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Oncologic outcomes based on lymphovascular space invasion in node-negative FIGO 2009 stage I endometrioid endometrial adenocarcinoma: a multicenter retrospective cohort study
  1. Christian Dagher1,
  2. Pernille Bjerre Trent2,3,
  3. Rofieda Alwaqfi4,
  4. Ben Davidson3,5,
  5. Lora Ellenson4,
  6. Qin C Zhou6,
  7. Alexia Iasonos6,
  8. Jennifer J Mueller1,7,
  9. Kaled Alektiar8,
  10. Vicky Makker9,10,
  11. Sarah Kim1,7,
  12. Mario M Leitao Jr1,7,
  13. Nadeem R Abu-Rustum1,7 and
  14. Ane Gerda Z Eriksson2,3
    1. 1 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    2. 2 Department of Gynecologic Oncology, Division of Cancer Medicine, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway
    3. 3 Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    4. 4 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    5. 5 Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
    6. 6 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    7. 7 Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, New York, USA
    8. 8 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    9. 9 Gynecology Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    10. 10 Department of Medicine, Weill Cornell Medical College, New York, New York, USA
    1. Correspondence to Dr Nadeem R Abu-Rustum, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA; abu-rusn{at}mskcc.org

    Abstract

    Background The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system includes lymphovascular invasion quantification as a staging criterion for endometrioid endometrial carcinomas; no lymphovascular invasion and focal invasion (≤4 vessels involved) are grouped as one category, and substantial invasion as another.

    Objective To assess the association between lymphovascular invasion and oncologic outcomes.

    Methods We retrospectively identified patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with total hysterectomy and lymph node assessment at two tertiary care centers between January 1, 2012, and December 31, 2019. Lymphovascular space invasion was categorized as focal (<5 vessels involved), substantial (≥5 vessels involved), and no lymphovascular invasion using WHO criteria.

    Results Of 1555 patients included, 65 (4.2%) had substantial, 119 (7.7%) had focal, and 1371 (88.2%) had no lymphovascular invasion. Median age was 64 years (range 24–92). Thirty-five patients (53.8%) with substantial, 44 (37%) with focal, and 115 (8.4%) with no lymphovascular invasion had stage IB disease (p<0.001); 21 (32.3%) with substantial, 24 (20.2%) with focal, and 91 (6.6%) with no lymphovascular invasion had grade 3 disease (p<0.001). Thirty-six patients (55.4%) with substantial, 80 (67.2%) with focal, and 207 (15.1%) with no lymphovascular invasion received adjuvant treatment (p<0.001). Median follow-up was 61.5 months (range 0.8–133.9). Five-year progression-free survival rates were 68.7% (substantial), 70.5% (focal), and 90.7% (no invasion) (p<0.001). On multivariate analysis, any lymphovascular invasion was associated with increased risk of progression/death (adjusted HR (aHR)=1.84 (95% CI 1.73 to 1.96) for focal; 2.17 (95% CI 1.96 to 2.39) for substantial). Compared with focal, substantial lymphovascular invasion was associated with an aHR for disease progression of 1.18 (95% CI 1.00 to 1.39).

    Conclusions Focal and substantial lymphovascular invasion were associated with increased risk of disease progression and do not appear to be prognostically distinct. Focal versus no lymphovascular invasion have different prognostic outcomes and should not be combined into one category.

    • endometrium
    • retrospective study
    • lymphatic metastasis

    Data availability statement

    Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

    https://doi.org/10.1136/ijgc-2024-005746

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • Lymphovascular space invasion portends poor outcome in endometrioid endometrial cancer. The extent of lymphovascular space invasion was included as a determinant of stage in myoinvasive grades 1 and 2 endometrioid endometrial cancer in the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system; tumors with either no invasion or only focal lymphovascular space invasion are considered to have a similar prognosis, and those with substantial lymphovascular invasion are upstaged.

      WHAT THIS STUDY ADDS

      • In a comprehensively surgically staged group of patients with stage I endometrioid endometrial cancer, focal or substantial lymphovascular space invasion increased the risk of disease progression and death. Moreover, both substantial and focal lymphovascular invasions were associated with similar rates of progression-free survival, differing markedly from cases with no lymphovascular space invasion, even among patients with myoinvasive grade 1 or 2 endometrioid endometrial cancer.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • Our findings provide evidence in support of revising the 2023 FIGO classification and considering the removal of extent of lymphovascular invasion from the staging system.

      INTRODUCTION

      Lymphovascular space invasion is defined as the presence of tumor cells in blood or lymphatic vessels outside of the main tumor.1 Approximately 10–15% of patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I endometrioid endometrial cancer have lymphovascular invasion identified at the time of definitive pathology.2 Lymphovascular invasion is associated with high-risk features in endometrial cancer, such as deep myometrial invasion, and high-grade histologies.3 4 Studies of patients with unstaged endometrial cancer have noted a strong association between the presence of lymphovascular invasion and pelvic nodal recurrence.5 6

      Historically, lymphovascular invasion in endometrial cancer has been evaluated qualitatively, as either present (detected), suspicious, or absent (not detected). While semiquantitative approaches to classify lymphovascular invasion have existed for a while,7 8 recently they have garnered a lot of interest.5 6 9–11 The shift to semiquantitative approaches was prompted by findings from a pooled analysis of the PostOperative Radiation Therapy in Endometrial Carcinoma (PORTEC) 1 and 2 trials, which suggested a link between substantial lymphovascular invasion (defined as diffuse or multifocal invasion rather than a specific number of vessels involved) and a higher rate of pelvic nodal recurrences and poorer overall survival.5 Additional analysis of these data attempted to define a cut-off point for the number of vessels involved with the greatest association of pelvic nodal recurrence rate.5 Nodal evaluation was not required in the PORTEC studies, however, suggesting that the association with lymphovascular invasion might be based on unrecognized nodal involvement, and casting doubt on the utility of this quantification system given that bilateral pelvic sentinel node mapping is currently the standard of care in most guidelines.12–15 A recent study by Pifer et al of patients with pathology-confirmed negative lymph nodes found no significant correlation between the extent of lymphovascular invasion and oncologic outcomes, although the study used a different cut-off point to define extent of lymphovascular invasion.11

      FIGO integrated extent of lymphovascular invasion into its 2023 endometrial cancer staging system,16 adopting the WHO definition for substantial lymphovascular invasion of ≥5 vessels involved on at least one pathology slide.17 Given this integration and heterogeneity in the reported data, we examined oncologic outcomes associated with the extent of lymphovascular invasion as measured by WHO criteria, while accounting for nodal status by including only patients with FIGO 2009 stage I endometrioid endometrial cancer and confirmed negative lymph nodes.

      METHODS

      This study was approved by the institutional review boards of Memorial Sloan Kettering Cancer Center and Norwegian Radium Hospital/Oslo University Hospital. The study was conducted in accordance with the Declaration of Helsinki. Informed consent was waived in accordance with institutional guidelines.

      This international, retrospective, multi-institutional cohort study included patients who were diagnosed with FIGO 2009 stage IA or IB endometrioid endometrial cancer and underwent surgical staging, including bilateral pathological evaluation of pelvic lymph nodes, between January 1, 2012, and December 31, 2019. Patients with positive lymph nodes, incomplete nodal assessment (empty nodal packets), isolated tumor cells, positive peritoneal cytology, or synchronous ovarian tumors were excluded.

      Patients were grouped by extent of lymphovascular invasion (none, focal, or substantial). Lymphovascular invasion was defined as the presence of a tumor embolus in an endothelial-lined space within the myometrium beyond the invasive front of the tumor. Extent of lymphovascular invasion was defined using the WHO definition.17 Tumors are considered to have no lymphovascular invasion if no invasion is seen on any pathology slide, focal lymphovascular invasion if 1 to 4 vessels are involved on at least one pathology slide, and substantial lymphovascular invasion if ≥5 vessels are involved on at least one pathology slide.

      Central pathology re-review was conducted by expert gynecologic pathologists (LE, RA, BD). Tumors previously reported as having present or suspicious lymphovascular invasion were identified and re-reviewed for extent of invasion. To minimize the effect of suboptimal inter-observer concordance, pathologists convened regularly and agreed on definitions and workflows. At our centers, a tumor is considered to be suspicious for lymphovascular invasion when pathologists are unable to characterize a focus of invasion despite the use of immunohistochemical stains (RG, D2-40, and CD31) targeting endothelial cells.2 6 Cases suspected for lymphovascular invasion can be particularly challenging to diagnose in a binary grading system, as this can lead to significant disagreements among pathologists.6 18 By using this approach, cases considered negative for lymphovascular invasion are confidently determined to harbor no lymphovascular invasion and re-reviewing them would not be resource efficient. On the other hand, cases with suspicious lymphovascular invasion were re-reviewed to ensure that all were read by the same pathologist and that immunohistochemical staining was performed, consequently maximizing the chance of detecting a missed focus of invasion.

      Data on demographics, disease characteristics, treatment modalities, and outcomes were extracted from electronic health records and compiled in a centralized database. Surgical staging included hysterectomy, with or without oophorectomy, and nodal evaluation, with or without peritoneal cytology sampling. The method of nodal evaluation was at the physician’s discretion and adhered to local guidelines.19 The decision for post-surgical treatment was made on an individual basis, involved shared decision-making between the patient and treating physician, and varied by center according to local guidelines.

      Following initial treatment, patients were surveilled with follow-up examination every 3 to 6 months for the first 2 to 3 years, then every 6 months for the following 2 to 3 years. Imaging was at the physician’s discretion and was based on onset of new symptoms or concerns about recurrence. The primary outcome, progression-free survival, was calculated from date of surgery to date of recurrence, death, or last follow-up. The secondary outcome, overall survival, was calculated from date of surgery to date of death or last known alive date.

      Clinical, surgical, and pathological characteristics were collected. Comparisons between groups were performed using the Kruskal-Wallis test for continuous variables, and the Fisher exact test for categorical variables. Five-year progression-free survival and overall survival rates were calculated using the Kaplan-Meier method. A Cox proportional hazards model accounting for clustering effect (for centers) using Wei, Lin, Weissfeld’s method20 was fit for assessment of independent prognostic factors for survival. A multivariate model was built using variables that were statistically significant on univariate analysis. To account for the time-dependent nature of adjuvant treatment, a landmark analysis was conducted to evaluate the impact of adjuvant treatment on progression-free and overall survivals, using a landmark time of 3 months following surgery. A subgroup survival analysis was conducted for cases with myoinvasive grade 1 or 2 endometrioid endometrial cancer to evaluate the role of the extent of lymphovascular invasion. This analysis focused on the subgroup of patients for whom the FIGO 2023 classification considers the extent of lymphovascular invasion to be a determinant of stage (IA2, IB1, and IIB).16 All p values were calculated as two-sided, and values of p<0.05 were considered statistically significant. All analyses were performed using R 4.3.1 (https://www.R-project.org/).

      RESULTS

      A total of 1555 patients met the inclusion criteria; 1279 patients (82.3%) in the New York cohort and 276 (17.7%) in the Oslo cohort (Online Supplemental Figure 1). Details of patient distribution per center are listed in Online Supplemental Table 1. Of 1555 patients, 1371 (88.2%) had tumors with no lymphovascular invasion and 184 (11.8%) with suspected or confirmed lymphovascular invasion. Overall, 184 tumors underwent central pathology re-review for determination of the extent of lymphovascular invasion; 119 tumors (7.7%) had focal and 65 (4.2%) had substantial invasion (Online Supplemental Table 2).

      Supplemental material

      Clinicopathological and demographic characteristics are listed in Table 1. Median age at surgery was 60 years (range 27–92) for patients with no lymphovascular invasion compared with 67 years (range 35–87) for patients with focal and 64 years (range 24–90) for patients with substantial lymphovascular invasion (p<0.001). Among 1371 patients with no lymphovascular invasion, 119 patients with focal invasion, and 65 patients with substantial invasion, deep myometrial invasion was noted in 115 patients (8.4%), 44 patients (37.0%), and 35 patients (53.8%), respectively (p<0.001); grade 3 disease was observed in 91 patients (6.6%), 24 patients (20.2%), and 21 patients (32.3%), respectively (p<0.001); and laparotomy was performed in 163 patients (11.9%), 14 patients (11.8%), and 17 patients (26.2%), respectively (p=0.019).

      View this table:
      Table 1

      Demographic, clinical, histological, and surgical characteristics of patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with pathology-proven negative nodes, according to extent of lymphovascular invasion (n=1555)

      Overall, 323 (20.8%) of 1555 patients received adjuvant therapy: 282 patients received intravaginal brachytherapy and 41 received chemotherapy. Intravaginal brachytherapy was given to 184 (13.4%) of 1371 patients, 73 (61.3%) of 119 patients, and 25 (38.5%) of 65 patients with no, focal, and substantial lymphovascular invasion, respectively; chemotherapy was given to 23 patients (1.7%), 7 patients (5.9%), and 11 patients (16.9%), respectively (p<0.001).

      Median follow-up duration for survivors was 61.5 months (range 0.8–133.9), and 174 patients experienced disease recurrence or death. The 5-year progression-free survival rates were 90.7% (95% CI 88.6% to 92.3%) for patients with no lymphovascular invasion compared with 70.5% (95% CI 60.3% to 78.6%) for those with focal invasion and 68.7% (95% CI 55.2% to 78.8%) for those with substantial invasion (p<0.001) (Figure 1). On univariate analysis, patients with focal or substantial lymphovascular invasion had a hazard risk of 2.80 (95% CI 2.39 to 3.27) and 3.13 (95% CI 2.58 to 3.79), respectively, for disease recurrence or death compared with patients with no invasion. This remained significant on multivariate analysis (Table 2). Table 3 depicts the univariate and multivariate analyses using focal lymphovascular invasion as the reference. Patients with substantial lymphovascular invasion had an adjusted hazard risk of 1.18 (95% CI 1.00 to 1.39) for disease recurrence or death compared with those with focal invasion (p=0.049).

      Figure 1
      Figure 1

      Kaplan-Meier curves for progression-free survival of patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with pathology-proven negative nodes, according to extent of lymphovascular space invasion (n=1555). FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymphovascular space invasion.

      View this table:
      Table 2

      Univariate and multivariate analyses of progression-free survival for patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with pathology-proven negative nodes (n=1555)

      View this table:
      Table 3

      Univariate and multivariate analyses of progression-free survival and overall survival for patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with pathology-proven negative nodes using focal LVSI as reference category (n=1555)

      At the time of last data collection, 118 patients had died of any cause, including 33 cancer-related deaths, 42 deaths due to other cause, and 43 deaths of unknown cause. The 5-year overall survival rates were 95.4% (95% CI 94.0% to 96.5%) for patients with no lymphovascular invasion compared with 82.2% (95% CI 73.0% to 88.5%) for focal invasion and 76.5% (95% CI 63.5% to 85.5%) for substantial invasion (p<0.001) (Online Supplemental Figure 2). On univariate analysis, patients with focal or substantial lymphovascular invasion had a hazard risk of 2.79 (95% CI 1.89 to 4.12) and 3.8 (95% CI 3.26 to 4.43), respectively, for death from any cause compared with patients with no invasion. This remained significant on multivariate analysis (Online Supplemental Table 3). On multivariate analysis, using focal as the reference, substantial lymphovascular invasion had an adjusted hazard risk of 1.32 (95% CI 1.04 to 1.68) for death from any cause (Table 3).

      On landmark analysis, receipt of any adjuvant treatment was not associated with improved progression-free survival (HR=1.4, 95% CI 0.5 to 3.6) or overall survival (HR=1.6, 95% CI 0.6 to 4.3) and was not included in the multivariate analysis. The extent of lymphovascular invasion, age at surgery, surgical approach, depth of myoinvasion, and histological grade were significant predictors for both progression-free and overall survivals and were included in the multivariate analysis. The extent of lymphovascular invasion remained independently associated with both progression-free and overall survivals on multivariate Cox regression analysis (Table 2, Online Supplemental Table 3).

      A separate analysis was performed of patients with myoinvasive grade 1 or 2 endometrioid endometrial cancer (Figure 2). The 5-year progression-free survival rate for patients with no lymphovascular invasion was 87.3% (95% CI 83.4% to 90.4%) compared with 65.2% (95% CI 53.0% to 75.0%) for focal and 68.0% (95% CI 50.2% to 80.6%) for substantial lymphovascular invasion (p<0.001). On univariate analysis, the HR for focal and substantial lymphovascular invasion were 2.44 (95% CI 1.94 to 3.08) and 2.24 (95% CI 1.68 to 2.99), respectively, compared with no invasion. Using focal lymphovascular invasion as the reference, the HR for substantial invasion was 0.92 (95% CI 0.87 to 0.97).

      Figure 2
      Figure 2

      Kaplan-Meier curves for progression-free survival of patients with FIGO 2009 stage I, grade 1 or 2 endometrioid endometrial cancer, excluding patients with no myometrial invasion who were treated surgically with pathology-proven negative nodes, according to extent of lymphovascular space invasion (n=606). FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymphovascular space invasion.

      The 5-year overall survival rate for patients with no lymphovascular invasion was 93.3% (95% CI 90.3% to 95.4%) compared with 79.6% (95% CI 68.6% to 87.1%) for focal and 79.4% (95% CI 62.8% to 89.2%) for substantial lymphovascular invasion (p<0.001) (Online Supplemental Figure 3). On univariate analysis, the HR for focal and substantial lymphovascular invasion were 2.05 (95% CI 1.90 to 2.22) and 2.19 (95% CI 1.60 to 3.00), respectively, compared with no invasion. Using focal lymphovascular invasion as the reference, the HR for substantial invasion was 1.07 (95% CI 0.72 to 1.58).

      DISCUSSION

      Summary of Main Results

      In this retrospective cohort study of patients with stage I surgically staged endometrioid endometrial cancer, we identified associations with oncologic outcomes for both focal and substantial lymphovascular invasion as defined by WHO criteria. Even after limiting the analysis to patients with myoinvasive grade 1 or 2 endometrioid endometrial cancer, our findings demonstrated that the prognosis associated with focal lymphovascular invasion was distinct from that of no lymphovascular invasion, reinforcing that these should not be considered equivalent prognostically. Furthermore, we found no clinically significant differences in progression-free survival between focal and substantial lymphovascular invasion, indicating that these two categories share similar prognostic outcomes.

      Results in the Context of Published Literature

      The Lymphovascular Space Invasion in Early-Stage Endometrial Cancer (LySEC) study is one of the largest cohort studies to examine lymphovascular invasion in early-stage endometrioid endometrial cancer. The LySEC study reported a prevalence of 13.4% (443 of 3308 patients) for the presence of any lymphovascular invasion in patients with FIGO 2009 stage I endometrioid endometrial cancer, which is similar to the overall rate we report in the current study.18 In the LySEC study, the presence of any lymphovascular invasion was associated with a poorer 5-year disease-free survival rate compared with patients whose tumors did not show any lymphovascular invasion (92% vs 79%, p<0.001), underscoring its role as a strong prognostic factor in endometrioid endometrial cancer.

      There has been an increasing interest in quantifying the extent of lymphovascular invasion and identifying associations between the extent of invasion and oncologic outcomes.5 6 9 10 Some studies have reported that the presence of substantial lymphovascular invasion was associated with a higher risk of pelvic nodal recurrence at 5 years compared with focal or no lymphovascular invasion (15.3% vs 2.5% and 1.7%, respectively).5 6 Nodal involvement was not evaluated at the time of surgical staging in the PORTEC 1 and 2 studies, raising questions about unrecognized nodal involvement at the time of surgical staging. Recently, Pifer et al evaluated the role of the extent of lymphovascular invasion in 335 patients with stage I endometrioid endometrial cancer and bilateral pathology-proven negative nodes and concluded that there was no association with 2-year overall survival rates (97.6%, 98.1%, and 98.2% for no invasion, focal invasion, and substantial lymphovascular invasion, respectively; p=0.879).11 While Pifer et al used the cut-off point previously established by Peters et al (≥4 vessels involved to define substantial lymphovascular invasion), the 2023 FIGO staging guidelines employ the WHO cut-off point of ≥5, making extrapolations from existing research difficult. Furthermore, and based on the work of Peters et al, it appears that there are no marked differences in outcomes between the different cut-off values ranging from 2 and higher.6

      Lymphovascular invasion undoubtedly provides important prognostic information and has been used to guide treatment decisions15 21; however, variable detection rate and the potential for misinterpretation contradict its formal integration into staging criteria. A study examining the reproducibility of assessing the presence/absence of lymphovascular invasion by six expert gynecological pathologists noted full or partial agreement in 33 (69%) of 48 patients and no agreement in 15 (31%) of 48 patients, resulting in an intra-class correlation coefficient of 0.6, corresponding to a moderate reliability according to established scoring guidelines.22 When the same authors examined the reproducibility of the lymphovascular invasion grading (extent) system, the intra-class correlation coefficient was 0.54 (0.62 in cases with known lymphovascular invasion),1 which further raises concerns over its inclusion in the staging system.

      Strengths and Weaknesses

      Strengths of our study include a large patient sample size using well-annotated databases, its collaborative nature involving multiple institutions, and the extended follow-up period. The retrospective study design and variations in baseline patient characteristics across the two centers, however, introduces potential ascertainment bias. The differences in baseline characteristics, while statistically challenging, mirror real-world scenarios, highlighting the divergent nature of referral systems between Norway and the United States. Patients in the Norwegian cohort were older, and a higher proportion underwent laparotomy and had higher grade and more deeply invasive tumors. The presence of high-risk factors among patients who underwent laparotomy could explain the increased risk associated with use of laparotomy observed in our multivariate analyses. The heightened risk is more likely to be related to the frequent use of laparotomy among high-risk patients rather than a deficiency in the technique. To account for the between-center differences, we employed statistical modeling in our survival analyses, which can yield reliable survival estimates with reduced variance; however, it also carries the risk of producing false positive results, evidenced by significant p values that correspond with only minimal differences in survival estimates.19 20 In our study, this could explain the observed significant p values in the comparison of focal versus substantial lymphovascular invasion, despite the marginal differences in survival outcomes.

      The absence of molecular data is another limitation of our study. However, given that the 2023 FIGO classification accounts for scenarios in which molecular information is unavailable, we believe this study is vital for depicting real-world experiences. This approach helps to reduce the potential for selection bias that could arise if the study included only patients whose tumors were subject to molecular testing.

      Implications for Practice and Future Research

      Our findings do not support inclusion of the extent of lymphovascular invasion as a determinant of stage in endometrial cancer as proposed by the 2023 FIGO staging system. Future research could include molecular information and explore the association between the extent of lymphovascular invasion and the pattern of disease recurrence.

      CONCLUSIONS

      Our results do not support that substantial and focal lymphovascular invasion are prognostically distinct even in myoinvasive grades 1 and 2 endometrioid endometrial cancer. More importantly, focal lymphovascular invasion (with ≤4 vessels involved in at least one pathology slide) and no lymphovascular invasion do not share the same prognostic outcome.

      Data availability statement

      Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants and was approved by the institutional review boards of Memorial Sloan Kettering Cancer Center and Norwegian Radium Hospital/Oslo University Hospital. Informed consent was waived in accordance with institutional guidelines.

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      Footnotes

      • X @ChrisDagherMD, @BjerreTrent, @leitaoMD, @AbuRustumMD, @agz_eriksson

      • Presented at This work was presented as an oral plenary session at the 2024 European Society of Gynaecologic Oncology Annual Meeting.

      • Contributors CD: conceptualization, methodology, data curation, visualization, writing - original draft. PKBT: data curation, writing - review and editing. RA, BD, LE: pathology review, writing - review and editing. QCZ, AI: formal analysis, visualization, writing - review and editing. JM, KA, VM: writing - review and editing. SK: resources. ML: supervision, conceptualization, writing - review and editing. NRA-R: supervision, conceptualization, methodology, writing – original draft, guarantor. AGE: supervision, conceptualization, writing - review and editing.

      • Funding This research was funded in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. CD was supported in part by the Bobst International Fellowship for Citizens of Lebanon.

      • Competing interests AGE reports speakers fee from Intuitive Surgical and GSK. BD is a speaker and consultant for MSD. NRA-R reports research funding from GRAIL paid to the institution. ML reports personal fees from Medtronic, Intuitive Surgical, J&J/Ethicon, and Immunogen. VM is supported (all funding to institution)/unpaid consultancy/advisory board membership from AstraZeneca, Clovis, Duality, Eisai, Faeth, Genentech, GSK, Immunocore, iTEOS, Kartos, Karyopharm, Moreo, Morphosys, MSD, Novartis, Takeda, and Zymeworks. The other authors have nothing to disclose.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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