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The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: This is a feasibility study to determine whether circulating tumour cells (CTCs) are detectable and suitable for molecular profiling in advanced endometrial cancer (aEC)., Method: Between October 2012 and February 2014, 30 patients with aEC had baseline and up to 3 follow-up samples. CTCs and stathmin expression were evaluated using the CellSearch platform. Epithelial cell adhesion molecule (EpCAM) and stathmin immunohistochemistry were performed on FFPE tumour tissue., Results: Eighteen from 30 (60%) patients had detectable CTCs during study [1 CTC (n = 7), 2 (n = 4), 3 (n = 1), 4 (n = 2), 7 (n = 1), 8 (n = 1), 22 (n = 1), 172 (n = 1) in 7.5 ml blood]. Ten from 18 patients had between 50 and 100% of detectable CTCs that were stathmin positive. More CTC-positive than CTC-negative patients had non-endometrioid versus endometrioid histology, tumour size ≥5 versus <5 cm, higher-stage disease and worse survival [hazard ratio 3.3, p > 0.05, 95% confidence interval 0.7-16.2]. Twenty-one tumour blocks were tested for EpCAM and stathmin immunohistochemistry (IHC). Stathmin tumour immunostaining scores (TIS) on IHC were higher in CTC-positive patients., Conclusion: CTC enumeration and molecular profiling with stathmin on the CellSearch platform is feasible in aEC. Stathmin TIS on IHC, a known prognostic marker in EC, was associated with CTC positivity., (© 2016 S. Karger AG, Basel.)

Background: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development., Methods and Findings: Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression., Conclusions: HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

Endometrial cancer has become the most common gynecological cancer in developed countries. Postmenopausal bleeding is indicative of the disease in only 1 of 10 women with this symptom. A noninvasive tool to identify women with cancer would be highly desirable. We analyzed more than 27,000 CpGs in normal endometrial tissue (n = 23) and endometrial cancers (n = 64) and found that DNA methylation of GALR1 is among the most frequent epigenetic alterations in this cancer. We then developed a real-time polymerase chain reaction-based GALR1 methylation test and applied this test to vaginal swabs from 79 women who presented with postmenopausal bleeding. The receiver operating characteristics area under the curve, describing sensitivity and specificity to correctly identify the 41 women with both premalignant and malignant endometrial changes, was 0.93 (95% confidence interval, 0.87-0.97; P < 0.0001).GALR1 DNA methylation is one of the most common molecular alterations in endometrial cancer, and the presence of GALR1 methylation in vaginal swabs from women with postmenopausal bleeding indicates the presence of endometrial malignancy with a sensitivity of 92.7% and a specificity of 78.9%.

Background: The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort., Methods: We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978., Findings: 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5)., Interpretation: Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To assess the feasibility, associated anaesthetic and surgical morbidity in all morbidly obese women with endometrial cancer treated with total laparoscopic hysterectomy bilateral salpingo-oophorectomy (TLHBSO)., Study Design: Data was collected prospectively and analysed retrospectively on all morbidly obese women who had TLHBSO between February 2003 and January 2007., Results: One case was converted to laparotomy. The mean postoperative stay was 4.04 (3-7) days. The only postoperative surgical complication was an incisional port site hernia. Comorbidities were present in 76% (26/34) of women, 29% (10/34) had a single comorbid condition, and 26% (9/34) had two. A further 21% (7/34) had more than two. There were no major anaesthetic complications. Patients with a BMI > 50 required ventilation with high airway pressure despite using ventilatory strategies to keep them to a minimum., Conclusion: TLHBSO in the obese population is safe in the hands of experienced surgeons and anaesthetists. The safety of a total laparoscopic approach in the surgical management of uterine cancer remains to be demonstrated in prospective randomised trials.

Background: Women with polycystic ovary syndrome (PCOS) are assumed to be at increased risk of endometrial cancer (EC), albeit of a more differentiated type with better prognosis than in normal women. This study was designed to test these assumptions, as evidence for them is lacking., Methods: The prevalence of polycystic ovaries (PCO), as a marker of PCOS, was investigated in ovarian sections from 128 women with EC and 83 with benign gynaecological conditions. The expression of the prognostic markers p53, Ki67, Bcl2 and cyclin D1 was also investigated by immunohistochemistry in endometrial tumours from 11 women with PCO and 16 with normal ovaries., Results: Overall, PCO were similarly prevalent in women with EC (8.6%) and benign controls (8.4%); however, in women aged <50 years, PCO were more prevalent in women with EC (62.5 versus 27.3%, P = 0.033). Cyclin D1-expressing endometrial tumours tended to be more prevalent in women with PCO compared to normal ovaries (36.4 versus 6.25%, respectively, P = 0.071). Bcl2-, p53- and Ki67-expressing tumours were similarly prevalent., Conclusions: The association between PCOS and EC appears confined to premenopausal women. The tendency for cyclin D1-expressing endometrial tumours to be more prevalent in women with PCO challenges the assumption that EC prognosis is improved in women with PCOS.

To evaluate the feasibility of total laparoscopic hysterectomy as the primary treatment for endometrial cancer in morbidly obese women, an audit was carried out during an 18-month period in a tertiary referral centre for gynaecological oncology. Four women who had laparoscopic surgery were compared with a similar cohort who had open surgery. The mean operating time was equivalent, without evidence of excess morbidity with the laparoscopic approach. However, inpatient stay was longer with open versus laparoscopic surgery (11.5 vs 4 days). Laparoscopic surgery is safe to use in morbidly obese women with endometrial cancer.