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Tamoxifen exposure is a recognised risk for primary endometrial cancer. This case serves as a reminder to meticulously check the past medical history and inform patients of the risk-benefit of treatment as part of a shared-decision making process.

Approximately 12% of routinely examined fallopian tubes of endometrial carcinoma (EC) cases have intraluminal tumor cells (ILTCs). ILTC associations with EC characteristics and outcomes are understudied, and unknown in serially examined and embedded tubal fimbriae. Glass slides of serially examined and embedded tubal fimbriae for 371 EC cases were independently reviewed by 2 pathologists who recorded ILTC presence and characterized them as mucosal if involved and floating if not. Disagreements were reviewed by a third pathologist, and agreement between any 2 determined final ILTC status. Clinico-pathologic associations and ILTC presence were tested for significance (P

The case demonstrates the use of bariatric surgery to improve a patient’s candidacy for surgical treatment for endometrial cancer (EC). A 50-year-old morbidly obese woman with early-stage EC was initially treated with levonorgestrel-releasing intrauterine system (52 mg) . She had to reduce her body mass index (BMI) to become eligible for definite EC treatment. Using conservative methods, she was unable to lose weight effectively. She then underwent bariatric surgery that reduced her BMI from 71.3 to 54.3 kg/m2. She maintained her weight and was eligible for total hysterectomy and bilateral salpingo-oopherectomy. Her procedure was successful and had no complications. She has 6-monthly follow-ups, and the most recent review showed no evidence of recurrence.

The primary aim of this study was to develop and validate radiomics models, applied to ultrasound images, capable of differentiating from other cancers high-risk endometrial cancer, as defined jointly by the European Society for Medical Oncology, European Society of Gynaecological Oncology and European Society for RadiotherapyOncology (ESMO-ESGO-ESTRO) in 2016. The secondary aim was to develop and validate radiomics models for differentiating low-risk endometrial cancer from other endometrial cancers.This was a multicenter, retrospective, observational study. From two participating centers, we identified consecutive patients with histologically confirmed diagnosis of endometrial cancer who had undergone preoperative ultrasound examination by an experienced examiner between 2016 and 2019. Patients recruited in Center 1 (Rome) were included as the training set and patients enrolled in Center 2 (Milan) formed the external validation set. Radiomics analysis (extraction of a high number of quantitative features from medical images) was applied to the ultrasound images. Clinical (including preoperative biopsy), ultrasound and radiomics features that were statistically significantly different in the high-risk group vs the other groups and in the low-risk group vs the other groups on univariate analysis in the training set were considered for multivariate analysis and for developing ultrasound-based machine-learning risk-prediction models. For discriminating between the high-risk group and the other groups, a random forest model from the radiomics features (radiomics model), a binary logistic regression model from clinical and ultrasound features (clinical-ultrasound model) and another binary logistic regression model from clinical, ultrasound and previously selected radiomics features (mixed model) were created. Similar models were created for discriminating between the low-risk group and the other groups. The models developed in the training set were tested in the validation set. The performance of the models in discriminating between the high-risk group and the other groups, and between the low-risk group and the other risk groups for both validation and training sets was compared.The training set comprised 396 patients and the validation set 102 patients. In the validation set, for predicting high-risk endometrial cancer, the radiomics model had an area under the receiver-operating-characteristics curve (AUC) of 0.80, sensitivity of 58.7% and specificity of 85.7% (using the optimal risk cut-off of 0.41); the clinical-ultrasound model had an AUC of 0.90, sensitivity of 80.4% and specificity of 83.9% (using the optimal cut-off of 0.32); and the mixed model had an AUC of 0.88, sensitivity of 67.3% and specificity of 91.0% (using the optimal cut-off of 0.42). For the prediction of low-risk endometrial cancer, the radiomics model had an AUC of 0.71, sensitivity of 65.0% and specificity of 64.5% (using the optimal cut-off of 0.38); the clinical-ultrasound model had an AUC of 0.85, sensitivity of 70.0% and specificity of 80.6% (using the optimal cut-off of 0.46); and the mixed model had an AUC of 0.85, sensitivity of 87.5% and specificity of 72.5% (using the optimal cut-off of 0.36).Radiomics seems to have some ability to discriminate between low-risk endometrial cancer and other endometrial cancers and better ability to discriminate between high-risk endometrial cancer and other endometrial cancers. However, the addition of radiomics features to the clinical-ultrasound models did not result in any notable increase in performance. Other efficacy studies and further effectiveness studies are needed to validate the performance of the models. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Rationale and Objectives To compare the diagnostic performance of orthogonal pelvis-axial (OPA) contrast-enhanced (CE) and orthogonal uterus-axial (OUA) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) protocols in assessing the depth of myometrial invasion (MI) of endometrial carcinoma (EC). Materials and Methods Preoperative MRI of 398 consecutive EC patients (197 patients with OPA CE-MRI protocol and 201 patients with OUA DCE-MRI protocol) was analyzed. Two radiologists independently interpreted the depth of MI, with postoperative histopathology as the reference standard. The chi-square test, Fisher's exact test, and receiver operating characteristic curve analysis were used for diagnostic performance comparison. Results OUA DCE-MRI showed a significantly larger area under the curve than OPA CE-MRI in detecting the presence of MI for radiologist 1 (0.71 versus 0.49, p 0.05). Compared to OPA CE-MRI, OUA DCE-MRI significantly improved the diagnostic accuracy of non-MI and superficial MI (radiologist 1: 45.5% versus 0 and 88.7% versus 86.4%, p = 0.045 and 0.567, respectively; radiologist 2: 45.5% versus 12.5% and 88.7% versus 78.8%, p = 0.177 and 0.027, respectively) and of EC with adenomyosis/submucous myomas, cornual tumor, and antero-posterior diameter ≤ 10 mm (radiologist 1: 86.4% versus 71.4%, 91.2% versus 67.7%, and 90.1% versus 81.1%, p = 0.048, 0.018, and 0.081, respectively; radiologist 2: 86.4% versus 64.3%, 88.2% versus 64.5%, and 87.0% versus 71.6%, p = 0.006, 0.023, and 0.019, respectively). Conclusion The OUA DCE-MRI protocol was superior to the OPA CE-MRI protocol in assessing the depth of MI of EC.

Objective This study was aimed to compare the oncologic outcomes of patients with non-endometrioid endometrial cancer who underwent minimally invasive surgery with the outcomes of patients who underwent open surgery. Method This is a retrospective, multi-institutional study of patients with non-endometrioid endometrial cancer who were surgically staged by either minimally invasive surgery or open surgery. Oncologic outcomes of the patients were compared according to surgical approach. Results 113 patients met the inclusion and exclusion criteria. 57 underwent minimally invasive surgery and 56 underwent open surgery. Patients who underwent minimally invasive surgery had smaller tumors (median size, 3.3 vs. 5.2%, p = 0.0001) and a lower lymphovascular space invasion rate (29.8% vs. 48.2%, p = 0.045). In the overall population, the numbers and rate of recurrence were significantly higher in the open surgery group (p = 0.016). In multivariate analysis, disease stage and tumor size were associated with DFS in contrast to surgical procedure. Conclusion Minimally invasive surgery showed similar survival outcomes when compared to open surgery in non-endometrioid endometrial cancer patients, irrespective of disease stage. When minimally invasive surgery is managed by expert surgeons, non-endometrioid histological subtypes should not be considered a contraindication for minimally invasive surgery.

Introduction The diagnostic role of lymph node (LN) assessment is established in endometrial cancer. Our study assesses whether surgical removal of metastatic LNs has oncologic benefit in high-grade endometrial cancer. Materials and methods High-grade endometrial cancer cases (2000–2010) were collected from two tertiary cancer centres. In patients with at least one positive LN, recurrence free survival (RFS) was compared by the number of LNs removed. Factors predicting nodal recurrence (NR) were explored. Univariate statistical analyses by log rank test and multivariable cox proportional hazards model were performed using SAS version 9.4. Results Of 570 patients identified, 334 patients underwent staging lymphadenectomy, 74 (22.2%) patients had at least one positive LN. The median RFS with at least one positive lymph node was 87.1 months (95% CI ≥ 14.3) when greater than 15 LNs were removed, compared to 16.9 months (95% CI, 13.6–35.6) and 17.3 months (95% CI, 8.5–39.8) when 5–15 and less than 5 LNs were removed, respectively (p = 0.02). In the cohort of 570 patients, there were 167 disease recurrences with location described on imaging, 98 (58.7%) had a NR and 69 (41.3%) recurred at other sites. Multivariable modeling identified that only positive LNs at surgical staging predicted NR (HR 3.8, 95% CI 1.4–10.2). Conclusion In high-grade endometrial cancer, positive LNs predict NR, and RFS is longer with a more extensive LN dissection in women with positive LNs. Future prospective studies should evaluate the oncologic benefit of surgical removal of metastatic LNs in high-grade endometrial cancer.

High-grade endometrial carcinoma (HGEC) is a heterogeneous group of tumors with various morphologic, genetic, and clinical characteristics. Morphologically, HGEC includes high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. The morphologic classification has been used for prognostication and treatment decisions. However, patient management based on morphologic classification is limited by suboptimal interobserver reproducibility, variable clinical outcomes observed within the same histotype, and frequent discordant histotyping/grading between biopsy and hysterectomy specimens. Recent studies from The Cancer Genome Atlas (TCGA) Research Network established four distinct molecular subtypes: POLE-ultramutated, microsatellite unstable, copy number high, and copy number low groups. Compared to histotyping, the TCGA molecular classification appears superior in risk stratification. The best prognosis is seen in the POLE-ultramutated group and the worst in copy number high group, while the prognosis in the microsatellite unstable and copy number low groups is in between. The TCGA subtyping is more reproducible and shows a better concordance between endometrial biopsy and resection specimens. It has now become apparent that the molecular classification can supplement histotyping in patient management. This article provides an overview of the pathologic diagnosis/differential diagnosis of HGEC and the TCGA classification of endometrial cancers, with the clinical significance and applications of TCGA classification briefly discussed when appropriate.

To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC).A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes.A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79).Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.

Universal screening of endometrial cancer for underlying Lynch syndrome (LS) using DNA mismatch repair immunohistochemistry (MMR IHC) has been recommended. The objective of this study was to assess the feasibility and outcomes of using office endometrial samplings in a community LS screening program.A community laboratory adopted Cancer Care Ontario's LS screening recommendations. All new endometrial cancers in women aged70 years were screened for LS using MMR IHC and MLH1 promoter methylation testing cascade for MLH1/PMS2-deficient cases. This retrospective validation study analyzes the first year's results.Of 693 new endometrial cancers, 467 (67.4%) were eligible for LS screening. Both MMR IHC and MLH1 promoter methylation testing were conclusive in98% of cases. MMR deficiency (MMRd), which includes LS screen-positive cases, was identified in 25.9% of patients (121/467). LS screen-positive tumours comprised 5.9% (27/467) of all cases.Endometrial samplings from community practice are suitable for pre-operative LS screening. This testing can identify MMRd endometrial cancers with significant prognostic implications. Approximately 1 in 20 Ontario women70 years of age with endometrial cancer screen positive for LS. Pre-operative and/or operative assessment for co-existent colonic neoplasms needs to be considered in this high-risk group. In addition, these women should be referred to genetic counselling.

The adjuvant and post-surgical treatment of gynaecological cancers has historically been guided by the estimation of relapse risk based on clinicopathological factors determined at the time of cancer diagnosis. The recent advancement of genomic and molecular characterisation of gynaecological cancers has begun to shift paradigms in the selection of adjuvant treatment strategy. Recent data regarding the predictive and/or prognostic value of molecular tests in the treatment of advanced ovarian cancer as well as early stage endometrial cancer have been the first such examples to enter adjuvant treatment guidelines for these diseases. In this article, we discuss the current state and future development of molecular assays for gynaecological cancers and how they impact upon treatment selection for ovarian, endometrial and cervical cancers in the post-surgical setting.

Endometrial cancer (EC) usually presented as a localized disease at diagnosis (67%), 20% of patients diagnosed with regional spread, and distant metastasis accounted for 9%. The standard treatments include hysterectomy, bilateral salpingo-oophorectomy, and pelvic with/without paraaortic lymph node dissection/biopsy. Adjuvant therapy is arranged according to risk factors and stages. Risk group classification varied among different guidelines and studies and evolved with time. Adjuvant modalities include chemotherapy, radiotherapy, chemoradiotherapy, antiangiogenesis agents, immune checkpoint inhibitors, and multi-target agents. We review the recent literature to incorporate important advances in trial results, real-world big data, and knowledge in biomarkers of EC to update appropriate adjuvant therapy and post-surgical treatment of EC patients.

Objective To evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC). Methods Data of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. Results Records of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7–117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5–44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1–56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery. Conclusions In apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.

Objectives: We examined the use and long-term outcomes of vaginal hysterectomy for women with early-stage endometrial cancer. Methods: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify women with stage I-II endometrial cancer treated with primary hysterectomy from 2000-2015. Multivariable models were developed to examine clinical, demographic, and pathologic factors associated with performance of TVH. The association between route of hysterectomy and cancer specific and overall survival was examined using multivariable Cox proportional hazards models. Results: A total of 19,212 patients including 837 (4.6%) who underwent TVH were identified. Performance of vaginal hysterectomy declined from 4.5% in 2000 to 2.2% in 2015 (P 80 years old (aRR=1.60; 95% CI, 1.30-1.97) were more likely to undergo TVH. There was no association between either overall co-morbidity (Charlson index) or any individual comorbidities and performance of TVH. Women with high grade tumors were less likely to undergo TVH. Five-year survival was 78.4% (95% CI: 77.6-79.2) in those who underwent abdominal hysterectomy, 83.3% (95% CI: 82.1-84.4) in those who had a laparoscopic hysterectomy and 80.9% (95% CI: 77.8-83.5) in those who underwent TVH. In multivariable models, there was no adverse impact between TVH and either overall (HR=1.06; 95% CI, 0.94-1.19) or cancer-specific (HR=0.95; 95% CI, 0.70-1.28) survival. Download : Download high-res image (83KB) Download : Download full-size image Conclusions: Use of vaginal hysterectomy for stage I/II endometrial cancer has decreased in the U.S. Chronologic age is the greatest predictor of performance of TVH. Performance of TVH does not negatively impact survival for women with early-stage endometrial cancer.

Study Objective Preoperative detection of uterine leiomyosarcoma is important in hysterectomies performed for presumed benign indications. This study examined the effectiveness of endometrial sampling for preoperative diagnosis of leiomyosarcoma and the factors associated with a false negative. Design This is a retrospective analysis of linked data from the New York Statewide Planning and Research Cooperative System and the New York State Cancer Registry. Using procedure codes, we identified women who underwent preoperative endometrial sampling and hysterectomy in 2003-2015. We further limited the sample to women who had a subsequent diagnosis of uterine leiomyosarcoma based on histology, site and behavioral codes. We estimated the proportion of patients whose leiomyosarcoma was diagnosed preoperatively, and compared their characteristics with patients whose leiomyosarcoma was missed preoperatively (i.e., diagnosed postoperatively) using chi-square/Fisher's exact test and Wilcoxon rank sum test. Setting Inpatient and outpatient encounters at civilian hospitals and ambulatory surgery centers in New York state. Patients or Participants 79 adult women with leiomyosarcoma who underwent endometrial sampling (biopsy or dilation and curettage) within 90 days before hysterectomy. Interventions N/A Measurements and Main Results Among the 79 patients with leiomyosarcoma, 46 (58.2%) were diagnosed preoperatively, whereas 33 (41.8%) were diagnosed postoperatively. Patients diagnosed postoperatively did not differ significantly from those diagnosed preoperatively in cancer stage, grade, age, bleeding symptoms, or comorbidities. However, tumor size was larger among patients who were diagnosed postoperatively than those diagnosed preoperatively (median=12 versus 9 centimeters, p=0.04). The rate of preoperative diagnosis was higher among patients who underwent sampling with hysteroscopic guidance (66.7%) than sampling without hysteroscopic guidance (31.6%) (p=0.007). Among patients diagnosed postoperatively, 21.2% underwent a supracervical hysterectomy, compared to 0% among those diagnosed preoperatively (p=0.002). Conclusion Endometrial sampling was instrumental in diagnosing approximately half of uterine leiomyosarcomas preoperatively, which was more commonly achieved with hysteroscopic guidance.

The World Health Organization endorses molecular subclassification of endometrial endometrioid carcinomas (EECs). Our objectives were to test the sensitivity of tumor morphology in capturing p53 abnormal (p53abn) cases and to model the impact of p53abn on changes to ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology) risk stratification. A total of 292 consecutive endometrial carcinoma resections received at Foothills Medical Centre, Calgary, Canada (2019–2021) were retrieved and assigned to ESGO risk groups with and without p53 status. Three pathologists reviewed the representative H&E‐stained slides, predicted the p53 status, and indicated whether p53 immunohistochemistry (IHC) would be ordered. Population‐based survival for endometrial carcinomas diagnosed during 2008–2016 in Alberta was obtained from the Alberta Cancer Registry. The cohort consisted mostly of grade 1/2 endometrioid carcinomas (EEC1/2; N = 218, 74.6%). One hundred and fifty‐two EEC1/2 (52.1% overall) were stage IA and 147 (50.3%) were low risk by ESGO. The overall prevalence of p53abn and subclonal p53 was 14.5 and 8.3%, respectively. The average sensitivity of predicting p53abn among observers was 83.6%. Observers requested p53 IHC for 39.4% with 98.5% sensitivity to detect p53abn (99.6% negative predictive value). Nuclear features including smudged chromatin, pleomorphism, atypical mitoses, and tumor giant cells accurately predicted p53abn. In 7/292 (2.4%), p53abn upgraded ESGO risk groups (2 to intermediate risk, 5 to high risk). EEC1/2/stage IA patients had an excellent disease‐specific 5‐year survival of 98.5%. Pathologists can select cases for p53 testing with high sensitivity and low risk of false negativity. Molecular characterization of endometrial carcinomas has great potential to refine ESGO risk classification for a small subset but offers little value for approximately half of endometrial carcinomas, namely, EEC1/2/stage IA cases.

Objective The evaluation of women with perimenopausal abnormal uterine bleeding (AUB) and postmenopausal bleeding (PMB) to detect endometrial cancer (EC) and its precursors is not standardized and can vary widely. Consequently, costs associated with the workup and management undoubtedly vary. This study aimed to quantify costs of AUB/PMB evaluation to understand the healthcare burden associated with securing a pathologic diagnosis. Methods Women ≥45 years of age presenting to a single institution gynecology clinic with AUB/PMB for diagnostic workup were prospectively enrolled February 2013–October 2017 for a lower genital tract biospecimen research study. Clinical workup of AUB/PMB was determined by individual provider discretion. Costs of care were collected from administrative billing systems from enrollment to 90 days post enrollment. Costs were standardized and inflation-adjusted to 2017 US Dollars (USD). Results In total, there were 1017 women enrolled with 5.6% diagnosed with atypical hyperplasia or endometrial cancer (EC). Within the full cohort, 90-day median cost for AUB/PMB workup and management was $2279 (IQR $512–4828). Among patients with a diagnostic biopsy, median 90-day costs ranged from $2203 (IQR $499–3604) for benign or disordered proliferative endometrium (DPE) diagnosis to $21,039 (IQR $19,084-24,536) for a diagnosis of EC. Conclusions The costs for diagnostic evaluation of perimenopausal AUB and PMB vary greatly according to ultimate tissue-based diagnosis. Even reassuring benign findings that do not require further intervention—the most common in this study's cohort—yield substantial costs. The development of sensitive, specific, and more cost-effective diagnostic strategies is warranted.

Objective To compare oncological outcomes in women with lower uterine segment involvement (LUSI) in endometrial carcinoma (EC) stage ≥ II - staged by a minimally invasive surgery (MIS) versus laparotomy. Study design A retrospective multi-center cohort study. Univariate analysis, Kaplan-Meier survival and Cox proportional hazard analysis were performed to compare between women staged by MIS and those staged by laparotomy. Results Over a median follow-up period of 3 years (interquartile range, 1.5–6 years) 212 women were included, 68 (32.1%) were surgically staged by MIS. Stages of disease did not vary between MIS and laparotomy and were 32.1%, 51.9%, and 16.0%, in stages II, III and IV – respectively. Adjuvant radiation and chemotherapy rate did not differ between groups. Overall recurrence rate was comparable (p = 0.084). Locoregional recurrence rate was higher in the MIS group odds ratio 2.17, 95% confidence interval 1.19–4.20). Overall and progression free survival were similar in both groups (log rank test p = 0.08 and p = 0.912 respectively). In Cox regression model adjusting for age, comorbidities, tumor grade, stage and adjuvant therapy, route of surgery (MIS vs. laparotomy) was not associated with overall survival (p = 0.169). Conclusions In women with advanced EC and LUSI, although MIS is associated with locoregional recurrences, survival is comparable to laparotomy.

Objective The study aimed to evaluate site‐specific recurrent patterns via competing risks analysis and hazard function to provide evidence for adjuvant treatment and follow‐up for early staged endometrial cancer (EC). Methods A total of 858 patients with International Federation of Gynecology and Obstetrics stage I–II EC who received adjuvant radiotherapy at our institution (2000–2017) were included. The radiotherapy modality comprised external beam radiotherapy (EBRT) with or without vaginal brachytherapy (VBT) or VBT alone. Competing risks analysis and hazard rate function were employed to evaluate the recurrence rate according to the ESMO–ESGO–ESTRO risk classification. Results The 5‐year overall survival rates of the low‐risk (LR), intermediate‐risk (IR), high–intermediate risk (HIR), and high‐risk (HR) groups were 96.1%, 95%, 93%, and 89.7%, respectively (p = 0.018). Sixty‐eight patients developed recurrence. The 5‐year incidence of distant recurrence was the highest in the HR group (14.87%), followed by the HIR (7.71%), IR (5.27%), and LR (1.26%) groups (Gray's test, p, The recurrence pattern of endometrial cancer is affected by risk groups and adjuvant treatment. The time‐varying competing risk analysis and hazard function modeling were established. The site‐specific recurrence patterns differed across the risk classification and adjuvant radiotherapy modality. More intense and targeted follow‐up schedules should be administrated to the high‐risk group.

To examine trends and outcomes related to sentinel lymph node (SLN) biopsy for stage II endometrial cancer.This is a retrospective observational cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 6,314 women with T2 endometrial cancer who underwent hysterectomy from 2010-2018. Exposure allocation was based on nodal evaluation type: lymphadenectomy (LND; n=4,915, 77.8%), SLN biopsy (n=340, 5.4%), or no surgical nodal evaluation (n=1,059, 16.8%). The main outcomes were (i) trends and characteristics related to nodal evaluation assessed by multinomial regression, and (ii) overall survival (OS) assessed by an inverse probability of treatment weighting propensity score analysis. A sensitivity analysis was performed to examine concurrent LND in women who underwent SLN biopsy.The utilization of SLN biopsy increased from 1.6% to 16.1%, while the number of LND decreased from 81.5% to 65.7% between 2010-2018 (P0.05). In multivariable analysis, the utilization of SLN biopsy increased 45% annually (adjusted-odds ratio 1.45, 95% confidence interval [CI] 1.37-1.54, P0.001). The frequency of SLN biopsy alone exceeded the frequency of SLN biopsy with concurrent LND in 2017 (6.8% versus 3.4%), followed by continued increase in SLN biopsy alone (11.2% versus 4.9%) in 2018. In the weighted model, the 3-year OS rate was 79.9% for the SLN biopsy group and 78.6% for the LND group (hazard ratio 0.98, 95%Cl 0.80-1.20, P=0.831). Similarly, the SLN biopsy alone without concurrent LND had comparable OS compared to the LND group (hazard ratio 0.90, 95%CI 0.59-1.36, P=0.615).Utilization of SLN biopsy in stage II endometrial cancer increased significantly over time, and SLN biopsy-incorporated nodal assessment was not associated with worsened short-term survival outcome.

Objective: Dual-specificity phosphatase 6 (Dusp6) was proposed as a predictive marker of response of atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC) to conservative treatment. However, its predictive accuracy has never been calculated. We aimed to define it in conservatively treated AEH and EEC. Methods: All patients

PurposeThe efficacy of programmed cell death protein 1(PD-1)/Programmed cell death 1 ligand 1 (PD-L1) inhibitors for endometrial cancer remain controversial, and guidelines are unconsistent on which are preferred theropies for advanced disease, or who develop metastases and recurrence. Therefore we aimed to estimate the efficacy and safety of PD-1/PD-L1 inhibitors in endometrial cancer on a more complete database by adding multiple randomized trials. Methods:A systematic and comprehensive search was carried out in PD-1/PD-L1 inhibitors monotherapy. Results: The ORR of PD-1/PDL-1 inhibitors was 29%, and subgroup analysis showed that the pooled ORR of the proficient mismatch repair (pMMR) group was 4% and which was 45% of the deficient mismatch repair (dMMR) group. The DCR of PD-1/PD-L1 inhibitors was 48%, through subgroup analysis, we found that DCR of the pMMR group was 21% and which was 58% of the dMMR group. The proportion of patients occurring overall adverse events was 65% and grade three or higher adverse events was 14%. The proficient mismatch repair (pMMR) group and the deficient mismatch repair (dMMR) group showed different results. Conclusion: PD-1/PD-L1 inhibitors had shown little success in the pMMR population and better efficacy in the dMMR population.

Background: The impact of weight change, physical activity, and sedentary behavior on endometrial cancer risk among the Asian population is uncertain. We investigated the association of those factors with endometrial cancer risk among Japanese women with a low body mass index level. Methods: We performed a large-scale nationwide cohort study consisting of 33,801 female participants aged 40–79 years. The Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident endometrial cancer. Results: The mean body mass index of participants was 22.8 kg/m2. During a median follow-up of 14.8 years, 79 participants developed endometrial cancer. After adjustment for potential confounding factors, body mass index over 23.0 kg/m2 was linearly associated with the risk of endometrial cancer. The HR per 5 kg/m2 increase was 1.80 (95% CI, 1.28–2.54). Weight increment ≥+5 kg since age 20 was associated with an increased risk of endometrial cancer compared to a weight change of −5 to

Lymph node (LN) evaluation in endometrial cancer is controversial. Sentinel lymph node biopsy (SLNB) allows for an accurate nodal assessment while minimising the risks of a full pelvic lymph node dissection (PLND). The aims of this study are to examine the characteristics and peri-operative outcomes of women with atypical hyperplasia (AH) or endometrial cancer undergoing robotic-assisted hysterectomy (RAH) ± SLNB or PLND; to examine the utilisation, feasibility and role of SLNB and compare their peri-operative outcomes. Retrospective cohort study from December 2018 to February 2021 of women who underwent RAH ± LN assessment for endometrial cancer or AH. 115 women underwent RAH. 59% had SLNB, 29% had no LN assessment, and 12% had PLND. The final diagnosis was mostly early stage low-grade disease; Stage 1A-50%, Grade 1 endometrioid adenocarcinoma (EAC)-56%. The detection rate was 90%. There was a statistically significant trend towards performing SLNB over time (P value 0.004). There was a statistically shorter length of stay, less estimated blood loss, and shorter surgical duration in the SLNB cohort, compared to the no LN assessment cohort (P values 0.02, 0.01, and 0.03, respectively). There was statistically significant less estimated blood loss and surgical duration in the SLNB compared to the PLND cohort (P values 0.03 and 0.001, respectively). SLNB at RAH was utilised and feasible. It was safe with a low complication rate and had advantages compared to PLND cohort. SLNB should be considered in suitable selected women undergoing surgery for endometrial cancer or AH.

To develop and validate a comprehensive overall survival (OS) risk-scoring model in women with endometrioid endometrial cancer (EC).Patients with EC diagnosed from 2004 to 2013 were identified through the National Cancer Database (NCDB). Patients with known lymphovascular space invasion (LVSI) status who were treated surgically (with or without adjuvant therapy) were included. Cox proportional hazards analysis was used to identify prognostic factors for OS. This model was used to assign points based on hazard ratios for risk factors and a risk score was obtained. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups. Results were internally validated in a cohort of patients from our institution (CCF cohort). Risk scores were calculated and assessed in a Cox regression model, and Harrell's c-index was calculated to assess model fit.Among 349,404 women with EEC during the study period, 42,107 fulfilled inclusion criteria. Factors associated with worse OS were age ≥ 60, African American race, Charlson-Deyo score 1 or 2+, higher grade, LVSI, tumor size ≥2 cm, and no lymphadenectomy performed. Six risk groups were identified (scores 0-30) and OS estimated for each risk group. Risk score per 1-point increase in HR were comparable between NCDB and CCF cohorts (HR 1.21 (1.20-1.22 p 0.001 vs 1.18 (1.12-1.25), p 0.001), and c-index 0.80 (0.79-0.81) vs. 0.77 (0.68-0.86). Similar analysis was done in stage IA and IB. Adjuvant therapy had a beneficial effect on survival in the majority of stage IB patients, but only one of the six risk groups in stage IA EC.We report a comprehensive validated OS risk-scoring model for patients with.

Background: The present paper reports on analysis of 184 patients who were diagnosed with endometrial cancer. The main objective of this study was to address parameter V rec(30Gy) which determines a volume of the rectum irradiated with a dose of 30 Gy during radiotherapy. Material and methods: All patients were irradiated with an IMRT technique on linear accelerators. The planning target volume (PTV) contour was determined by a radiation oncologist. The clinical target volume (CTV) was drawn on CT images obtained in a prone position. For statistical analysis, appropriate tests (e.g. the Shapiro-Wilk, Wilcoxon) were used. Results and discussion: The performed analysis showed that the recommended condition for V rec(30Gy) is met only in 3% of patients and the observed median value exceeds 90%. The obtained results were compared with the studies in which the V rec(30Gy) values were related to various radiotherapy techniques. Conclusions: The analysis showed that the condition for V rec(30Gy) is satisfied in the case of only 3% of patients. Due to the difficulty with meeting the condition, it should be reconsidered based on real results.

Uterine serous carcinoma accounts for 3–10% of endometrial cancers, but it is the most lethal histopathological subtype. The molecular characterization of endometrial carcinomas has allowed novel therapeutic approaches for these patients. We undertook a retrospective analysis of patients with uterine serous carcinomas treated in our hospital within the last two decades to identify possible changes in their management. The patients and their characteristics were evenly distributed across the two decades. Treatment modalities did not change significantly throughout this period. After adjuvant treatment, patients’ median disease-free survival was 42.07 months (95% CI: 20.28–63.85), and it did not differ significantly between the two decades (p = 0.059). The median overall survival was 47.51 months (95% Cl: 32.18–62.83), and it significantly favored the first decade’s patients (p = 0.024). In patients with de novo metastatic or recurrent disease, median progression-free survival was 7.8 months (95% Cl: 5.81–9.93), whereas both the median progression-free survival and the median overall survival of these patients did not show any significant improvement during the examined time period. Overall, the results of our study explore the minor changes in respect of uterine serous carcinoma’s treatment over the last two decades, which are reflected in the survival outcomes of these patients and consequently underline the critical need for therapeutic advances in the near future.

BackgroundPembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy.Primary ObjectiveTo compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease.Study HypothesisPembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers).Trial DesignPhase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no).Major Inclusion/Exclusion CriteriaAdults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded.Primary EndpointsProgression-free and overall survival (dual primary endpoints).Sample SizeAbout 875 patients.Estimated Dates for Completing Accrual and Presenting ResultsEnrollment is expected to take approximately 24 months, with presentation of results in 2022.Trial RegistrationClinicalTrials.gov, NCT03884101.

Insulin resistance and hyperinsulinemia play a key role in type 1 endometrial cancer pathogenesis. Most of these cancers develop on a background of overweight or type 2 diabetes mellitus (T2DM). One of the medications widely used in the treatment of T2DM is biguanide derivative, metformin, which exerts promising anticancer properties principally through activation of adenosine monophosphate kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) pathways. Many epidemiological studies on diabetic patients show potential preventative role of metformin in endometrial cancer patients, but data regarding its therapeutic role is still limited. So far, most of attention has been paid to the concept of metformin use in fertility sparing treatment of early-stage cancer. Another investigated alternative is its application in patients with primary advanced or recurrent disease. In this review we present the latest data on clinical use of metformin in endometrial cancer patients and potential underlying mechanisms of its activity. Finally, we present some most important clinical information regarding metformin efficacy in other gynaecological malignancies, mainly breast and ovarian cancer.

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest, differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase, histone deacetylase inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising therapeutic agents in the treatment of patients with endometrial cancer.

Background Microsatellite instability-high is a known biomarker for anti-PD-1/PD-L1 immune checkpoint therapy. It is also a known tumour feature of Lynch syndrome, detected most frequently in endometrial cancer. However, it remains unclear how microsatellite instability testing is carried out in the clinical field. Methods Ninety-nine patients with gynaecological malignant tumours who underwent microsatellite instability testing as a companion diagnosis for pembrolizumab and 16 patients who previously underwent microsatellite instability testing as a screening for Lynch syndrome were recruited. Clinical information, microsatellite instability status, outcomes, genetic assessments and information about cancer tissue were retrospectively analysed. Results Ninety-nine patients had 101 gynaecologic malignant tumours including 26 endometrial, 38 ovarian and 28 cervical cancers, 9 with other tumours including 2 synchronous endometrial and ovarian cancers. All tissue samples were successfully tested, even though some were ≥10-year-old samples. Three cases (3.0%, 3/99) showed microsatellite instability-high; all cases were endometrial cancers with one case of synchronous endometrial and ovarian cancer [11.5% (3/26) in endometrial cancer, 2.6% (1/38) in ovarian cancer], and there was no microsatellite instability-high in cervical and other cancers. One of the endometrial cancer patients received pembrolizumab treatment, but finally died of cancer. Two other cases underwent genetic testing; both were diagnosed as Lynch syndrome. Six cases (37.5%) showed microsatellite instability-high in screening for Lynch syndrome. Conclusions Microsatellite instability-high was less commonly detected as a companion diagnosis for pembrolizumab in unselected gynaecologic patients. Genetic counselling should be always provided along with treatment selection.

INTRODUCTION The objective of this study was to assess the diagnostic utility of CD10 in the differential diagnosis of grade 1-endometrial endometrioid carcinoma (G1-EEC) and the metaplastic changes associated with the endometrial glandular and stromal breakdown (EGBD) on liquid-based cytological (LBC) samples. METHODS (1) The type and distribution of CD10-positive cells in EGBD and G1-EEC patients were evaluated. (2) Based on the results from (1), histological and cytological specimens were double-immunostained with CD31 and CD10 to confirm whether CD10-positive tubular-canalicular material found in (1) was represented by fine threads of endometrial-type fibrovascular stroma. (3) Based on the results from (2), additional immunostaining of histological specimens was performed for CD146 and αSMA as markers of perivascular cells. RESULTS (1) CD10 positive cells showed two main patterns of expression: cytoplasmic immunoreactivity in the form of dense brown granules in EGBD and tubular-canalicular branching patterns in G1-EEC. (2) The tubular-canalicular material observed in cytological specimens of G1-EEC samples co-expressed CD10 and CD31, and was interpreted as representing fine threads of endometrial fibrovascular stroma in the corresponding histological samples. Conversely, metaplastic changes in EGBD cases, only a few CD31-positive signals were found inside the condensed stromal clusters with CD10-positive. (3) Cells surrounding the CD31-positive vascular endothelial cells expressed CD146 and αSMA; moreover, some of the thin CD10-positive fibrous stromal strands also co-expressed αSMA. CONCLUSIONS CD10 is a very useful immunomarker for distinguishing between G1-EEC and the metaplastic changes of EGBD in LBC samples.

Objective To compare disease-free survival between minimally invasive surgery and open surgery in patients with high-risk endometrial cancer. Methods We conducted a multicentric, propensity-matched study of patients with high-risk endometrial cancer who underwent hysterectomy, bilateral salpingo-oophorectomy, and staging between January 1999 and June 2016 at two centers. High-risk endometrial cancer included grade 3 endometrioid, serous, clear cell, undifferentiated carcinoma or carcinosarcoma with any myometrial invasion. Patients were categorized a priori into two groups based on surgical approach, propensity scores were calculated based on potential confounders and groups were matched 1:1 using nearest neighbor technique. Cox hazard regression analysis and Kaplan-Meier curves evaluated the association of surgical technique with survival. Results Of 626 eligible patients, 263 (42%) underwent minimally invasive surgery and 363 (58%) underwent open surgery. In the matched cohort, there were no differences in disease-free survival rates at 5 years between open (53.4% [95% CI 45.6-60.5%]) and minimally invasive surgery (54.6% [95% CI 46.6-61.8]; P=.82). Minimally invasive surgery was not associated with worse disease-free survival (hazard ratio [HR] 0.85, 95% CI 0.63-1.16; P=.30), overall survival (HR 1.04, 95% CI 0.73-1.48, P=.81), or recurrence rate (HR 0.99; 95% CI 0.69-1.44; P=.99) compared with open surgery. Use of uterine manipulator was not associated with worse disease-free survival (HR 1.01, 95% CI 0.65-1.58, P=.96), overall survival (HR 1.18, 95% CI 0.71-1.96, P=.53), or recurrence rate (HR 1.12, 95% CI 0.67-1.87; P=.66). Conclusion There was no difference in oncologic outcomes comparing minimally invasive and open surgery among patients with high-risk endometrial cancer.

BackgroundSentinel node biopsy is a surgical technique to explore lymph nodes for surgical staging of endometrial cancer, which has replaced full retroperitoneal lymph node dissection. However, the effectiveness of sentinel node biopsy, its value to patients, and potential harms compared with no-node dissection have never been shown in a randomized trial.Primary ObjectivesStage 1 will test recovery from surgery. Stage 2 will compare disease-free survival at 4.5 years between patients randomized to sentinel node biopsy versus no retroperitoneal node dissection.Study HypothesisThe primary hypothesis for stage 1 is that treatment with sentinel node biopsy will not cause detriment to patient outcomes (lymphedema, morbidity, loss of quality of life) and will not increase treatment-related morbidity or health services costs compared with patients treated without a retroperitoneal node dissection at 12 months after surgery. The primary hypothesis for stage 2 is that disease-free survival at 4.5 years after surgery in patients without retroperitoneal node dissection is not inferior to those receiving sentinel node biopsy.Trial DesignThis phase III, open-label, two-arm, multistage, randomized non-inferiority trial (ENDO-3) will determine the value of sentinel node biopsy for surgical management of endometrial cancer. Patients with endometrial cancer are randomized to receive: (1) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy with sentinel node biopsy or (2) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection. In stage 1, 444 patients will be enrolled to demonstrate feasibility and quality of life. If this is demonstrated, we will enroll another 316 patients in stage 2.Major Inclusion and Exclusion CriteriaInclusion criteria include women aged 18 years or older with histologically confirmed endometrial cancer; clinical stage 1, who meet the criteria for laparoscopic or robotic total hysterectomy and bilateral salpingo-oophorectomy. Patients with uterine mesenchymal tumors are excluded.Primary EndpointsThe endpoint for stage 1 is surgical recovery, with the proportion of patients returning to usual daily activities at 3 months post-surgery as measured with the EQ-5D. Stage 2 is disease-free survival at 4.5 years.Sample Size760 participants (both stages).Estimated Dates for Completing Accrual and Presenting ResultsStage 1 commenced in January 2021 and is planned to be completed in December 2024 when 444 participants have completed 12 months' follow-up. Stage 2 will enroll a further 316 participants for a total of 760 patients.Trial RegistrationNCT04073706.

Objective: To define the factors that determine survival after extrapelvic recurrence in patients with endometrioid type endometrial cancer (EC).objective Materials and methods: Clinicopathological and survival data of surgically treated endometrioid type EC patients who recurred outside pelvis were reviewed. Patients who had non-endometrioid tumor, sarcomatous component in the final pathology and synchronous tumor were excluded. The period from surgery to recurrence was defined as time to recurrence (TTR) and the period from recurrence to death or last visit was defined as post-recurrence survival (PRS). Results: Sixty-six patients with extrapelvic recurrence were included in the study. No residual disease was achieved in all patients at initial surgery. Median TTR was 18 months (range, 2–84). Recurrence developed within 1 year in 24 (36.4%) patients and between 13 and 24 months in 22 (33.3%) patients. Fifty-three of 66 patients (80.3%) had extraabdominal recurrence. The 2-year PRS of the all cohort with extrapelvic recurrence was 56%. In the univariate analysis, advanced FIGO stage, lymph node metastasis, adnexal metastasis and short TTR were associated with diminished PRS (p

Background Surgeons sometimes have difficulty determining which result to favor when preoperative results (MRI + preoperative endometrial biopsy [pre-op EB]) differ from intraoperative frozen section histology (FS) results. Investigation of how FS can complement ordinary preoperative examinations like MRI and pre-op EB in identification of patients at high risk of lymph node metastasis (high-risk patients) could provide clarity on this issue. Therefore, the aim of this study is to assess the utility of pre-op EB, MRI and FS results and determine how to combine these results in identification of high-risk patients. Methods The subjects were 172 patients with endometrial cancer. Patients with a histological high-grade tumor (HGT), namely, grade 3 endometrioid cancer, clear cell carcinoma or serous cell carcinoma, or with any type of cancer invading at least half of the uterine myometrium were considered high-risk. Tumors invading at least half of the uterine myometrium were classified as high-stage tumors (HST). We compared (a) detection of HGT using pre-op EB versus FS, (b) detection of HST using MRI versus FS, and (c) identification of high-risk patients using MRI + pre-op EB versus FS. Lastly, we determined to what degree addition of FS results improves identification of high-risk patients by routine MRI + pre-op EB. Results (a) Sensitivity, specificity, and accuracy for detecting HGT were 59.6, 98.4 and 87.8% for pre-op EB versus 55.3, 99.2 and 87.2% for FS (P = 0.44). (b) These figures for detecting HST were 74.4, 83.0 and 80.8% for MRI versus 46.5, 99.2 and 86.0% for FS (P < 0.001). (c) These figures for identifying high-risk patients were 78.3, 85.4 and 82.6% for MRI + pre-op EB versus 55.1, 99.0 and 81.2% for FS (P < 0.001). The high specificity of FS improved the sensitivity of MRI + pre-op EB from 78.3 to 81.2%, but this difference was not statistically significant (P < 0.16). Conclusion Frozen section enables identification of high-risk patients with nearly 100% specificity. This advantage can be used to improve sensitivity for identification of high-risk patients by routine MRI + pre-op EB, although this improvement is not statistically significant.

PURPOSE: Despite widespread provision of Lynch syndrome (LS) screening programs, questions remain about the most effective and efficient protocol for LS case finding. The purpose of this study was to explore the performance of the two protocols widely shown to be the most efficient and effective, respectively: immunohistochemical (IHC) staining of tumor and direct-to-sequencing (DtS) in endometrial cancer populations. METHODS: Simulation models were developed to explore performance of the IHC and DtS protocols, updated to reflect current evidence. Analyses explicitly account for protocol complexity and failure points, as well as decreased sequencing costs. Key outcomes are percent of LS cases identified, total protocol costs and efficiency, and break-even analyses of sequencing costs. All costs are in 2020 US dollars (USD). RESULTS: Under plausible conditions, the IHC protocol is expected to identify 40%-78% of LS cases and DtS protocol from 49% to 97%. When the key variable success in proceeding to sequencing is fixed for both protocols at 50%, 75%, and 100%, the DtS protocol is 9%, 12%, and 16% better at case finding, respectively, than the IHC protocol. The break-even cost of sequencing is about $488 USD when the outcome is total direct testing protocol costs; it is about $670 USD when the outcome is cost per LS case detected. CONCLUSION: This study quantifies the plausible differences in the clinical effectiveness and cost-effectiveness of the two LS case-finding protocols. We demonstrate the large influence of success in proceeding to sequencing and potential impact of decreasing sequencing prices.

OBJECTIVE To investigate factors predicting the risk of developing 90-day postoperative complications and lymphatic-specific morbidity in patients undergoing surgical staging for high-risk endometrial cancer. METHODS This is a multi-institutional retrospective cohort study. Patients affected by apparent early-stage high-risk endometrial cancer (endometrioid FIGO grade 3 with deep myometrial invasion and non-endometrioid endometrial cancer) undergoing surgical staging between 2007 and 2019. Complications were graded according to the Clavien-Dindo classification system. Martin criteria were applied to improve quality of complications reporting. RESULTS Charts of 279 patients were evaluated. Lymphadenectomy, sentinel node mapping (SNM), and SNM followed by back-up lymphadenectomy were performed in 83 (29.7%), 50 (17.9%), and 146 (52.4%) patients, respectively. The former group of patients included 13 patients who had lymphadenectomy after the failure of the SNM technique. Thirteen (4.6%) patients developed severe postoperative events (grade 3 or worse). At multivariate analysis, body mass index (OR: 1.08 (95%CI: 1.01, 1.17)) and open abdominal surgery (OR: 2.27 (95%CI: 1.02, 5.32)) were the two independent factors predictive of surgery-related morbidity. Seven severe lymphatic complications occurred. The adoption of laparoscopic approach (p��

Objective To describe the practice patterns and outcomes of patients with stage 3B endometrial cancer. Methods We queried the National Cancer Database for all surgically staged, stage 3 patients between 2012 and 2016. Patients who received any pre-operative therapy were excluded. Demographics, tumor factors, and adjuvant therapy for the stage 3 substages were compared. Logistic regression was used to identify factors associated with adjuvant therapy. Kaplan Meier curves were generated and compared using the log-rank test. Multivariable Cox Proportional Hazards Model was used to adjust for prognostic factors. Findings with p Results Of 7363 patients with stage 3 disease, 478 (6%) had stage 3B; 1732 (23%) had stage 3A, 3457 (48%) had stage 3C1, and 1696 (23%) had stage 3C2 disease. Post-surgical treatment consisted of: combined chemotherapy (CT) and radiation (RT) (49%), CT alone (28%), RT alone (9%), 14% received no postoperative therapy. Among all stage 3 substages, patients with stage 3B disease were the least likely to receive any CT, and the most likely to receive RT alone. After adjusting for known prognostic factors, patients with stage 3A (Hazard ratio (HR) of death = 0.64) and 3C1 (HR of death = 0.79) disease had significantly worse overall survival compared to stage 3B; survival was not demonstrably different from patients with stage 3C2 disease. Patients with stage 3B disease who received CT + RT had the best overall survival. Conclusion Survival of patients with stage 3B disease is similar to that of patients with para-aortic node metastases and is inferior to all others with stage 3 endometrial cancer. Less frequent CT and a higher rate of post-operative RT alone, describes a distinct practice from that seen in other stage 3 patients.

Summary In humans, atypical endometrial hyperplasia (AEH) is considered as a precancerous lesion of endometrial adenocarcinoma (EA), from which it must be distinguished. Precancerous lesions have not been reported in cats with EA. We now document the histopathological features of endometrial lesions in six cats, which histopathologically resembled human AEH and had a good prognosis following ovariohysterectomy. Grossly, one cat presented with papillomatous nodules and three cats had pyometra. Histopathologically, proliferation of endometrial epithelial cells without atypia was observed in all cases. In some regions of the endometrium, cells had increased atypia and were arranged in stratified layers, which formed irregular ducts and papillary structures. No invasive behaviour or vascular invasion was observed. On the basis of these findings, the cats were diagnosed with non-invasive or early-stage adenocarcinoma. Immunohistochemistry for oestrogen receptor and progesterone receptor revealed an inverse correlation with the severity of the endometrial lesions and degree of malignancy of tumour cells. Ki67 labelling revealed that mitotic activity increased as the lesion developed. All cats survived, with a median survival time of 385 days (range: 229–744 days). The distribution of the histopathological endometrial changes and the non-invasive behaviour in these feline cases resemble cases of AEH in humans.

ObjectiveEndometrial cancer prognosis is related to stage, histology, myometrial invasion, and lymphovascular space invasion. Several studies have examined the association between pretreatment thrombocytosis and patient outcomes with contrasting results regarding prognosis. Our aim was to evaluate the association of pretreatment platelet count with outcomes in endometrial cancer patients.MethodsThis is an Israeli Gynecologic Oncology Group multicenter retrospective cohort study of consecutive patients with endometrial cancer, who underwent surgery between January 2002 and December 2014. Patients were grouped as low risk (endometrioid G1-G2 and villoglandular) and high risk (endometrioid G3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma). Those with stage I disease were compared with stages II–IV. Disease stages were reviewed and updated to reflect International Federation of Gynecology and Obstetrics (FIGO) 2009 staging. All patients underwent pelvic washings for cytology and total abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Pelvic lymph node assessment was performed in patients with tumors of moderate–high risk histology or deep myometrial invasion. Para-aortic sampling was performed at the surgeon’s discretion. Patients were categorized by pretreatment platelet count into two groups: ≤400×109/L and >400×109/L (defined as thrombocytosis). Clinical and pathological features were compared using Student t-test, χ2 or Fisher’s exact test. Survival measures were plotted with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariable comparison of associations.ResultsOf the 1482 patients included, most had stage I disease (961; 74.8%) and most had endometrioid histology (927; 64.1%). A total of 1392 patients (94%) had pretreatment platelet counts ≤400×109/L and 90 (6%) had pretreatment thrombocytosis. Patients with thrombocytosis had a significantly higher rate of high-grade malignancy, advanced stage, lymphovascular space invasion, low uterine segment involvement, and lymph node metastases. They also had shorter 5 year disease-free survival (65% vs 80%, p=0.003), disease-specific survival (63% vs 83%, pConclusionsPretreatment thrombocytosis is an independent prognostic factor for decreased disease-specific survival and overall survival among patients with endometrial cancer, and can serve as a predictor of poor outcome.

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

Objective Sentinel lymph node (SLN) sampling in endometrial cancer staging has become an acceptable standard. Indocyanine green dye injected into the cervix and detected by near-infrared light is technically simple and sensitive. We aimed to evaluate SLN sampling in robot-assisted surgical staging of endometrial cancer at a university-affiliated teaching hospital. Methods A retrospective chart review, from January 2016 to December 2017, of patients who underwent robot-assisted surgical staging with cervical injection of indocyanine green dye detected by near-infrared light. The map rate, sensitivity, false negatives, and negative predictive value were calculated. Results A total of 105 charts were reviewed; 79 patients met inclusion criteria. The mean age was 65 (range 38-93) and the mean body mass index was 33.3 (range 16-49). Most patients (72.2%) had stage I disease and grade 1 or 2 histology (77.1%). Eight (10.1%) patients had lymph node metastasis. Seventy-two (91.1%) patients had positive mapping to at least 1 SLN. Sixty-two (78.5%) patients had bilateral mapping. Forty-four patients had concurrent pelvic ± para-aortic lymph node dissection and were included in the sensitivity analysis. Five of 44 cases had LN metastasis. The sensitivity was 80%, and the negative predictive value of SLN sampling was 97.5%. Conclusions SLN mapping and sampling at a university-affiliated teaching hospital have comparable map rate, sensitivity, and negative predictive value as demonstrated in multiple trials. The technique has the potential to standardize endometrial cancer staging across different practice settings.

Background Associations have been observed between obesity defined by the body mass index (BMI) and the incidence of endometrial cancer. However, the impact of obesity on the prognosis of endometrial cancer is not yet clear. Recently, visceral fat has been considered to have a greater impact on malignant disease in obese patients than subcutaneous fat. In this study, we investigated the association between prognostic factors of type 1 and type 2 endometrial cancer and obesity parameters. Methods The impacts of clinical factors on the progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in 145 primary endometrial cancer patients. The factors included age, BMI, pathological findings, Federation of Gynecology and Obstetrics (FIGO) stage, status of lymph node metastasis, and the amounts of visceral and subcutaneous fat obtained from computed tomography (CT) data. Results Only the visceral-to-subcutaneous fat ratio (V/S ratio) (cutoff value 0.5) corresponded to a significant difference in OS and PFS in type 1 endometrial cancer (p = 0.0080, p = 0.0053) according to the results of log-rank tests of Kaplan–Meier curves. The COX regression univariate analysis revealed that only the V/S ratio was a significant prognostic factor for PFS, but not OS (p = 0.033 and p = 0.270, respectively). Conclusion A V/S ratio > 0.5 is a possible factor for poor prognosis in type 1 endometrial cancer. Further research is needed to investigate the preventive and therapeutic effects of reducing visceral fat on the prognosis of this type of cancer.

There are limited data regarding the correlation of clinical and pathologic parameters with mismatch repair (MMR) protein-deficient subgroups and methylation status. In this study, we analyzed the status of MMR proteins in resection specimens of 198 consecutive endometrial carcinomas and the methylation status in tumors with MLH1 and PMS2 deficiency. We, therefore, assessed the correlation of clinical and pathologic parameters with MMR protein-deficient subgroups. Univariate analysis revealed that deeper myometrial invasion and the presence of tumor-associated lymphocytes were more frequently observed in tumors with MMR protein deficiency ( P =0.023 and 0.001, respectively). The multivariate logistic regression analysis revealed that only the presence of tumor-associated lymphocytes was significantly associated with MMR protein deficiency ( P =0.002, odds ratio=2.674, 95% confidence interval=1.418-5.045). We also compared MLH1 and PMS2 deficiency with other protein deficiency regarding clinical and pathologic parameters. Furthermore, we compared MLH1 methylated tumors with MMR protein-deficient nonmethylated tumors regarding clinical and pathologic parameters. MLH1 was methylated in 51 of 54 tumors with MLH1 and PMS2 deficiency. In univariate analysis, a larger tumor size was significantly associated with MLH1 and PMS2 deficiency and with MLH1 methylation ( P =0.004 and 0.005, respectively). The multivariate logistic regression analysis revealed that a larger tumor size was significantly associated with MLH1 and PMS2 deficiency and MLH1 methylation ( P =0.002, odds ratio=14.222, 95% confidence interval=2.560-79.026, P =0.008, odds ratio=22.222, 95% confidence interval=2.220-222.395, respectively). Our results showed a slightly higher rate of MLH1 and PMS2 deficiency (34.3%) than in previous studies. This may likely be due to ethnic differences in frequency of various mutations.

To describe the sonographic findings of endometrial intraepithelial neoplasia (EIN), a precursor of endometrial cancer.Cases were found by word search of pathology database 1/2013 to 6/2019. One hundred and seventy-eight patients with ultrasound1 year prior to biopsy were included. Medical records were searched for patient data. Two radiologists blindly classified images. Differences of opinion were decided by clinical report. Univariate and multivariate analyses were performed.Median time between ultrasound and first sampling procedure was 49 days. Median age was 55 (range 28-85) years. Endometrial thickness ranged from 2 to 90 mm. Mean endometrial thickness was 13 ± 6 mm in the noncancer group and 16 ± 11 mm in the cancer group (P = .02). The endometrium was almost always heterogeneous 175/178 (98%). Cysts were almost always multiple (89/109, 82%) and1 mm (72/109, 66%). Masses were most often5 mm (56/105, 55%) and ill-defined (41/105, 39%). Vascularity was present in 93/178 examinations (52%) and always associated with cysts and/or mass. There were 92 cancers, 25 with invasion (including 4 with tumor extension into adenomyosis). In 47 cases, the endometrial-myometrial interface was graded as ill-defined, 39 of whom had hysterectomy. There was macroscopic cancer in 11, microscopic cancer in 4, and invasive carcinoma in 12 patients (P for invasive cancer versus other outcomes = .02). Depth of invasion was 5-95%, with 6 cancers50%. Multivariate analysis showed thickness, polyps, and type of bleeding as the best set of independent variables for cancer (area under the receiver operating characteristic (ROC) curve [AUC] = .75). Replacing type of bleeding with age or menopausal status had AUC of .73 and .74, respectively.EIN has a variety of sonographic appearances with thickened endometrium with cysts and masses being common. Ill-definition of the endometrial-myometrial interface is a poor prognostic finding when seen in the absence of adenomyosis.

Aim Our study aims to investigate the safety and effectiveness of sentinel lymph node biopsy using indocyanine green (ICG) for the surgical staging of early-stage endometrial cancer in comparison to technetium-99 m use. Methods We conducted an observational retrospective study with patients diagnosed of endometrial cancer and FIGO stages I-II. All participants were injected technetium-99m the day prior to the surgery and underwent lymphoscintigraphy along with single-photon emission computed tomography. In addition, all patients were administered intraoperatively ICG injection to detect sentinel lymph node biopsy. The surgical staging was then completed according to the European Society for Medical Oncology preoperative risk category. Data obtained from the analysis of technetium-99m detection was compared to ICG detection. Results A total of 53 women with endometrial cancer were included in the study, 49 (92.5%) of them showed drainage preoperatively in the single-photon emission computed tomography and/or lymphoscintigraphy. The intraoperative bilateral detection rate for technetium-99 m was 26 (49.1%) patients compared to 40 (75.5%) patients with ICG (p = 0.013). We observed a 42.5% increase in the mean number of lymph nodes retrieved by ICG compared to technetium-99m (2.85 vs 2,0 nodes; p = 0.002). We intraoperatively identified 164 lymph nodes, 104 (63.4%) located in both obturator areas and external iliac vessels. Conclusion The use of ICG for the performance of sentinel node biopsy in patients with endometrial cancer seems safe and could be superior to technetium-99 m, since it offers a higher bilateral detection rate and nodal retrieval, resulting in the possibility to perform safely less full staging lymphadenectomies.

ONC201 demonstrated promising activity in patients with advanced endometrial cancer in a Phase I clinical trial. ONC201 activates the integrated stress response (ISR) and upregulates TRAIL and its receptor DR5. We hypothesized ONC201 upregulation of DR5 could sensitize tumors to TRAIL and combination of ONC201 and TRAIL would lead to enhanced cell death in endometrial cancer models. Five endometrial cancer cell lines AN3CA, HEC1A, Ishikawa, RL952, and KLE as well as a murine xenograft model were treated with ONC201 alone or in combination with TRAIL. ONC201 decreased the cell viability of all five endometrial cancer cell lines at clinically achievable low micro-molar concentrations (2–4 μM). ONC201 activated the ISR and induced protein expression of TRAIL and DR5 at the cell surface. Pretreatment with ONC201 sensitized endometrial cancer cell lines to TRAIL, leading to increased cell death induction compared to either agent alone. Tumor growth was reduced in vivo by the ONC201/TRAIL combination treatment in the xenograft model of endometrial cancer (p = .014). Mice treated with combination treatment survived significantly longer than mice from the three control groups (p = .018). ONC201 decreased cell viability in endometrial cancer cells lines primarily through growth arrest while the combination of ONC201 and TRAIL promoted cell death in vitro and in vivo. Our results suggest a novel cancer therapeutic strategy that can be further investigated in the clinic.

ObjectiveSecond-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer.MethodsThirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0–5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.ResultsMedian age (range) was 65 (51–78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort.ConclusionsIn patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.

AIMS The aim of this study was to identify to what extent the sentinel lymph node (SLN) technique is utilised by gynaecological oncologists in Australia and New Zealand, identifying the techniques used, any barriers to uptake, and management of isolated tumour cells (ITCs) and micrometastases. MATERIALS AND METHODS We conducted an online survey of all practising gynaecological oncologists in Australia and New Zealand. They were asked whether they utilised SLN biopsy and in what circumstances, how they managed non-mapping and how their multidisciplinary team managed small volume disease. Those who did not were asked to identify their concerns with the procedure, reasons for non-uptake and their alternate technique. RESULTS We surveyed 63 gynaecological oncologists of whom 59 were practising, and 48 (81%) responded. Six members (11%) do not utilise SLN biopsy, and 42 (89%) do. Areas where clinicians differ in practice are those areas that are most controversial and include the use of SLN biopsy in complex atypical hyperplasia, the management of ITCs and micrometastases and procedures on unilateral or bilateral non-mapping. Those who do not utilise the technique cite concerns about the false-negative rate, equipment and training issues. CONCLUSIONS The utilisation of SLN biopsy in endometrial cancer is well established in Australia and New Zealand, with similar practices and concerns to those of other international groups.