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Background: To date, 11 DNA polymerase epsilon (POLE) pathogenic variants have been declared "hotspot" mutations. Patients with endometrial cancer (EC) characterized by POLE hotspot mutations (POLEmut) have exceptional survival outcomes. Whereas international guidelines encourage deescalation of adjuvant treatment in early-stage POLEmut EC, data regarding safety in POLEmut patients with unfavorable characteristics are still under investigation. On the other hand, the spread of comprehensive genome profiling programs has underscored the need to interpret POLE variants not considered to be hotspots., Methods: This study provides a comprehensive analysis of 596 sequenced patients with EC. The genomic landscape of POLEmut EC was compared with cases harboring nonhotspot POLE mutations within the exonuclease domain. Additionally, the genomic characteristics of multiple classifiers, as well as those exhibiting unfavorable histopathological and clinical features, were examined., Results: No significant genomic differences were observed among patients with POLEmut EC when comparing multiple classifiers to not-multiple classifiers or those with unfavorable clinical features. However, the tumor mutational burden differed in both comparisons, whereas the percentage of C>G mutations only differed in the comparison based on clinical features. Specific POLE mutations, even if not considered to be hotspots, have genomic features comparable to POLEmut., Conclusions: The present findings confirm the absence of significant genomic differences among POLEmut patients regardless of multiple-classifier status or association with high-risk clinical features. Prognostic data will be essential to elucidate the clinical significance of POLE mutations not classified as hotspots that exhibit genomic characteristics similar to those in POLEmut patients., (© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: This retrospective, multicenter, observational study aimed to refine patient selection criteria for secondary cytoreductive surgery in recurrent endometrial cancer. The objective was to identify preoperative predictors of complete cytoreduction, assess surgical complexity, and propose a preoperative predictive scoring system to identify suitable candidates for secondary cytoreductive surgery., Methods: Data from 331 women with recurrent endometrial cancer were analyzed across three Italian centers from January 2010 to December 2021. Patients were categorized based on treatment received (medical treatment, diagnostic laparoscopy/examination under anesthesia, or secondary cytoreductive surgery). Preoperative predictors, surgical complexity, complications, and a predictive scoring system were assessed. Logistic regression and receiver operating characteristic analysis were used for statistical evaluation., Results: Of the cohort, 56.2% underwent debulking surgery, 17.2% had diagnostic laparoscopy, and 26.6% received medical treatment. Patients undergoing secondary cytoreductive surgery were younger, with a lower body mass index, better performance status, and fewer comorbidities. Single site locoregional relapse was common in secondary cytoreductive surgery patients. Age <65 years, single site relapse, lymph node, and hematogenous relapse were independent predictors of complete cytoreduction. A predictive scoring system demonstrated a clear relationship between the score and the likelihood of complete cytoreduction., Conclusion: This study identified age <65 years, single site recurrence, as well as nodal and hematogenous recurrence, as predictive factors for achieving optimal cytoreduction. A predictive scoring system incorporating these factors has been proposed to identify optimal candidates for secondary cytoreductive surgery in recurrent endometrial cancer. The scoring system showed promising predictive accuracy and could aid in refining the decision making process, ensuring appropriate patient selection for secondary cytoreductive surgery. Further prospective studies are warranted to validate and enhance the predictive model., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Genomic profiling-based model (GP-M) is the gold-standard for endometrial cancer (EC) molecular classification, but several issues related to the availability of genomic sequencing in low-income settings remain and health disparities in the management are increasing. This study aims to investigate the non-inferiority of the immunohistochemistry-alone model in classifying ECs compared to the standard genomic profiling-based model in terms of oncologic outcomes., Methods: All preoperative uterine-confined ECs undergoing surgical staging were retrospectively included. Patients classified by IHC-M were stratified into: MMR-proficient (MMRp), p53 wild type (p53wt) and estrogen receptor (ER) positive, 2) MMRp, p53wt and ER-negative, 3) MMRd, and 4) p53abn. A case-control comparison was performed between the IHC-M and GP-M cohorts. Then, a propensity-matched analysis was performed: ECs classified by IHC-M were matched in a 3:1 ratio with patients classified by GP-M., Results: 1587 patients with EC were included. The Kaplan-Meier survival curves for disease-free survival and overall survival demonstrated that the two models performed similarly in risk-stratifying the study population (p < 0.0001). Moreover, the AUC-ROC showed overlapping results: 0.77 (0.66-0.87) for IHC-M and 0.72 (0.63-0.81) for GP-M, indicating that both models were able to successfully identify patients at high-risk and low-risk of disease recurrence/progression., Conclusion: The IHC-M showed overlapping classification performance compared to the GP-M in terms of oncologic outcomes. This study may lay the basis to further investigate the real-life clinical impact of POLE sequencing in molecular classification and the potential stand-alone prognostic role of ER status for further allocation of EC patients into risk classes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: To evaluate the prognostic impact of substantial lymph vascular space invasion (LVSI) on the sentinel lymph node involvement and recurrence rate of patients with apparent uterine-confined endometrial cancer., Materials and Methods: We enrolled consecutive patients with apparent confined endometrial cancer who underwent surgical staging with sentinel node mapping from 14 European reference centers. LVSI was analyzed semi-quantitatively, according to a 3-tiered scoring system classified as absent, focal, and substantial., Results: Among 2352 eligible patients, 1980 were included in the analysis. Upon final pathology 226 patients (11.4 %) had SLNs involvement. LVSI was diagnosed focal in 152 patients (7.7 %), whereas 357 patients (18.0 %) showed substantial LVSI. Focal or substantial LVSI rate were significantly higher in patients with positive SLNs when compared to patients without SLNs involvement (p < 0.0001). On overall patient-based analysis, the sensitivity, specificity, positive predictive value, and negative predictive value of LVSI for sentinel lymph node metastases were 73 %, 80 %, 32 %, and 96 %, respectively. The 3-year multivariate analysis of recurrence-free survival showed that only the presence of substantial LVSI, and grade 3 disease were associated with relapse. Neither positive sentinel lymph node, deep myometrial infiltration, nor age at surgery were statistically significant., Conclusions: In patients having undergone sentinel node biopsy, positive LVSI demonstrated moderate sensitivity and reasonable specificity in detecting SLN involvement. LVSI positivity does not correlate with nodal involvement. The presence of substantial LVSI remains a strong independent risk factor for recurrence, indicating a role for potential hematogenous dissemination in patients with early-stage disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Uteri from women undergoing chemoradiotherapy (CRT) may show reactive atypia which may mimic serous endometrial intraepithelial carcinoma (SEIC). We aimed to assess the prevalence and morphological/immunohistochemical features of post-radiotherapy serous-like endometrial changes (PoRSEC) in women undergone CRT for locally advanced cervical cancer, with a focus on the differential diagnosis with SEIC. Consecutive patients with locally advanced cervical cancer undergone CRT between 2011 and 2018 were reviewed. Endometrial histological specimens were assessed for the presence of PoRSEC. Twenty-two cases of SEIC were included for comparison. Immunohistochemistry for p53, p16, and Ki67 was performed. Out of 244 reviewed patients, 36 (14.7%) showed PoRSEC. The degree of nuclear atypia was similar between PoRSECs and SEIC. However, a papillary architecture with areas of confluent papillae was only observed in SEIC. SEIC cases showed a high mitotic activity as opposed to PoRSEC cases. The expression of p53 was aberrant in all SEICs but in none of the PoRSECs; however, 13/36 PoRSECs showed p53 positivity in most tumor cells, potentially mimicking a mutation pattern. A block-type p16 expression was observed in all SEICs and in 16/36 PoRSECs. Mean Ki67 expression was 26.9% in SEIC (range 5-70%) and 8.16% in PoRSEC (range 5-35%). While SEIC showed sharp morphological and immunohistochemical demarcation, PoRSEC were more heterogenous and merged imperceptibly with normal endometrium. In conclusion, PoRSEC may mimic SEIC both morphologically and immunohistochemically. However, a papillary architecture with cytological demarcation is typically observed in SEIC but not in PoRSEC., Competing Interests: Declarations. Consent to participate: A written consent was obtained from the patient. Data were anonymized. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Transvaginal ultrasound is typically the initial diagnostic approach in patients with postmenopausal bleeding for detecting endometrial atypical hyperplasia/cancer. Although transvaginal ultrasound demonstrates notable sensitivity, its specificity remains limited. The objective of this study was to enhance the diagnostic accuracy of transvaginal ultrasound through the integration of artificial intelligence. By using transvaginal ultrasound images, we aimed to develop an artificial intelligence based automated segmentation model and an artificial intelligence based classifier model., Methods: Patients with postmenopausal bleeding undergoing transvaginal ultrasound and endometrial sampling at Mayo Clinic between 2016 and 2021 were retrospectively included. Manual segmentation of images was performed by four physicians (readers). Patients were classified into cohort A (atypical hyperplasia/cancer) and cohort B (benign) based on the pathologic report of endometrial sampling. A fully automated segmentation model was developed, and the performance of the model in correctly identifying the endometrium was compared with physician made segmentation using similarity metrics. To develop the classifier model, radiomic features were calculated from the manually segmented regions-of-interest. These features were used to train a wide range of machine learning based classifiers. The top performing machine learning classifier was evaluated using a threefold approach, and diagnostic accuracy was assessed through the F1 score and area under the receiver operating characteristic curve (AUC-ROC)., Results: 302 patients were included. Automated segmentation-reader agreement was 0.79±0.21 using the Dice coefficient. For the classification task, 92 radiomic features related to pixel texture/shape/intensity were found to be significantly different between cohort A and B. The threefold evaluation of the top performing classifier model showed an AUC-ROC of 0.90 (range 0.88-0.92) on the validation set and 0.88 (range 0.86-0.91) on the hold-out test set. Sensitivity and specificity were 0.87 (range 0.77-0.94) and 0.86 (range 0.81-0.94), respectively., Conclusions: We trained an artificial intelligence based algorithm to differentiate endometrial atypical hyperplasia/cancer from benign conditions on transvaginal ultrasound images in a population of patients with postmenopausal bleeding., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

P53-abnormal endometrial carcinomas are high-grade and aggressive tumors which should be treated with chemo-/radiotherapy. In low-grade endometrioid carcinoma (LGEC), abnormal expression of p53 is an exceptional finding and is typically accompanied by patchy p16 positivity and diffuse hormone receptor expression., Herein, we report a case of LGEC exhibiting both p53 and p16 overexpression, highlighting the diagnostic pitfalls related to such phenotype., A 60-year-old woman underwent hysterectomy and bilateral salpingo-oophorectomy with pelvic lymphadenectomy due to a deeply myoinvasive endometrial mass. The tumor showed glandular architecture, low-grade nuclei and glandular differentiation. Focal lymphovascular space invasion and no lymph node metastases were observed. Immunohistochemically, the tumor showed p53 overexpression, p16 block-type positivity, diffuse hormone receptors positivity and retained mismatch repair proteins expression. No POLE mutations were identified. A diagnosis of p53-abnormal LGEC was eventually made., A glandular neoplasm with p53 and/or p16-overexpression on endometrial biopsy specimens may raise the concern of other entities such as serous carcinoma, HPV-related endocervical adenocarcinoma, and gastric-type adenocarcinoma. An immunohistochemical panel including hormone receptors, p53, p16 and mismatch repair proteins appears necessary for an accurate diagnosis of uterine adenocarcinomas., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Objective: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification., Methods: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens., Results: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001)., Conclusions: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the risk of endometrial carcinoma following a diagnosis of atypical hyperplasia/endometrioid intraepithelial neoplasia by endometrial biopsy, stratified based on integrated histological parameters., Methods: All women with atypical hyperplasia/endometrioid intraepithelial neoplasia undergoing hysterectomy within 1 year of diagnosis without progestin treatment were included. Patients were subdivided into three study groups, based on two criteria: (a) grade of nuclear atypia and (b) foci (<2 mm) of confluent glands with no intervening stroma: low-grade, high-grade, and confluent glands. The rate of endometrial carcinoma on the subsequent hysterectomy was assessed in each study group, and differences between study groups were assessed using Fisher's exact test, with a significant p value <0.05. Reproducibility was assessed by using Cohen's κ., Results: Ninety-six patients were included. Overall, 36 of 96 patients (37.5%) had endometrial carcinoma on the subsequent hysterectomy. The number of endometrial carcinomas was 4 of 42 (9.5%) in the low-grade group, 14 of 28 (50.0%) in the high-grade group, and 18 of 26 (69.2%) in the confluent glands group. The rate of endometrial carcinoma was significantly higher in the high-grade group than in the low-grade group (p<0.001), whereas it did not significantly differ between the high-grade group and the confluent glands group (p=0.176). The reproducibility among pathologists was moderate for low-grade versus high-grade (κ=0.58) and substantial for confluent glands versus low-grade (κ=0.63) and high-grade (κ=0.63)., Conclusion: Atypical hyperplasia/endometrioid intraepithelial neoplasia can be stratified into prognostically relevant groups based on integrated histological parameters, with a possible major impact on patient management., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs)., Methods: Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models., Results: A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy., Conclusion: Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the molecular characteristics of the tumor. This study aims to assess the feasibility of obtaining reliable molecular classification status from biopsy specimens collected during hysteroscopy to better modulate the appropriate surgical treatment., Methods: This monocentric, retrospective, observational study was conducted on 106 patients who underwent a biopsy procedure followed by radical surgery for endometrial cancer, with concurrent molecular investigation. The molecular classification was determined through immunohistochemical staining for p53 and mismatch repair proteins, along with gene sequencing for POLE., Results: Overall, 106 patients underwent molecular investigation, which was finally achieved on 99 patients (93.4%). Among these, the molecular analysis was conducted in 71 patients (67%) on the pre-operative endometrial biopsy and on the final uterine specimen in 28 patients (26.4%). Most of the endometrial biopsies were performed using Bettocchi hysteroscopy (66%). Molecular analysis was not possible in seven patients (6.6%), with six cases due to sample inadequacy and one case attributed to intra-mucosal carcinoma. The molecular results showed that the copy number low sub-group was the most common, and five cases of 'multiple classifiers' were observed in the low-risk category., Conclusion: Our experience in obtaining molecular information from biopsy samples underscores the feasibility and efficacy of this technique, even in small tissue samples. This capability helps define the prognostic group of patients, facilitates timely decision-making, and develops a personalized strategy for each patient., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Editor's Note. - RadioGraphics Update articles supplement or update information found in full-length articles previously published in RadioGraphics . These updates, written by at least one author of the previous article, provide a brief synopsis that emphasizes important new information such as technological advances, revised imaging protocols, new clinical guidelines involving imaging, or updated classification schemes.

Objective: Retifanlimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1 being investigated in several solid tumor types. We report final results from patients with recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer treated with retifanlimab in a POD1UM-101 expansion cohort., Methods: Eligible patients (≥18 years; histologically proven/unresectable/recurrent, MSI-H/dMMR endometrial cancer; checkpoint inhibitor naive) received retifanlimab 500 mg intravenously every 4 weeks for ≤2 years. Primary endpoint was safety/tolerability., Results: At data cutoff (May 17, 2023), 76 patients had received at least one retifanlimab dose. Median (range) age was 67 (49-88) years; 88.2% of patients had recurrent metastatic disease and 80.3% had visceral metastases. Seventy-five patients (98.7%) had received at least one prior systemic therapy. Median retifanlimab exposure was 10.0 (0.03-25.9) months; 23 patients completed treatment. 38 patients (50.0%) had grade ≥3 treatment-emergent adverse events (TEAEs), most commonly anemia (n = 10 [13.2%]). 63 patients (82.9%) had treatment-related AEs (TRAEs; grade ≥3, n = 14 [18.4%]); most common was fatigue (n = 14 [18.4%]). Two patients had TEAEs that led to death; no TRAEs were fatal. 39 patients had objective responses (51.3%; 95% CI, 39.6-63.0%); 19 patients (25.0%) had complete response and 20 (26.3%) had partial response. Median progression-free survival was 12.2 months; 30 patients (76.9%) had duration of response (DOR) ≥12 months. Median DOR was not reached after median follow-up time of 26.0 months., Conclusions: Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer., Competing Interests: Declaration of competing interest Patricia Pautier received travel funding from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, and Tesaro; had an advisory role with AstraZeneca, Genmab, MSD, Onxeo, PharmaMar, and Roche; and received honoraria from AstraZeneca, Eisai, MSD, and PharmaMar. Domenica Lorusso had consultancy roles with Novartis and PharmaMar; had advisory and invited speaker roles with AstraZeneca, Clovis Oncology, Genmab, GlaxoSmithKline, ImmunoGen, MSD, and Seagen; received institutional support from Clovis Oncology, Corcept, Genmab, ImmunoGen, and MSD; and received grants for academic trials from Clovis Oncology, GlaxoSmithKline, and MSD. Christine Gennigens received a grant from AstraZeneca, GlaxoSmithKline; received consulting fees from Ispen, GlaxoSmithKline, and MSD; received honoraria for lectures from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, MSD, Pfizer, and PharmaMar; received support for meetings and/or travel from GlaxoSmithKline, Ipsen, MSD, Pfizer, and PharmaMar; and participated in a data safety monitoring board/advisory board for AstraZeneca, Bristol Myers Squibb, Eisai, GlaxoSmithKline, Ipsen, and MSD. Laurence Gladieff participated in an advisory board for AstraZeneca, Clovis Oncology, GlaxoSmithKline, and MSD; received honoraria from AstraZeneca, GlaxoSmithKline, MSD, PharmaMar, and Roche; and received congress funding from GlaxoSmithKline, PharmaMar, Roche, and Viatris. Jill Bowman, Chuan Tian, and Mark Cornfeld have employment and stock ownership at Incyte Corporation. Toon Van Gorp received consulting fees from AstraZeneca, BionTech, Eisai, GlaxoSmithKline, ImmunoGen, Incyte, Karyopharm, MSD, OncXerna, Seagen, Tubulis, and Zentalis; had corporate-sponsored research from Amgen, AstraZeneca, and Roche; and received honoraria for lectures from GlaxoSmithKline, ImmunoGen, and MSD. All payments were via the institution. Dominique Berton and Anna Kryzhanivska have no conflict of interest related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the prevalence of concurrent endometrial cancer in patients pre-operatively diagnosed with atypical endometrial hyperplasia undergoing hysterectomy. Additionally, we assessed the occurrence of high to intermediate-risk and high-risk tumors according to the ESGO-ESTRO-ESP classification. The study also compared surgical outcomes and complications between patients undergoing simple hysterectomy and those undergoing hysterectomy with sentinel lymph node biopsy., Methods: In this multicenter retrospective study, patients with a pre-operative diagnosis of atypical endometrial hyperplasia were identified and divided into two groups: Group 1, which included patients treated with total hysterectomy with or without bilateral salpingo-oophorectomy, and Group 2, where sentinel lymph node biopsy was incorporated into the standard surgical treatment., Results: Among 460 patients with atypical endometrial hyperplasia, 192 received standard surgical management (Group 1) and 268 underwent sentinel lymph node biopsy (Group 2). A total of 47.2% (95% CI 42.6% to 51.7%) of patients were upgraded to endometrial cancer on final histopathological examination. High to intermediate-risk and high-risk tumors constituted 12.3% and 9.2% in Group 2 and 7.4% and 3.7% in Group 1. Lymph node metastases were identified in 7.6% of patients with concurrent endometrial cancer who underwent nodal assessment with at least unilateral mapping. Of the 12 sentinel lymph node metastases, 75.0% were micrometastases, 16.7% macrometastases, and 8.3% isolated tumor cells. No significant differences were found in estimated blood loss, operative time, and intra-operative and post-operative complications between the two groups. The rate of patients undergoing sentinel lymph node biopsy doubled every 2 years (OR 2.010, p<0.001), reaching 79.1% in the last 2 years., Conclusion: This study found a prevalence of concurrent endometrial cancer of 47.2%, and sentinel lymph node biopsy provided prognostic and therapeutic information in 60.8% of cases. It also allowed for the adjustment of adjuvant therapy in 12.3% of high to intermediate-risk patients without increasing operative time or complication rates., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

A corded and hyalinized pattern has been described in endometrial endometrioid carcinoma. Herein, we describe a clinicopathological and molecular analysis of the first reported case of endometrial serous carcinoma with a corded and hyalinized pattern., A 64-year-old woman underwent hysterectomy and bilateral salpingo-oophorectomy due to a 5.5 cm endometrial lesion. Histologically, the tumor was composed of a minor (20%) serous carcinoma component and a predominant corded component embedded in a hyaline-to-myxoid matrix. This component showed diffuse and strong p53 and p16 expression, heterogeneous positivity for epithelial markers and WT1, focal positivity for estrogen and progesterone receptors, retained MMR, SMARCA4/BRG1, and SMARCB1/INI1 expression, and negativity for smooth muscle, germ cell, sex cord, neuroendocrine, endothelial, and melanocytic markers and GATA3. Next-generation sequencing showed a mutation of uncertain significance in APC and no mutations in MLH1, MSH2, MSH6, PMS2, MUTYH, POLE, POLD1, EPCAM, or CTNNB1. The patient had a recurrence on the vaginal stump after 15 months., In conclusion, endometrial serous carcinoma can show a corded and hyalinized pattern, which may represent a diagnostic challenge., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Purpose: The primary aim was to analyze the current practices on the use of operative hysteroscopy for preserving fertility in patients diagnosed with endometrial cancer and premalignancies. Our secondary objectives included investigating medical therapy and analyzing reported pregnancy-related outcomes subsequent to fertility preservation procedures., Methods: We performed a semi-systematic literature review on PubMed, employing pertinent terms related to hysteroscopy, fertility preservation, and endometrial cancer and premalignancies. Patients undergoing operative hysteroscopy with or without following medical treatment were included. We adhered to the PRISMA 2020 statement and utilized Covidence software to manage our systematic review. We performed a pooled analysis on various outcomes., Results: Our final analysis included 15 studies evaluating 458 patients, where 238 (52.0%) were diagnosed with endometrial cancer, and 220 (48.0%) had endometrial premalignancies. With 146 pregnancies in our study, the overall pregnancy rate was 31.9%. Among these, 97 resulted in live births, accounting for 66.4% of the reported pregnancies. In terms of medical treatment, various forms of progestins were reported. Complications or adverse effects related to operative hysteroscopy were not reported in more than half of the studies. Among those studies that did report them, no complications nor adverse effects were documented. After hysteroscopic resection, complete response to medical treatment has been reported in 65.5% of the overall cases., Conclusion: Our review sheds light on the contemporary landscape of operative hysteroscopy for fertility preservation in endometrial cancer and premalignancies. Future studies should include the integration of molecular classification into fertility-preserving management of endometrial malignancies to offer a more personalized and precise strategy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Nearly 65% of patients with endometrial cancer who undergo primary hysterectomy have concurrent obesity. Retrospective data show advantages in using robotic surgery in these patients compared with conventional laparoscopy, namely lower conversion rate, increased rate of same-day discharge, and reduced blood loss. Nevertheless, to date no prospective randomized controlled trials have compared laparoscopic surgery versus robotic-assisted surgery in morbidly obese patients., Primary Objective: The robotic-assisted versus conventional laparoscopic surgery in the management of obese patients with early endometrial cancer in the sentinel lymph node era: a randomized controlled study (RObese) trial aims to find the most appropriate minimally invasive surgical approach in morbidly obese patients with endometrial carcinoma., Study Hypothesis: Robotic surgery will reduce conversions to laparotomy in endometrial cancer patients with obesity compared with those who undergo surgery with conventional laparoscopy., Trial Design: This phase III multi-institutional study will randomize consecutive obese women with apparent early-stage endometrial cancer to either laparoscopic or robot-assisted surgery., Major Inclusion/exclusion Riteria: The RObese trial will include obese (BMI≥30 kg/m 2 ) patients aged over 18 years with apparent 2009 Federation of Gynecology and Obstetrics (FIGO) stage IA-IB endometriod endometrial cancer., Primary Endpoint: Conversion rate to laparotomy between laparoscopic surgery versus robot-assisted surgery., Sample Size: RObese is a superiority trial. The clinical superiority margin for this study is defined as a difference in conversion rate of -6%. Assuming a significance level of 0.05 and a power of 80%, the study plans to randomize 566 patients., Estimated Dates for Completing Accrual and Presenting Results: Patient recruitment will be completed by 2026, and follow-up will be completed by 2029 with presentation of data shortly thereafter. Two interim analyses are planned: one after the first 188 and the second after 376 randomized patients., Trial Registration: NCT05974995., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted., Methods: We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3)., Results: Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%., Conclusions: Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Lymph nodal involvement is a prognostic factor in endometrial cancer. The added value of para-aortic lymphadenectomy compared with pelvic nodal evaluation alone remains a matter of debate in the management of patients with intermediate- and high-risk endometrial cancer. A systematic review and meta-analysis was conducted to assess the prognostic value of para-aortic lymphadenectomy in terms of overall survival and disease-free survival in patients with intermediate- and high-risk endometrial cancer., Methods: The study adhered to the PRISMA guidelines. PubMed, Google Scholar and ClinicalTrials.gov were searched from January 2000 to April 2023. Studies on intermediate- and high-risk patients who underwent pelvic versus pelvic and para-aortic dissection were included in the analysis. The Methodological Index for Nonrandomized Studies (MINORS) and the Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2) were used for quality assessment of the selected articles., Results: Fourteen studies were identified, encompassing 9415 patients with a median age of 62 years (IQR 56.5-66.5). The majority had International Federation of Gynecology and Obstetrics stage I-II disease (76%) and endometrioid histology (89%). The 72% of patients who underwent only pelvic nodal evaluation and the 87% who underwent pelvic and para-aortic lymphadenectomy received adjuvant treatment (p=0.44). Pelvic and para-aortic lymphadenectomy was associated with a significant improvement in 5-year overall survival (RR=0.71, 95% CI 0.57 to 0.88, p<0.01), translating to a 41% reduction in the risk of overall death. However, no significant differences were observed in the 5-year risk of recurrence (RR=1.12, 95% CI 0.94 to 1.34, p=0.15). Additionally, patients undergoing pelvic and para-aortic lymphadenectomy experienced a 26% increased risk of post-operative complications (RR=1.26, 95% CI 1.04 to 1.53, p=0.03) and prolonged operative times (MD=56.27, 95% CI 15.94 to 96.60, p<0.01)., Conclusion: Pelvic and para-aortic lymphadenectomy appears to confer a prognostic benefit in patients with intermediate- and high-risk endometrial cancer. Robust prospective studies are needed to further validate these findings and elucidate the precise role of para-aortic lymphadenectomy in the optimal management of these patients., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Precision medicine through molecular profiling has taken a prominent role in the treatment of solid tumors and it is widely expected that this will continue to expand. With respect to gynecological cancers, a major change has particularly been observed in the treatment landscape of epithelial ovarian, endometrial, and cervical cancers. Regarding the former, maintenance therapy with either poly(ADP-ribose) polymerase inhibitors (PARPi) and/or bevacizumab has become an indispensable treatment option following the traditional combination of cytoreductive surgery and platinum-based chemotherapy. Considering endometrial cancer, the molecular classification system has now been incorporated into virtually every guideline available and molecular-directed treatment strategies are currently being researched, presumably leading to a further transformation of its treatment paradigm. After all, treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor has already been shown to significantly improve disease outcomes in these patients, especially in those with mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) disease. Similarly, in recurrent/metastatic cervical cancer patients, these agents elicited improved survival rates when being added to platinum-based chemotherapy with or without bevacizumab. Interestingly, implications of these targeted therapies for surgical management have been touched on to a minor extent, but are at least as intriguing. This review therefore aims to address the wide-ranging opportunities the molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and recurrent setting., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Endometrial carcinoma (EC) is the commonest gynecological cancer affecting women in Western populations. To predict patient risk, the 2020 edition of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract stressed the importance of integrated histo-molecular classification of the disease. This survey analysis poses attention on the most frequently used immunohistochemical and molecular markers adopted in daily categorization of ECs in European laboratories., Methods: We analyzed data collected through questionnaires administered to 40 Italian, 20 Spanish, 3 Swiss and 6 United Kingdom (UK) laboratories. We collected information regarding daily practice in EC evaluation, specifically concerning mismatch repair status (MMR) and microsatellite instability (MSI). Summary and descriptive statistical analyses were carried out to evaluate the current practice of each laboratory., Results: The results show that MMR status is mainly evaluated by using immunohistochemistry (IHC) on most EC samples. The most frequent approach for the analysis of MMR status is IHC of four proteins (PMS2, MSH6, MSH2, MLH1). MSI analysis by molecular methods is uncommon but useful as a supplemental tool in specific conditions. MLH1 promoter hypermethylation and BRAF V600 mutations analysis are performed in case of negative expression of MLH1/PMS2. Other markers (mainly p53 followed by POLE and PTEN) are investigated in particular in Spain and Switzerland in a consistent number of cases., Conclusion: Guidelines consultation and standardization of laboratory procedures are efficient means for EC prognostic risk stratification and improving the quality of care., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation., Materials and Methods: In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome., Results: As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed., Conclusion: Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications., Clinicaltrials.gov Id: NCT03517449., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Sentinel lymph node mapping by intracervical indocyanine green injection is the preferred method for surgical staging in endometrial cancer. Adverse reactions to indocyanine green are extremely rare, and information about the safety of this tracer in patients with a history of other allergies, asthma, or comorbidities is limited. We aim to evaluate the rate of adverse reactions to indocyanine green injected during sentinel lymph node mapping in patients with endometrial cancer and review the etiology of such reactions., Methods: All patients with endometrial cancer undergoing sentinel lymph node mapping with indocyanine green cervical stroma injection at the Mayo Clinic in Rochester, Minnesota between June 2014 and December 2018 were retrospectively evaluated. Any adverse reaction occurring intra-operatively or within 7 days after surgery was identified. A thorough chart review was performed by an allergy specialist physician for any patient with an allergic-type reaction., Results: We included 923 patients of which 565 (61.2%) had a history of allergy to antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), other medications, and/or environmental exposures. Of 490 patients who had previously received contrast media, 25 (5.1%) had a history of an adverse reaction. No immediate anaphylaxis or other allergic reactions were observed after indocyanine green injection. 10 (1.1%) patients developed a transient skin reaction within 7 days after surgery. None of these patients had a history of contrast media reaction. Based on timing and clinical/peri-operative history of affected patients, it was determined that skin reactions were likely induced by other newly prescribed medications or contact sensitivity, not administration of indocyanine green., Conclusion: Indocyanine green injection for sentinel lymph node mapping in patients with endometrial cancer caused no immediate/delayed anaphylactic or other severe allergic reactions. This included patients with a history of other allergies, asthma, and comorbidities. The myth of iodine's relationship to allergic reactions must be refuted to allow indocyanine green use in patients with a history of contrast media or shellfish allergy., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To evaluate the sensitivity and specificity of sentinel-lymph-node mapping compared with the gold standard of systematic lymphadenectomy in detecting lymph node metastasis in apparent early stage ovarian cancer., Methods: Multicenter, prospective, phase II trial, conducted in seven centers from March 2018 to July 2022. Patients with presumed stage I-II epithelial ovarian cancer planned for surgical staging were eligible. Patients received injection of indocyanine green in the infundibulo-pelvic and, when feasible, utero-ovarian ligaments and sentinel lymph node biopsy followed by pelvic and para-aortic lymphadenectomy was performed. Histopathological examination of all nodes was performed including ultra-staging protocol for the sentinel lymph node., Results: 174 patients were enrolled and 169 (97.1 %) received study interventions. 99 (58.6 %) patients had successful mapping of at least one sentinel lymph node and 15 (15.1 %) of them had positive nodes. Of these, 11 of 15 (73.3 %) had a correct identification of the disease in the sentinel lymph node; 7 of 11 (63.6 %) required ultra-staging protocol to detect nodal metastasis. Four (26.7 %) patients with node-positive disease had a negative sentinel-lymph-node (sensitivity 73.3 % and specificity 100.0 %)., Conclusions: In a multicenter setting, identifying sentinel-lymph nodes in apparent early stage epithelial ovarian cancer did not reach the expected sensitivity: 1 of 4 patients might have metastatic lymphatic disease unrecognized by sentinel-lymph-node biopsy. Nevertheless, 35.0 % of node positive patients was identified only thanks to ultra-staging protocol on sentinel-lymph-nodes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results., Areas Covered: This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies., Expert Opinion: EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.

Metastatic or recurrent endometrioid adenocarcinoma of the uterine corpus is often incurable with limited treatment options. First-line treatment often includes cytotoxic chemotherapy, which incurs significant toxicities for many patients. Endometrial cancer, specifically endometrioid cancer, is a hormone-sensitive disease and, while single-agent hormonal therapies have demonstrated clinical benefit, resistance to these agents often leads to the use of chemotherapy. There is a lack of approved endocrine treatment options in the metastatic setting for most recurrent endometrial cancers, representing an unmet clinical need. Emerging evidence suggests that hormonal therapy in combination with other targeted treatments, such as cyclin dependent kinase (CDK)4/6 inhibitors, is well tolerated and effective in select patient populations. We discuss the clinical evidence suggesting that the combination of CDK4/6 inhibitors and hormonal therapy has the potential to represent an important addition to the first-line treatment options for patients with low-grade advanced or recurrent endometrial cancer., Competing Interests: Competing interests: The authors disclose the following potential conflicts of interest: IR-C: Grants or contracts from any entity: MSD, Roche, BMS, Novartis, AstraZeneca, Merck Sereno; Consulting fees: Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis, Adaptimmun, DAICHI Sankyo, ESAI, Immunogen, Seagen, Blueprint, Takeda, Chugai; Travel support: Roche, AstraZeneca, MSD, ESAI, GSK; Participation on a Data Safety Monitoring Board or Advisory Board: Athena, ATTEND, AGOOVAR57; MITO25; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid: Chair GINECO. DL: Consulting fees: AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis, PharmaMar; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar; Payment for expert testimony: Clovis Oncology; Support for attending meetings and/or travel: AstraZeneca, Clovis Oncology, GSK; Participation on a Data Safety Monitoring Board or Advisory Board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro, AstraZeneca, GSK; Leadership or fiduciary role in other board, society, committee, or advocacy group, unpaid: GCIG, Member, Board of Directors; Receipt of equipment, materials, drugs, medical writing, gifts, or other services (payments made to institution): Clovis Oncology, GSK, MSD, PharmaMar; Institutional funding for work in clinical trials: AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, PharmaMar, Seagen, Immunogen, Novartis, Roche, Incyte. VU: Stock or stock options: EQRx. RG: Stock or stock options: EQRx, Ironwood Pharmaceuticals, Cyclerion. AH: Stock or stock options: EQRx, Bolt Biotherapeutics, Roche. BJM: Consulting fees: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, VBL, Verastem, Zentalis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: AstraZeneca, Easai, Myriad, Roche/Genentech, TESARO/GSK. BS: Consulting fees: AstraZeneca, Clovis, GSK, Genentech, Lilly, Novartis, Gilead, Seagen, Karyopharm, Addy, Circulogene, GOG Foundation, Merck, Imvax, EQRx, Nuvation; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: Seagen. The remaining authors declare no conflicts of interest., (© IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging., Methods: Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1-2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses., Results: 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5-52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06-0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07-0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively)., Conclusion: Staging lymphadenectomy in grade 2 endometrioid ovarian carcinoma patients was associated with improved DFS and OS. Grade 1 and grade 2 might be considered as two different entities, which could benefit from different approach in terms of surgical staging. Prospective studies, including molecular profiles are needed to confirm the survival drivers in this rare setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Selinexor is an oral inhibitor of the nuclear export protein called Exportin 1 (XPO1) with demonstrated antitumor activity in hematological and solid tumors. Selinexor, blocking XPO1, induces nuclear localization of tumor suppressor proteins (including p53, p73, BRCA1, and pRB), leading to the selective induction of apoptosis, and inhibition of DNA damage repair proteins. XPO1 overexpression is common in endometrial cancers. Phase I and II trials reported the antitumor activity of selinexor in patients with endometrial carcinoma. The preliminary results of the phase III Selinexor in ENDOmetrial Cancer (SIENDO/ENGOT-EN5/GOG-3055) trial supported the use of selinexor as maintenance therapy in advanced endometrial cancer patients achieving at least partial response after a minimum of 12 weeks of first-line platinum-based chemotherapy. Selinexor maintenance resulted in a (nonsignificant) 30% reduction in the risk of disease progression or death. Looking at the endometrial cancer molecular subgroup characterized by TP53 wild type, the antitumor activity of selinexor seemed more pronounced, resulting in approximately a 60% reduction in the risk of disease progression or death. The SIENDO and the XPORT-EC trials will clarify the benefits and risks of adding selinexor as a first-line chemotherapy maintenance treatment in all-comer and TP53 wild-type endometrial cancers. Preclinical data highlights the potential for selinexor to be synthetically lethal with PARP inhibitors and may also plan a role in overcoming acquired resistance to those therapies. Therefore, new possible combinations with PARP inhibitors and should be evaluated. Furthermore, the combination of selinexor plus immune checkpoint inhibitors deserves further investigation in clinical trials., Competing Interests: Declaration of Competing Interest Giorgio Bogani: Novartis AG Pharma (C/A, H), Italian Ministry of Health (RG); Bradley J Monk: AstraZeneca (SH, SAB), GSK (SH, SAB), Incyte (SAB), Merck (SH, SAB), Roche/Genentech (SH, SAB), Eisai (SAB), GOG-Foundation (E), US Oncology (E); Ana Oaknin: Roche (SAB), AstraZeneca (SAB), PharmaMar (SAB), Clovis Oncology (SAB), Tesaro (SAB), ImmunoGen (SAB), Genmab (SAB), Mersana (SAB), GSK (SAB), Deciphera (SAB), AGENUS (SAB), Corcept Therapeutics (SAB), Eisai (SAB), EMD Serono (SAB), Medison (SAB), Merck Sharp and Dohme (SAB), Novocure, prIME Oncology (SAB), Shattuck Labs (SAB), Sutro Biopharma (SAB), ITeos Therapeutics(SAB), Amgen (SAB), Karyopharm Therapeutics (RF); Ignace Vergote: Consulting fees from Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Regeneron, Seagen, Sotio, Verastem Oncology, Zentalis. Contracted research (via KULeuven) Oncoinvent AS Corporate sponsored research: Amgen, Roche Accommodations, travel expenses: Karyopharm, Genmab, Novocure; Bruno Bolognese: Karyopharm Therapeutics (OI). The other authors indicated no financial relationship. Legend: consulting/advisory relationship (CA); speaker honoraria (SH); honoraria (H); research funding (RF); ownership interest (OI); intellectual propriety/patent holder (IP); scientific advisory board (SAB)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Endometrial cancer is the most common gynecologic malignancy in developed countries, with increasing incidence and mortality rates worldwide. While most cases are successfully treated with surgery, first-line treatment options for metastatic or recurrent endometrial cancer involve significant toxicities. Imprecise classification of heterogeneous subgroups further complicates treatment decisions and interpretation of clinical trial results. Recent advances in molecular classification are guiding treatment decisions for metastatic or recurrent endometrial cancers. Integrating molecular characteristics with traditional clinicopathology can both reduce overtreatment or undertreatment and help guide the appropriate choice of therapies and effective design of future studies. Here we discuss the treatment of metastatic or recurrent low-grade endometrioid adenocarcinoma of the uterine corpus, which is distinct from high-grade tumors histologically, molecularly, and in treatment response., Competing Interests: Competing interests: The authors disclose the following potential conflicts of interest: IRC: Grants or contracts from any entity: MSD, Roche, BMS, Novartis, AstraZeneca, Merck Sereno; Consulting Fees: Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis, Adaptimmun, DAICHI Sankyo, ESAI, Immunogen, Seagen, Blueprint, Takeda, Chugai; Travel Support: Roche, AstraZeneca, MSD, ESAI, GSK; Participation on a Data Safety Monitoring Board or Advisory Board: Athena, ATTEND, AGOOVAR57; MITO25; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid: Chair GINECO. DL: Consulting Fees: AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis, PharmaMar; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar; Payment for expert testimony: Clovis Oncology; Support for attending meetings and/or travel: AstraZeneca, Clovis Oncology, GSK; Participation on a Data Safety Monitoring Board or Advisory Board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro, AstraZeneca, GSK; Leadership or fiduciary role in other board, society, committee, or advocacy group, unpaid: GCIG, Member, Board of Directors; Receipt of equipment, materials, drugs, medical writing, gifts, or other services (payments made to institution): Clovis Oncology, GSK, MSD, PharmaMar; Institutional funding for work in clinical trials: AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, PharmaMar, Seagen, Immunogen, Novartis, Roche, Incyte. BJM: Consulting Fees: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, VBL, Verastem, Zentalis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: AstraZeneca, Easai, Myriad, Roche/Genentech, TESARO/GSK. BS: Consulting Fees: AstraZeneca, Clovis, GSK, Genentech, Lilly, Novartis, Gilead, Seagen, Karyopharm, Addy, Circulogene, GOG Foundation, Merck, Imvax, EQRx, Nuvation; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: Seagen. The remaining authors declare no conflicts of interest., (© IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer., Methods: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m 2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m 2  + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24., Results: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib., Conclusions: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable., Trial Registration: ClinicalTrials.gov number, NCT02725268., Competing Interests: Declaration of Competing Interest Ana Oaknin reports receiving institutional funding from Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis Oncology, Eisai Co., Ltd., F. Hoffmann–La Roche Ltd., Immunogen Inc., Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc., PharmaMar SA, Regeneron Pharmaceuticals and Tesaro Inc.; personal fees for travel and/or accommodation from AstraZeneca, PharmaMar and Roche; personal fees for advisory board membership from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai Co., Ltd., EMD Serono, F. Hoffmann–La Roche Ltd., Genmab, GSK, ImmunoGen, Itheos, Merck Sharp & Dohme de España, SA, Mersana Therapeutics, Novocure, PharmaMar, Sattucklabs, Seagen, and Sutro Biopharma; membership for ASCO, GOG, and SEOM; a non-remunerated role (member and Cervix Cancer Chair on behalf of GEICO) for GCIG; and being an unpaid member, Officer, Co-Chair of the ESMO Gynaecological Cancers Congress 2023–2025, Chair of the Gynaecological Track ESMO 2019, Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, and ESMO 2022, member of the Gynaecological Cancers Faculty, and Subject Editor for the Gynaecological Clinical Practice Guidelines. Francesco Raspagliesi has received payment or honoraria from GSK, MSD, and AstraZeneca as well as support for attending meetings and/or travel from GSK. Robert M. Wenham reports receiving personal and institutional fees from Merck and Ovation Diagnostics; institutional clinical trial fees from AstraZeneca, Abbvie, Regeneron, and Eisai Co., Ltd.; personal consulting fees from Merck, Legend Biotech, Novacure, Genentech, GSK/Tesaro, AstraZeneca, Abbvie, Ovation Diagnostics, Regeneron, Seagen, Shattuck Labs, Eisai Co., Ltd., and Immunogen; speakers fees from Clovis Oncology; support for attending meetings and/or travel as part of the consulting, board participation, or abstract preparation, not in isolation; travel fees from Sonnet Biotherapeutics and Eisai Co., Ltd.; personal/DSMB fees from Seagen and GSK/Tesaro; personal/scientific advisory board fees from Sonnet Biotherapeutics; and personal stock or stock options for Ovation Diagnostics. Elena Ioana Braicu reports receiving research funding from Bayer and Tesaro; personal fees from Clovis Oncology, Tesaro, Eisai Co., Ltd., and RochePharma; and both research funding and personal fees from Roche Diagnostics, GSK, and AstraZeneca. Vicky Makker reports research funding (institution) from AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Duality, Eisai Co., Ltd., Faeth Therapeutics, Karyopharm Therapeutics, Lilly, MSD, Takeda, and Zymeworks; an unpaid consulting or advisory role for ArQule, AstraZeneca, Clovis Oncology, Duality, Eisai Co., Ltd., Faeth Therapeutics, GlaxoSmithKline, IBM, Immunocore, ITeos Therapeutics, Kartos Therapeutics, Karyopharm Therapeutics, Lilly, MSD, Moreo, Morphosys, Novartis, Takeda, and Zymeworks; support for travel, accommodations, and/or expenses from Eisai Co., Ltd. and MSD. Eva María Guerra Alía reports advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar, and Roche; speaker bureau/expert testimony honorarium from AstraZeneca-MSD, PharmaMar, Roche, and GSK-Tesaro; and support for travel, accommodation, and/or expenses from Roche, GSK-Tesaro, and Baxter. Zhenqiang Su is an employee of Takeda. Sylvie Vincent is an employee of Takeda. Farhad Sedarati is an employee of Takeda. Douglas V. Faller reports consulting fees from Viracta Therapeutics, Briacell Therapeutics, and Molecular Partners; equity from Oryzon Genomics, Phoenicia Biosciences, Viracta Therapeutics, and Briacell Therapeutics; and employment at Oryzon Genomics, Phoenicia Biosciences, and Takeda Pharmaceuticals (ended in 2022). Sileny N. Han, Amit Oza, Nicoletta Colombo, Andrea Jewell, Jonathan Krell, Jean- François Baurain, Rachel Neuwirth, and Giovanni Scambia have no disclosures to report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze the clinicopathological features and outcomes in patients with endometrial cancer with isolated lymphatic recurrence after lymphadenectomy, stratified by different isolated lymphatic recurrence sites and treatment approaches., Methods: We retrospectively reviewed all surgically treated patients with endometrial cancer, identifying those with recurrence. We defined primary isolated lymphatic recurrence as the first and unique evidence of recurrence in lymph node-bearing areas, without concomitant vaginal, hematogenous, or peritoneal recurrence. Isolated lymphatic recurrences were classified as pelvic, para-aortic, distant, or multiple sites. Our primary outcome was cause-specific survival after diagnosis of the recurrence., Results: Among 4216 patients with surgically staged endometrial cancer, we identified 66 (1.6%) women with isolated lymphatic recurrence. The overall median cause-specific survival for patients with isolated lymphatic recurrence was 24 months. Although cause-specific survival was not significantly different between the four isolated lymphatic recurrence groups (p=0.21), 7 of 15 (47%) patients with isolated lymphatic recurrence in the para-aortic area were long-term survivors. At multivariate Cox regression, the absence of lymphovascular space invasion and grade 1 histology in the primary tumor were significantly associated with improved cause-specific survival. In addition, patients with isolated lymphatic recurrence who underwent surgery for recurrence (with/without other associated therapies) had improved cause-specific survival compared with patients who did not undergo surgery, also after adjusting for age., Conclusions: Low-grade histology and absence of lymphovascular space invasion in the primary tumor were predictors of improved prognosis in patients with endometrial cancer with isolated lymphatic recurrence. In addition, in this retrospective cohort, patients with isolated lymphatic recurrence who were selected for eradicative surgical treatment had improved cause-specific survival., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the diagnostic performance of the one-step nucleic acid amplification (OSNA) method for the detection of sentinel lymph node (SLN) metastases in women with apparent early-stage endometrial cancer compared with standard ultrastaging., Methods: Prospective, multicentric, interventional study. Patients with apparent early-stage endometrial cancer who underwent primary surgical staging with SLN mapping were included. SLNs were serially sectioned with 2 mm slices perpendicular to the longest axis of the node: the odd slices were submitted to ultrastaging, whereas the even slices were submitted to the OSNA analysis. Diagnostic performance was calculated taking ultrastaging as referral standard., Results: Three-hundred and sixteen patients with 668 SLNs were included. OSNA assay detected 22 (3.3%) positive SLNs, of which 17 (2.5%) were micrometastases and 5 (0.7%) macrometastases, whereas ultrastaging detected 24 (3.6%) positive SLNs, of which 15 (2.2%) were micrometastases and 9 (1.3%) macrometastases (p=0.48). Regarding negative SLNs, OSNA detected 646 (96.7%) negative nodes, including 8 (1.2%) isolated tumor cells, while ultrastaging detected 644 (96.4%) negative nodes with 26 (3.9%) isolated tumor cells. Specificity of OSNA was 98.4% (95% CI 97.5 to 99.4), accuracy was 96.7% (95% CI 95.4 to 98.1), sensitivity was 50% (95% CI 30.0 to 70.0), while negative predictive value was 98.1% (95% CI 97.1 to 99.2). Discordant results were found in 22 SLNs (3.3%) corresponding to 20 patients (6.3%). These were 10 (1.5%) false-positive SLNs (all micrometastases): one (0.1%) of these was a benign epithelial inclusion at ultrastaging. There were 12 (1.8%) false-negative SLNs of OSNA, of which 9 (1.3%) were micrometastases and 3 (0.5%) macrometastases. Overall, 17/668 (2.5%) benign epithelial inclusions were detected at ultrastaging., Conclusion: The OSNA method had high specificity and high accuracy in detecting SLN metastasis in apparent early-stage endometrial cancer. The advantage of the OSNA method could be represented as the possibility to analyze the entire lymph node thus eliminating sampling bias., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Endometrial cancer is the most common gynecologic neoplasm. To date, international guidelines recommend sentinel lymph node biopsy for low-risk neoplasms, while systematic lymphadenectomy is still considered for high-risk cases. This study aimed to compare the long-term survival of high-risk patients who were submitted to sentinel lymph node biopsy alone versus systematic pelvic lymphadenectomy., Methods: Patients with high-risk endometrial cancer according to the 2021 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology risk classification were retrospectively analyzed. The primary aim of the study was to compare the long-term overall survival and disease-free survival of high-risk endometrial cancer patients undergoing sentinel lymph node biopsy versus systematic lymphadenectomy. A supplementary post-hoc survival analysis of cases with nodal metastasis was performed to compare sentinel lymph node and lymphadenectomy survival outcomes in this subset of patients., Results: The study enrolled 237 patients with histologically proven high-risk endometrial cancer. Patients were followed up for a median of 31 months (IQR 18-40). During the follow-up, 38 (16.0%) patients had a recurrence, and 19 (8.0%) patients died. Disease-free survival (85.2% vs 82.8%; p=0.74) and overall survival (91.3% vs 92.6%; p=0.62) were not different between the sentinel lymph node alone and lymphadenectomy groups. Furthermore, neither overall survival (96.1% vs 91.4%; p=0.43) nor disease-free survival (83.7% vs 76.4%; p=0.46) were different among sentinel lymph node alone and lymphadenectomy groups in patients with nodal metastasis., Conclusions: Sentinel lymph node mapping alone in high-risk endometrial cancer appears to be an oncologically safe technique over a long observational time. Systematic lymphadenectomy in this population does not offer a survival advantage., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Corded and hyalinized endometrioid carcinoma (CHEC) represents a potential pitfall for pathologists. This study aimed to provide a complete overview of all clinicopathological and molecular features of CHEC. Electronic databases were searched for all published series of CHEC. Clinical, histological, immunohistochemical and molecular data about CHEC were extracted and pooled. Six studies with 62 patients were identified; mean age was 49.8 years (range 19-83). Most cases showed FIGO stage I (68%), low grade (87.5%), and a favorable outcome (78.4%), with "no specific molecular profile" (NSMP). A subset of cases showed high-grade features (12.5%), p53 abnormalities (11.1%) or mismatch repair (MMR) deficiency (20%) and occurred at an older age (mean age>60 years). Common features of CHEC were: superficial localization of the corded component (88.6%), squamous/morular differentiation (82.5%), nuclear β-catenin accumulation (92%), partial/total loss of CKAE1/AE3 (88.9%), estrogen receptor (95.7%) and e-cadherin (100%), stromal changes such as myxoid (38.5%), osteoid (24%) and chondroid (4.5%), CTNNB1 mutations (57.9%), and POLE-wild-type (100%); 24.4% of cases showed lymphovascular space invasion. A minority of cases (16.2%) showed poor outcome despite a low-grade, NSMP phenotype; the molecular basis for the aggressiveness of these cases is still undefined. Further studies are necessary in this field., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objective: In endometrial carcinoma patients, sentinel lymph node bilateral mapping fails in 20-25% of cases, with several factors affecting the likelihood of detection. However, pooled data about predictive factors of failure are lacking. The aim of this systematic review and meta-analysis was to assess the predictive factors of sentinel lymph node failed mapping in endometrial cancer patients undergoing sentinel lymph node biopsy., Methods: A systematic review and a meta-analysis was performed searching all studies assessing predictive factors of sentinel lymph node failed mapping in apparent uterine-confined endometrial cancer patients undergoing sentinel lymph node biopsy through the cervical injection of indocyanine green. The associations between sentinel lymph node failed mapping and predictive factors of failure were assessed, calculating the odds ratio (OR) with 95% confidence intervals., Results: Six studies with a total of 1345 patients were included. Compared with patients with sentinel lymph node bilateral successful mapping, patients with sentinel lymph node failed mapping showed: OR 1.39 (p=0.41) for body mass index >30 kg/m 2 ; OR 1.72 (p=0.24) for menopausal status; OR 1.19 (p=0.74) for adenomyosis; OR 0.86 (p=0.55) for prior pelvic surgery; OR 2.38 (p=0.26) for prior cervical surgery; OR 0.96 (p=0.89) for prior Cesarean section; OR 1.39 (p=0.70) for lysis of adhesions during surgery before sentinel lymph node biopsy; OR 1.77 (p=0.02) for indocyanine green dose <3 mL; OR 1.28 (p=0.31) for deep myometrial invasion; OR 1.21 (p=0.42) for International Federation of Gynecology and Obstetrics (FIGO) grade 3; OR 1.89 (p=0.01) for FIGO stages III-IV; OR 1.62 (p=0.07) for non-endometrioid histotype; OR 1.29 (p=0.25) for lymph-vascular space invasion; OR 4.11 (p<0.0001) for enlarged lymph nodes; and OR 1.71 (p=0.022) for lymph node involvement., Conclusion: Indocyanine green dose <3 mL, FIGO stage III-IV, enlarged lymph nodes, and lymph node involvement are predictive factors of sentinel lymph node failed mapping in endometrial cancer patients., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The aim of this study is to evaluate the impact of the oestrogen receptor (ER) profile on oncologic outcomes in the new endometrial cancer (EC) risk classification., Methods: Immunohistochemistry (IHC) analyses were performed in a retrospectively reviewed large series of ECs to assess the presence/absence of oestrogen receptors (ER0\1+ or ER2+\3+) and other molecular factors (i.e. p53 mutation, p53mut; and mismatch repair mutational status, MMRd (mismatch repair deficient) versus MMRp (mismatch repair proficient)), histopathologic and clinical outcomes. ER status was correlated with molecular, histologic, clinical and prognostic data., Results: 891 EC patients were included in the study (211 ER0\1+ and 680 ER2+\3+). The ER0\1+ phenotype was associated with an unfavourable clinicopathological profile (i.e. grading, histotype, lymphovascular space invasion (LVSI), stages, etc.). Simple regression showed that risk class, p53mut, and ER0/1+ impacted on both disease-free survival (DFS) and overall survival (OS) (p < 0.05). In the ER0/1+ population, p53mut no longer influenced DFS and OS (p > 0.05). In multiple regression, age, high and advanced/metastatic risk classes influenced survival outcomes (p < 0.05), but lost significance in the ER0/1+ population (p > 0.05). ER-positivity retained a remarkable prognostic impact even after stratification of the population according to the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Pathology (ESGO/ESTRO/ESP) 2021 risk classes and molecular classification. ER0/1+ intermediate, high-intermediate, high and advanced risk versus ER2+/3+ intermediate, high-intermediate, high and advanced risk classes showed statistically different OS and DFS (p< 0.001). ER0/1+ status was associated with a worse prognosis when associated with MMRp, MMRd and p53mut compared to the same molecular classes associated with ER2+/3 (p < 0.001)., Conclusions: We demonstrated that ER status has a significant impact on oncologic outcomes, regardless of risk class and p53/MMR status. Based on our results, we recommend the inclusion of ER assessment in featured EC risk classification system., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Lenvatinib and pembrolizumab (LEN+PEMBRO) demonstrated clinically meaningful and statistically significant improvements in efficacy versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer (aEC) in the phase 3 Study 309/KEYNOTE-775. Health-related quality-of-life (HRQoL) is reported., Patients and Methods: Patients were randomly assigned to receive LEN+PEMBRO (n = 411; LEN 20 mg/day; PEMBRO 200 mg Q3W) or TPC (n = 416; doxorubicin 60 mg/m 2 Q3W or paclitaxel 80 mg/m 2 [weekly, 3 weeks on/1 week off]). Impact of treatment on HRQoL assessed by the global health status/quality of life (GHS/QoL) score of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) was a secondary objective; other scales of the Quality-of-Life Questionnaire (QLQ-C30), EORTC QLQ-Endometrial, 24 questions (EORTC QLQ-EN24), and EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) were exploratory objectives. HRQoL was assessed on day 1 of each cycle. Completion/compliance, change from baseline, time to first and definitive deterioration were assessed. No multiplicity adjustments were applied for HRQoL endpoints., Results: The latest timepoint at which the predefined rates of completion (≥60%) and compliance (≥80%) were met was week 12. HRQoL at week 12 between treatment groups was generally similar. Time to first deterioration symptom scales favoured LEN+PEMBRO for QLQ-C30 dyspnoea, and QLQ-EN24 for poor body image, tingling/numbness, and hair loss; and TPC was favoured for QLQ-C30 pain, appetite loss, and diarrhoea, and QLQ-EN24 muscular pain. While the QLQ-C30 physical functional scale favoured TPC, other functional scales were generally similar between arms. Time to definitive deterioration favoured LEN+PEMBRO on most scales., Conclusion: HRQoL data from Study 309/KEYNOTE-775, with previously published efficacy and safety results, indicate that LEN+PEMBRO has an overall favourable benefit/risk profile versus TPC for the treatment of patients with aEC., Clinicaltrials: GOV: NCT03517449., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Domenica Lorusso: Advisory Board: GSK, AstraZeneca, MSD, Clovis Oncology, PharmaMar, Merck Serono, Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; Consultancy: PharmaMar, Amgen, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen; Funding (inst.): MSD, Clovis Oncology, GSK, PharmaMar, AstraZeneca, Seagen, Genmab, Immogen, Incyte, Novartis, Roche; Invited Speaker: Genmab, PharmaMar, MSD; Principal Investigator: AstraZeneca, MSD, Genmab, Immunogen, Clovis, Roche, Incyte; Board of Directors: GCIG Nicoletta Colombo: Honoraria: Amgen, AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, mersana, MSD Oncology, Novartis, Pfizer, PharmaMar, Roche/Genentech, Tesaro; Consulting or Advisory Role: AstraZeneca, BioCad, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, Mersana, MSD Oncology, Pfizer, PharmaMar, Roche/Genentech, Tesaro Antonio Casado Herraez: advisory boards for AstraZeneca, Clovis Oncology, Eisai, Merck, PharmaMar; some support for attending major international oncological conferences (virtually or face to face meetings) from PharmaMar, Lilly, Roche, AstraZeneca-Merck and GSK; Research support (institution): PharmaMar Alessandro Santin: grants from Puma, Immunomedics, Gilead, Synthon, Merck, Boehringer-Ingelheim, Genentech, Tesaro, Eisai; personal fees from Merck, Tesaro, Eisai Emeline Colomba: Honoraria: Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Merck; Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, Pfizer David Scott Miller: Advisory Board: Eisai, Karyopharm, Tesaro, Tarveda, Myriad, GlaxoSmithKline, AbbVie, AstraZeneca, EMD Serono, Seagen; Board of Directors/Leadership Role: NRG Oncology; Research Grant: NRG Oncology, Karyopharm, Advaxis, Immunogen, Advenchen, Regeneron, Merck, Agenus, Akesobio, EMD Serono Keiichi Fujiwara: Honoraria: Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Zeria Pharmaceutical; Consulting or Advisory Role: Abbvie, AstraZeneca, Eisai, Genmab, MSD, Pfizer, Taiho Pharmaceutical, Takeda; Research Funding (institution): AstraZeneca, Chugai Pharma, Eisai, Genmab, Immunogen, Kaken Pharmaceutical, Lilly, MSD, Oncotherapeutics, Ono Pharmaceutical, Regeneron, Shionogi, Zeria Pharmaceutical; Travel, Accommodations, Expenses: Abbvie, MSD, Pfizer; Consulting or Advisory Role - Abbvie; AstraZeneca; Eisai; Genmab; MSD; Pfizer; Taiho Pharmaceutical; Takeda; Research Funding - AstraZeneca (Inst); Chugai Pharma (Inst); Eisai (Inst); Genmab (Inst); Immunogen (Inst); Kaken Pharmaceutical (Inst); Lilly (Inst); MSD (Inst); Oncotherapeutics (Inst); Ono Pharmaceutical (Inst); Regeneron (Inst); Shionogi (Inst); Zeria Pharmaceutical (Inst); Travel, Accommodations, Expenses - Abbvie; MSD; Pfizer Sandro Pignata: Honoraria: AstraZeneca, MSD, Pfizer, PharmaMar, Roche, Tesaro; Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Pfizer, PharmaMar, Roche, Tesaro; Research Funding (institution) AstraZeneca, MSD, Pfizer, Roche Sally E. Baron-Hay: Consultancy fees: Eisai, Merck Sharp and Dohme (Australia Pty Ltd), Pfizer, AstraZeneca Australia; Honoraria: Amgen, Novartis Pharmaceuticals Australia Pty Ptd, Eli Lilly Australia, Roche, Merck Sharp and Dohme (Australia Pty Ltd) Isabelle Laure Ray-Coquard: Honoraria: Abbvie, Advaxis, Amgen, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, DECIPHERA, Genmab, GlaxoSmithKline, MERSANA, MSD Oncology, OxOnc, Pfizer, PharmaMar, Roche, Tesaro; Consulting or Advisory Role: Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Deciphera, Genmab, GlaxoSmithKline, Mersana, MSD Oncology, Pfizer, PharmaMar, Roche, Tesaro; Research Funding: BMS, MSD Oncology; Travel, Accommodations, Expenses: Advaxis, AstraZeneca, BMS, Clovis Oncology, GlaxoSmithKline, PharmaMar, Roche, Tesaro Ronnie Shapira-Frommer: Honoraria: AstraZeneca, Bristol Myers Squibb, Medison, MSD, NeoPharm, Novartis, Roche; Consulting or Advisory Role: MSD, VBL Therapeutics; Research Funding: MSD Yong Man Kim: Stock and Other Ownership Interests: Genolution, Johnson & Johnson; Research Funding: Regeneron, Roche Mary McCormack: Research Funding (institution): Roche/Genentech; Travel, Accommodations, Expenses: Roche; honoraria from GSK, AZ, and Eisai. Rachid Massaad: Full-time employee of MSD Europe Allison Martin Nguyen: Full-time employee/stock ownership: Merck & Co., Inc. Qi Zhao: Full time employee of Eisai Inc. Jodi McKenzie: Full time employee of Eisai Inc. Vimalanand S. Prabhu: Full-time employee/stock ownership: Merck & Co., Inc.; Travel, Accommodations, Expenses: Merck & Co., Inc Vicky Makker: study support (all funding to institution) / consultancy / advisory board membership from AstraZeneca, Clovis, Eisai, Faeth, Genentech, GSK, iTEOS, Karyopharm, Moreo, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Takeda, Zymeworks; Dr Makker is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m 2 intravenously once every 3 weeks or paclitaxel 80 mg/m 2 intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.

Background: The molecular classification of endometrial cancer revolutionized our knowledge of its biology but so far has not affected our surgical approach. The exact risk of extra-uterine metastasis and hence the type of surgical staging for each of the four molecular subgroups are currently unknown., Primary Objective: To determine the association between molecular classification and disease stage., Study Hypothesis: Each endometrial cancer molecular subgroup has a specific pattern of spread and this pattern of spread could guide the extent of surgical staging., Trial Design: Prospective, multicenter study MAJOR INCLUSION/EXCLUSION CRITERIA: Participants eligible for inclusion in this study must meet all the following criteria: women ≥18 years with primary endometrial cancer, any histology and stage., Primary Endpoint: Number and site of metastasis in each endometrial cancer molecular subgroup., Sample Size: 1000 patients will be enrolled., Estimated Dates for Completing Accrual and Presenting Results: The trial will last 6 years: 4 years of accrual, and 2 years of follow-up of all patients. Results on staging and oncological outcomes are expected in 2027 and 2029, respectively., Trial Registration: The study has been accepted by UZ Leuven Ethical Committee. Belg. Reg. nr: B3222022000997., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Corded and hyalinized endometrioid carcinoma (CHEC) typically shows low-grade features and "no specific molecular profile" (NSMP). This study aimed to perform a clinicopathological and molecular characterization of endometrial CHEC with high-grade features. Immunohistochemistry for cytokeratin AE1/AE3, e-cadherin, β-catenin, estrogen receptor, progesterone receptor, p53, p16, and mismatch repair proteins was performed. A next-generation sequencing kit was used to assess POLE, POLD1, APC, MLH1, MSH2, MSH6, PMS2, MUTYH, EPCAM, and CTNNB1. Molecular groups, i.e., POLE-mutant, mismatch repair deficient (MMRd), p53-abnormal, and NSMP, were assigned according to the TCGA classifier. Six high-grade endometrial CHECs were identified. The mean age was 57.5 years; 5/6 cases were uterine-confined. Five cases showed a diffusely and markedly atypical corded component and a MMRd or p53-abnormal signature; additional features included single-cell keratinization, necrosis, osteoid or myxoid/chondro-myxoid matrix, foci of anaplasia, and nuclear β-catenin expression. The remaining case showed a low mitotic count and a NSMP phenotype, with focal bizarre cells in an otherwise classical CH endometrioid carcinoma. All cases showed variably reduced expression of epithelial markers and hormone receptors in the corded component. No mutations were found in any of the analyzed genes. In conclusion, high-grade CHECs are a heterogeneous subset of biphasic endometrial carcinoma which show similarities and differences with classical CHEC and carcinosarcoma. These cases often show MMRd or p53-abnormal signatures., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor. Over the years, this novel class of drugs expanded to agents with a more sophisticated design and structure, targeting tissue factor (TF) in cervical cancer or human epidermal growth factor receptor 2 (HER2) in endometrial cancer. Despite the impressive number of patients included in clinical trials investigating different ADCs across gynecological cancers, it was only recently that the Food and Drug Administration (FDA) granted accelerated approvals to the first ADCs in gynecologic cancer. In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Currently, the field of ADCs is rapidly expanding and more than 20 ADC formulations are in clinical trials for the treatment of ovarian, cervical and endometrial tumors. This review summarizes key evidence supporting their use and therapeutic indications, including results from late-stage development trials investigating MIRV in ovarian cancer and TV in cervical cancer. We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination therapies, including chemotherapy, anti-angiogenic and immunotherapeutic agents., Competing Interests: Competing interests: SM: Research funding, advisory board, honorary or travel expenses: AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. DL: Research funding: Clovis Oncology, AstraZeneca, Corcept Therapeutics, GlaxoSmithKline, Genmab, ImmunoGen, Merck Sharp & Dohme, Novartis, PharmaMar, Roche, and Seagen; Consulting fees: Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and PharmaMar; Payment or honoraria for lectures: Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and Seagen; Support for attending meetings and/or travel: AstraZeneca, PharmaMar, and Roche; Participation on a data safety monitoring board or advisory board: Clovis Oncology, Agenus, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche; and serves on the board of directors for GCIG and as chair of GCA for ENGOT. KNM: Leadership: GOG Partners, NRG Oncology (Inst); Honoraria: Research To Practice, Prime Oncology, Physicans’ Education, Resource, Great Debates and Updates; Consulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, TESARO (Inst), VBL Therapeutics, Merck, Aravive, Eisai, Vavotar Life Sciences, Mersana (Inst), Myriad Genetics, Alkemeres (Inst), Blueprint Pharmacetuicals (Inst), GlaxoSmithKline/Tesaro (Inst), I-Mab (Inst), InxMed (Inst), Mereo BioPharma (Inst), OncXerna Therapeutics, Onconova Therapeutics, Mereo, BioPharma, Novartis; Research Funding: PTC Therapeutics (Inst), Lilly (Inst), Merck (Inst), Tesaro, (Inst), Genentech (Inst), Clovis Oncology (Inst), Lilly Foundation (Inst), Regeneron (Inst), Advaxis (Inst), Bristol Myers Squibb (Inst), Verastem (Inst), Novartis Pharmaceuticals UK Ltd (Inst), AstraZeneca (Inst), Agenus (Inst), Takeda (Inst), Forty Seven (Inst), Stem CentRx (Inst), Immunogen (Inst), Bayer (Inst), Novogen (Inst), AbbVie/Stemcentrx (Inst), artios (Inst), Bolt Biotherapeutics (Inst), Amgen (Inst), Daiichi Sankyo/Lilly (Inst), Cyteir (Inst), Immunocore (Inst) Patents, Royalties, Other Intellectual Property: UpToDate; Other Relationship: GOG Partners (Inst). RLC: Grants or contracts: Clovis Oncology, AstraZeneca, Gateway Foundation, Genelux, Genmab, Janssen, Merck, and Roche/Genentech; Consulting fees: Clovis Oncology, Agenus, Alkermes, AstraZeneca, Deciphera, Genelux, Genmab, GlaxoSmithKline, Immunogen, Janssen, OncoQuest, OncXerna, Onxeo, Regeneron, and Roche/Genentech., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Herein, we present a clinicopathological and molecular analysis of four cases of endometrial carcinoma (EC) diffusely exhibiting dyshesive cells with wide eosinophilic and vacuolated cytoplasm (histiocyte-like tumor cells, HLTCs). We compared these HLTCs to similar cells found in microcystic, elongated and fragmented (MELF) pattern (n = 20) or after neoadjuvant chemotherapy (NAC) (n = 5). The four cases were endometrioid, serous, clear cell, and gastric-type; all were at FIGO stage ≥ III. HLTCs showed an epithelial Müllerian phenotype and at least focal CK20, HNF1β, and CK5/6 expression, with aberrant e-cadherin and β-catenin expression; two cases were MMR-deficient, and one was p53-abnormal; all were POLE wild type. MELF-associated and NAC-associated HLTCs showed similar morphological/immunophenotypical features. However, MELF-associated HLTCs were mainly intraglandular and inflammation-associated, did not form a distinct tumor component, and showed no relationship with lymph node metastases. In conclusion, different histotypes of EC may show a prominent HLTC component, which shows peculiar morphological/immunophenotypical features and appears associated with aggressive behavior., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The standard surgical treatment of endometrial carcinoma, consisting of total hysterectomy with bilateral salpingo-oophorectomy, drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) provide comprehensive information on all relevant issues of diagnosis and treatment in endometrial carcinoma in a multidisciplinary setting. While addressing also work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility-sparing treatment.A collaboration was set up between the ESGO, the European Society of Human Reproduction and Embryology (ESHRE), and the European Society for Gynaecological Endoscopy (ESGE), aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment (patient selection, tumor clinicopathological characteristics, treatment, special issues) in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (11 experts from across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified by a systematic search, was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives., Competing Interests: Competing interests: GS has reported grants from MSD Italia S.r.l., advisory boards for Storz, Bayer, Astrazeneca, Metronic, TESARO Bio Italy S.r.l and Johnson & Johnson, and honoraria for lectures from Clovis Oncology Italy S.r.l. MG has reported advisory boards for Gedeon Richter and Merck; AR, FP, MA, ADSS, MF, MP, KP, NV, GZ,IZ and KLTM have reported no conflicts of interest., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma., Competing Interests: Competing interests: GB: Novartis AG Pharma (C/A, H), Italian Ministry of Health (RG); NC: AstraZeneca (C/A, SH), Seattle Genetics (C/A, SH), MSD (SAB), Mersana (C/A, SH), eTheRNA immunotherapies NV (C/A, SH), Roche (travel expenses), Genmab (travel expenses), Amgen (travel expenses). IR-C: honoraria from AstraZeneca, Clovis, GSK/Tesaro, and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro, Genmab, PharmaMar, MSD, Mersana, Deciphera, OncXea, Esai, BMS, Novartis, and Pfizer; research funding from MSD; travel expenses from AstraZeneca, GSK, and Roche. YS: AstraZeneca (CA), GSK (CA). PW: Amgen (SH, RF, SAB), AstraZeneca (SH, RF, H, SAB), Clovis (SH, RF, SAB), Eisai (SH, SAB), GSK (SH, SAB), Lilly (SH, SAB), MSD (SH, RF, SAB), Novartis (SH, RF, SAB), Pfizer (SH, RF, SAB), Roche (SH, RF, H, SAB), TEVA (SH, SAB). NYLN: AstraZeneca (SH), Janssen (SH). KT: AstraZeneca (SH), Chugai (SH, RF), Eisai (SH), MSD (SH), Mochida (SH), Takeda (SH). TE: Takeda (SH), Astra Zeneca (SH), Eisai (SH), Chugai Pharma (SH, RF), MSD (SH), Mochida (SH). DL: AstraZeneca (H, CA), Clovis (H, CA, RF), GSK/Tesaro (H, CA), Roche (CA), Genmab (CA), PharmaMar (CA, RF), MSD (CA, RF), Esai (CA), Merck Serono (CA), Novartis (CA), and PharmaMar (H); consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro. DMP: AstraZeneca (CA, SH, SAB), GSK (CA, SH, SAB). NRA-R: NIH/NCI Cancer Center support grant P30 CA008748 (F). HD: Roche (CA, SH, SAB), Pfizer (CA, SH, SAB), AstraZeneca (SH, SAB), Lily (SAB), GSK (SAB), Novartis (SH), Pharmamar (SH); BJM: AstraZeneca (SH, SAB), GSK (SH, SAB), Incyte (SAB), Merck (SH, SAB), Roche/Genentech (SH, SAB), Eisai (SAB), GOG-Foundation (E), US Oncology (E)., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies., Competing Interests: Funding All costs relating to this consensus conference were covered by the ESMO and the ISMPO from central dedicated funds. There was no external funding of the event or the manuscript production., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the histological assessment of endometrial carcinoma, the presence of squamous differentiation is generally considered inconsistent with a serous histotype. Herein, we report a case of endometrial serous carcinoma with extensive squamous differentiation mimicking squamous cell carcinoma, with literature review. A 67-years-old-woman underwent hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node resection, omental and peritoneal biopsies, due to a 8 cm endometrial mass. Histologically, the tumor showed squamous carcinoma features with positivity for squamous cell markers (p40, p63, cytokeratin-5/6, cytokeratin-34βE12) and negativity for Müllerian markers (PAX8, estrogen receptor, progesterone receptor). No immunohistochemical/molecular alterations typical of endometrioid carcinoma (i.e., PTEN loss, mismatch repair deficiency, nuclear β-catenin expression, POLE mutation) were observed. P53 showed aberrant pattern and p16 showed basal positivity. The tumor infiltrated the myometrium full-thickness with extensive lymphovascular space invasion. Surprisingly, the sentinel lymph node metastasis showed overt serous carcinoma features. Additional sampling of the endometrial mass revealed a minor. In conclusion, serous carcinoma may show diffuse squamous differentiation. In the case of suspected primary endometrial squamous cell carcinoma, an extensive sampling is warranted., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.