.ajog.2021.05.034 Get rights and content

Objective

A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280).

Data Sources

We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials.

Study Eligibility Criteria

We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data.

Methods

We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool.

Results

We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44–82.5 years) and the study-level median body mass index was 28.6 kg/m² (range, 19.4–43.7 kg/m²). The pooled detection rates were 91% per patient (95% confidence interval, 85%–95%; I²=59%) and 64% bilaterally (95% confidence interval, 53%–73%; I²=69%). The overall node positivity rate was 26% (95% confidence interval, 19%–34%; I²=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%–96%; I²=0%), a false negative rate of 8% (95% confidence interval, 4%–16%; I²=0%), and a negative predictive value of 97% (95% confidence interval, 95%–99%; I²=0%).

Conclusion

Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.

Introduction

Endometrial cancer (EC) is the most common gynecologic cancer in developed countries.¹ The incidence of both low- and high-grade EC continues to increase secondary to the rising rates in obesity and life expectancy.1, 2, 3 Because high-grade EC is less likely to be associated with estrogen-related risk factors and obesity, other unknown factors may also play a role in its rising incidence.³^,⁴

The standard management of early-stage, high-grade EC includes hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection to determine the stage of disease and the need for adjuvant treatment.⁵^,⁶ However, a complete pelvic lymphadenectomy (PLND) and para-aortic lymphadenectomy (PALND) are associated with substantial morbidity (nerve or vessel injury, blood loss, lymphocyst formation, and lymphedema) and adverse impacts on the quality of life.7, 8, 9

A sentinel lymph node biopsy (SLNB) based on the Memorial Sloan Kettering sentinel lymph node (SLN) algorithm¹⁰ has gained acceptance as an alternative to a full lymphadenectomy in low-grade EC (grade 1 or 2 endometrioid).⁶^,¹¹ The SLN algorithm includes peritoneal and serosal evaluation, retroperitoneal excision of the successfully mapped SLN in each hemipelvis, removal of any suspicious nodes, and most importantly, full side-specific PLND and PALND for failed mapping.¹⁰ SLNs are then processed using ultrastaging, defined as additional serial sectioning and review of multiple hematoxylin and eosin (H&E) stained slides with cytokeratin immunohistochemistry (IHC) staining when H&E sections are negative.⁶^,¹¹ The exact protocols vary across different centers.¹²^,¹³

The role of SLNBs in high-grade EC (grade 3 endometrioid, serous, clear cell, carcinosarcoma, dedifferentiated, and mixed histology) is less clear. The majority of studies on SLNBs in EC included patients with low-grade EC who are known to be at lower risk for lymph node involvement.⁷ Several studies have examined SLNBs in patients with a mix of high-risk features; however, only a subset specifically included patients with high-grade histology, including 13% in the Sentinel Node and Endometrial Cancer study,¹⁴ 28% in the FIRES study,¹⁵ 46% in the Pelvic Sentinel Lymph Node Detection in High-Risk Endometrial Cancer (SHREC) trial,¹⁶ and 80% in a study by Soliman et al.¹⁷ The recently published Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging (SENTOR) study had the largest cohort of patients with high-grade histology to date, used a contemporary tracer, and showed that SLNBs had acceptable diagnostic accuracy in this group of patients.¹⁸

Application of an SLNB in patients with high-grade EC may be associated with different performance characteristics and requires more evidence of accuracy before becoming the standard of care. We therefore performed a systematic review and meta-analysis to evaluate the performance characteristics of SLNBs using indocyanine green (ICG) among patients with EC with high-grade histologic subtypes who underwent a complete PLND (with or without PALND) as a reference standard.

Section snippets

Eligibility criteria

The protocol for this study was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under identifying number CRD42020160280, conducted according to the Cochrane Handbook,¹⁹ and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis²⁰ and the Meta-Analysis of Observational Studies in Epidemiology²¹ guidelines. We included prospective cohort studies that (1) evaluated SLNBs with cervical injection of ICG; (2)

Study selection

We identified 8620 records in the database searches from January 1, 2000, to January 26, 2021 (Figure 1). Seven additional records were identified through manual searching and citation tracking. Following the exclusion of duplicates, 5897 articles were left for evaluation. After title and abstract screening, 262 articles were selected for full-text screening.

Of the 262 full-text articles, 246 were excluded for reasons outlined in Figure 1 and Appendix 2 (Supplemental Table 2). There ultimately

Comment

In this comprehensive systematic review of 16 studies and 429 patients with high-grade EC eligible for meta-analysis we found (1) high pooled detection rates of 91% per patient (95% CI, 85%–95%; I²=59%) and 64% bilaterally (95% CI, 53%–73%; I²=69%); (2) high pooled sensitivity of 92% per patient (95% CI, 84%–96%; I²=0%) and 90% per hemipelvis (95% CI, 83%–94%; I²=0%); (3) high pooled NPV of 97% per patient (95% CI, 95%–99%; I²=0%) and 98% per hemipelvis (95% CI, 96%–99%; I²=8%).

Our findings are

References (57)

S.C. Dowdy et al.
Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer
Gynecol Oncol
(2012)
J.N. Barlin et al.
The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes
Gynecol Oncol
(2012)
R.W. Holloway et al.
Sentinel lymph node mapping and staging in endometrial cancer: a Society of Gynecologic Oncology literature review with consensus recommendations
Gynecol Oncol
(2017)
B. Cormier et al.
Sentinel lymph node procedure in endometrial cancer: a systematic review and proposal for standardization of future research
Gynecol Oncol
(2015)
E. Daraï et al.
Sentinel node biopsy for the management of early stage endometrial cancer: long-term results of the SENTI-endo study
Gynecol Oncol
(2015)
E.C. Rossi et al.
A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study
Lancet Oncol
(2017)
J. Persson et al.
Pelvic Sentinel lymph node detection in High-Risk Endometrial Cancer (SHREC-trial)-the final step towards a paradigm shift in surgical staging
Eur J Cancer
(2019)
P.T. Soliman et al.
A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer
Gynecol Oncol
(2017)
S. Hopewell et al.
Reporting of trials presented in conference abstracts needs to be improved
J Clin Epidemiol
(2006)
A.J. Bodurtha Smith et al.
Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis
Am J Obstet Gynecol
(2017)

V.W. Setiawan et al.

Type I and II endometrial cancers: have they different risk factors?

J Clin Oncol

(2013)

N. Concin et al.

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

Int J Gynecol Cancer

(2021)

Version 2. 2020

Cited by (42)

Sentinel node mapping in high-intermediate and high-risk endometrial cancer: Analysis of 5-year oncologic outcomes
2024, European Journal of Surgical Oncology
To assess 5-year oncologic outcomes of apparent early-stage high-intermediate and high-risk endometrial cancer undergoing sentinel node mapping versus systematic lymphadenectomy.
This is a multi-institutional retrospective, propensity-matched study evaluating data of high-intermediate and high-risk endometrial cancer (according to ESGO/ESTRO/ESP guidelines) undergoing sentinel node mapping versus systematic pelvic lymphadenectomy (with and without para-aortic lymphadenectomy). Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard methods.
Overall, the charts of 242 patients with high-intermediate and high-risk endometrial cancer were retrieved. Data on 73 (30.1%) patients undergoing hysterectomy plus sentinel node mapping were analyzed. Forty-two (57.5%) and 31 (42.5%) patients were classified in the high-intermediate and high-risk groups, respectively. Unilateral sentinel node mapping was achieved in all patients. Bilateral mapping was achieved in 67 (91.7%) patients. Three (4.1%) patients had site-specific lymphadenectomy (two pelvic areas only and one pelvic plus para-aortic area), while adjunctive nodal dissection was omitted in the hemipelvis of the other three (4.1%) patients. Sentinel nodes were detected in the para-aortic area in eight (10.9%) patients. Twenty-four (32.8%) patients were diagnosed with nodal disease. A propensity-score matching was used to compare the aforementioned group of patients undergoing sentinel node mapping with a group of patients undergoing lymphadenectomy. Seventy patient pairs were selected (70 having sentinel node mapping vs. 70 having lymphadenectomy). Patients undergoing sentinel node mapping experienced similar 5-year disease-free survival (HR: 1.233; 95%CI: 0.6217 to 2.444; p = 0.547, log-rank test) and 5-year overall survival (HR: 1.505; 95%CI: 0.6752 to 3.355; p = 0.256, log-rank test) than patients undergoing lymphadenectomy.
Sentinel node mapping does not negatively impact 5-year outcomes of high-intermediate and high-risk endometrial cancer. Further prospective studies are warranted.
Identifying safe diagnostic algorithms for sentinel lymph node mapping in high-risk endometrial cancer: The SENTIREC-endo study
2024, Gynecologic Oncology
It is unclear if sentinel node (SLN) mapping can replace pelvic- (PLD) and paraaortic lymphadenectomy (PALD) for high-risk endometrial cancer (EC). A diagnostically safe surgical algorithm, taking failed mapping cases into account, is not defined. We aimed to investigate the diagnostic accuracy of SLN mapping algorithms in women with exclusively high-risk EC.
We undertook a prospective national diagnostic cohort study of SLN mapping in women with high-risk EC from March 2017 to January 2023. The power calculation was based on the negative predictive value (NPV). Women underwent SLN mapping, PLD and PALD besides removal of suspicious and any FDG/PET–positive lymph nodes. Accuracy analyses were performed for five algorithms.
170/216 included women underwent SLN mapping, PLD and PALD and were included in accuracy analyses. 42/170 (24.7%) had nodal metastasis. The algorithm SLN and PLD in case of failed mapping, demonstrated a sensitivity of 86% (95% CI 74–100) and an NPV of 96% (95% CI 91–100). The sensitivity increased to 93% (95% CI 83–100) and the NPV to 98% (95% CI 94–100) if PLD was combined with removal of any PET-positive lymph nodes. Equivalent results were obtained if PLD and PALD were performed in non-mapping cases; sensitivity 93% (95% CI 83–100) and NPV 98% (95% CI 95–100).
SLN-mapping is a safe staging procedure in women with high-risk EC if strictly adhering to a surgical algorithm including removal of any PET-positive lymph nodes independent of location and PLD or PLD and PALD in case of failed mapping.
Robotic-assisted para-aortic lymphadenectomy: Technique and indications in gynecological oncology
2023, Best Practice and Research: Clinical Obstetrics and Gynaecology
The benefits of minimally-invasive surgeries have been documented, and they have been established as the preferred approach for gynecological surgeries. With the development of robotic surgery, many highly complex surgeries can benefit from these advantages. Due to the complexity of aortocaval lymphadenectomy, surgical technique protocols have been described to reduce risks by maximizing benefits.
We describe the technique using five ports (4 robotic arms and an assistant) to work the upper abdominal field, and different instruments recommended in each of their positions to reduce errors and optimize surgical time. After the “step by step” description, we summarize indications of aortocaval lymphadenectomy for every gynecological cancer in different stages.
Outcomes for patients with high-risk endometrial cancer undergoing sentinel lymph node assessment versus full lymphadenectomy
2023, Gynecologic Oncology
The objective of this study was to determine the progression free survival (PFS) and overall survival (OS) among patients with high-risk endometrial cancer (EC) who underwent sentinel lymph node (SLN) mapping and dissection compared to patients who underwent pelvic +/− para-aortic lymphadenectomy (LND).
Patients with newly diagnosed high-risk EC were identified. Inclusion criteria included patients who underwent primary surgical management from January 1, 2014 to September 1, 2020 at our institution. Patients were categorized into either the SLN or LND group based on their method of planned lymph node assessment. Patients in the SLN group had dye injected followed by successful bilateral lymph node mapping, retrieval, and processing per our institutional protocol. Clinicopathological and follow-up data were extracted from patient's medical records. The t-test or Mann-Whitney test was used to compare continuous variables and Chi-squared or Fisher's exact test were used for categorical variables. Progression-free survival (PFS) was calculated from the date of initial surgery to the date of progression, death, or last follow-up. Overall survival (OS) was calculated from the date of surgical staging to the date of death or last follow-up. Three-year PFS and OS were calculated using the Kaplan-Meier method, and the log-rank test was used to compare cohorts. Multivariable Cox regression models were used to assess the relationship between nodal assessment cohort and OS/PFS while adjusting for age, adjuvant therapy, and surgical approach. A result was considered statistically significant at the p < 0.05 level of significance and all statistical analysis was done using SAS version 9.4 (SAS Institute, Cary, NC).
Out of 674 patients diagnosed with EC during the study period, 189 were diagnosed with high-risk EC based on our criteria. Forty-six (23.7%) patients underwent SLN assessment and 143 (73.7%) underwent LND. No difference was observed between the two groups in regards to age, histology, stage, body mass index, tumors myometrial invasion, lymphovascular space invasion, or peritoneal washing positivity. Patients in the SLN group underwent robotic-assisted procedures more frequently than those in the LND group (p < 0.0001). The three-year PFS rate was 71.1% (95% CI 51.3–84.0%) in the SLN group and 71.3% (95% CI 62.0–78.6%) in the LND group (p = 0.91). The unadjusted hazard ratio (HR) for recurrence in the SLN versus LND group was 1.11 (95% CI 0.56–2.18; p = 0.77), and after adjusting for age, adjuvant therapy, and surgical approach, the HR for recurrence was 1.04 (95% CI 0.47–2.30, p = 0.91). The three-year OS rate was 81.1% (95% CI 51.1–93.7%) in the SLN group and 95.1% (95% CI 89.4–97.8%) in the LND group (p = 0.009). Although the unadjusted HR for death was 3.74 in the SLN vs LND group (95% CI 1.39–10.09; p = 0.009), when adjusted for age, adjuvant therapy, and surgical approach, it was no longer significant with a HR of 2.90 (95% CI 0.94–8.95, p = 0.06).
There was no difference in three-year PFS in patients diagnosed with high-risk EC who underwent SLN evaluation compared to those who underwent full LND in our cohort. The SLN group did experience shorter unadjusted OS; however, when adjusting for age, adjuvant therapy and surgical approach, there was no difference OS in patients who underwent SLN compared to LND.
Recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022-2023: Management of localized endometrial cancer
2023, Bulletin du Cancer
Le cancer de l'endomètre est le cancer gynécologique le plus fréquent dans les pays développés et son incidence augmente. La nouvelle classification moléculaire permet de déterminer le risque de récidive et de moduler la prise en charge thérapeutique. La chirurgie reste la pierre angulaire du traitement. La voie d'abord mini-invasive doit être privilégiée pour les stades I/II. Le geste opératoire repose sur l'hystérectomie avec annexectomie bilatérale, le ganglion sentinelle (GS) y compris pour les formes à haut risque et l'omentectomie pour les formes non endométrioïdes (à exception des tumeurs à cellules claires). Une préservation de la fertilité peut être proposée pour les tumeurs de bas grade de stade IA sans envahissement myométrial. Pour les stades III/IV, une adénectomie sélective sans lymphadénectomie complète est indiquée. En cas de carcinose péritonéale, une chirurgie de cytoréduction première est recommandée si la résection peut être complète. Les traitements adjuvants ne sont pas indiqués dans les tumeurs à bas risque. Pour les tumeurs à risque intermédiaire, une curiethérapie est indiquée. Pour les tumeurs à risque intermédiaire-haut, une curiethérapie ou une radiothérapie externe sont indiquées en fonction des facteurs pronostiques (stade II, emboles); la chimiothérapie adjuvante peut se discuter au cas par cas en fonction des facteurs de risque. Pour les tumeurs à risque haut, une chimiothérapie et une radiothérapie externe sont recommandées, de façon concomitante ou selon un schéma séquentiel.
Recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022–2023: Management of localized endometrial cancer
Endometrial cancer is the most frequent gynecological cancers in industrialized countries and its incidence increases. The newmolecularclassification allows determination of the risk of recurrence and helps orienting therapeutic management. Surgery remains the cornerstone of treatment. Minimally invasive approach must be preferred for stages I and II. Surgery includes hysterectomy with bilateral adnexectomy, sentinel lymph node biopsy even in high risk diseases and omentectomy for non-endometrioid tumors (except in case of clear cells tumors). Fertility preservation can be proposed in low grade, stage I tumors without myometrial involvement. In stage III/IV disease, lymph node debulking without totallymphadenectomy is indicated. In case of peritoneal carcinomatosis, first-line cytoreductive surgery is recommended if complete resection can be achieved. Adjuvant therapy is not recommended in low risk tumors. In intermediate risk tumors, curietherapy is indicated. In tumors with high-intermediate risk, curietherapy and external radiotherapy are indicated according to prognostic factors (stage II, lymphovascular invasion); adjuvant chemotherapy can be considered on a case-by-case basis. In high risk tumors, chemotherapy and external radiotherapy are recommended using a concomitant or sequential approach.
Diagnostic accuracy of frozen section and patterns of nodal spread in high grade endometrial cancer: A secondary outcome of the SENTOR prospective cohort study
2023, Gynecologic Oncology
The study aimed to define the accuracy of intraoperative frozen section (FS) for the detection of metastases in sentinel lymph node biopsy (SLNB) and describe the pattern of lymph node (LN) spread and relation to molecular classifiers in patients with high-grade endometrial cancer (EC).
We performed a secondary outcome of clinicopathologic data from the Sentinel Lymph Node Biopsy versus Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging (SENTOR) prospective cohort study evaluating SLNB in patients with clinical stage I high-grade EC (ClinicalTrials.gov ID: NCT01886066). The primary outcome was the sensitivity of FS of the sentinel lymph node (SLN) specimen, compared to a standardized ultrastaging protocol. Secondary outcomes included the pattern and characteristics of LN spread.
There were 126 patients with high-grade EC with a median age of 66 years (range:44–86) and a median Body Mass Index (BMI) of 26.9 kg/m² (range:17.6–49.3). FS was performed on surgical specimens from 212 hemipelves; SLNs were identified in 202 specimens (95.7%) and fatty tissue alone was identified in 10 specimens (4.7%). Of the 202 hemipelves in which SLNs were identified, 24 were positive for metastatic disease on final pathology. Initial FS correctly identified only 12, yielding a sensitivity of 50% (12/24, 95% CI 29.6–70.4) and a negative predictive value of 94% (178/190, 95% CI 89–96.5). A total of 24 patients (19%) had LN metastases: 16 (13%) had isolated pelvic metastases, 7 (6%) had both pelvic and para-aortic metastases and 1 (0.8%) had an isolated para-aortic metastasis.
Intraoperative FS of SLNs in high-grade EC patients has poor sensitivity. Since isolated para-aortic metastases are rare, para-aortic lymphadenectomy may be omitted in patients in which SLNs were successfully mapped to the pelvis.

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: The authors report no conflict of interest.

: This study received no financial support.

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Systematic ReviewsSentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics

Objective

Data Sources

Study Eligibility Criteria

Methods

Results

Conclusion

Introduction

Section snippets

Eligibility criteria

Study selection

Comment

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Lancet Oncol

Eur J Cancer

Gynecol Oncol

J Clin Epidemiol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Am J Obstet Gynecol

Int J Surg

J Obstet Gynaecol Can

Lancet Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Cancer statistics, 2019

CA Cancer J Clin

Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study

BMJ

Hysterectomy-corrected uterine corpus cancer incidence trends and differences in relative survival reveal racial disparities and rising rates of nonendometrioid cancers

J Clin Oncol

Type I and II endometrial cancers: have they different risk factors?

J Clin Oncol

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

Int J Gynecol Cancer

Version 2. 2020

Systematic Reviews
Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics