Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma.

The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Prediction of complete regression in fertility-sparing patients with endometrial cancer and apical hyperplasia: the GLOBAL model in a large Chinese cohort.

BACKGROUND: Fertility preservation treatment is increasingly essential for patients with apical endometrial hyperplasia (AEH) and early endometrial cancer (EEC) worldwide. Complete regression (CR) is the main endpoint of this treatment. Accurately predicting CR and implementing appropriate interventions during treatment are crucial for these patients. METHODS: We conducted a retrospective study involving 193 patients diagnosed with atypical AEH or EEC, enrolled from January 2012 to March 2022 at our center. We evaluated 24 clinical parameters as candidate predictors and employed LASSO regression to develop a prediction model for CR. Subsequently, a nomogram was constructed to predict CR after the treatment. We evaluated the performance of the nomogram using receiver operator characteristic (ROC) curve and decision curve analysis (DCA) to assess its predictive accuracy. Additionally, we employed cumulative curves to determine the CR rate among patients. RESULTS: Out of the 193 patients, 173 achieved CR after undergoing fertility preservation treatment. We categorized features with similar properties and provided a list of formulas based on their coefficients. The final model, named GLOBAL (including basic information, characteristics, blood pressure, glucose metabolism, lipid metabolism, immunohistochemistry, histological type, and medication), comprised eight variables identified using LASSO regression. A nomogram incorporating these eight risk factors was developed to predict CR. The GLOBAL model exhibited an AUC of 0.907 (95% CI 0.828-0.969). Calibration plots demonstrated a favorable agreement between the predicted probability by the GLOBAL model and actual observations in the cohort. The cumulative curve analysis revealed varying cumulative CR rates among patients in the eight subgroups. Categorized analysis demonstrated significant diversity in the effects of the GLOBAL model on CR among patients with different total points (p < 0.05). CONCLUSION: We have developed and validated a model that significantly enhances the predictive accuracy of CR in AEH and EEC patients seeking fertility preservation treatment.

An altered uterine microbiota with endometrial hyperplasia.

BACKGROUND: Endometrial hyperplasia (EH) is a precursor to endometrial cancer, and the role of the microbiome in its development is unclear. RESULTS: The present study investigated the uterine microbiome in patients with benign uterine conditions and endometrial hyperplasia. A significant structural shift in the uterine microbiome of patients with endometrial hyperplasia compared to those with benign conditions was found. Delftia, Serratia and Stenotrophomonas were significantly enriched in endometrial hyperplasia samples and associated with the presence of endometrial hyperplasia. CONCLUSIONS: The novel finding suggested that increased abundance of Delftia, Serratia and Stenotrophomonas is associated with the presence of endometrial hyperplasia. Further investigation is needed to determine the value of these microbes as biomarkers for endometrial hyperplasia.

Surgical nodal assessment for endometrial hyperplasia - A meta-analysis and systematic review.

OBJECTIVE: Endometrial intraepithelial neoplasia (EIN) and atypical hyperplasia (AH) are recognized precursors for endometrial cancer (EC). Most current guidelines do not recommend the routine surgical evaluation of lymph nodes (LN), although recent studies indicate increased use of sentinel lymph node (SLN) biopsy in patients with a preoperative diagnosis of EIN/AH. We aimed to evaluate the rates of positive LN and its effect on the incidence of upstaging of EIN/AH patients, complications, and adjuvant treatment administration. METHODS: A systematic review and meta-analysis was conducted in the following databases: MEDLINE(R) using the OvidSP interface and PUBMED, Embase, Web of Science, Clinicaltrials.gov and Cochrane Library. Included were studies investigating lymph node evaluation in patients diagnosed with EIN/AH, presenting results of LN assessment and/or comparisons of hysterectomy results with and without lymph node assessment. This analysis was registered at PROSPERO International prospective register of systematic reviews (CRD42023443598). RESULTS: A total of 447 studies were initially identified through database searching. The current analysis includes 7 studies comprising 1791 atypical endometrial hyperplasia patients who underwent hysterectomy with lymph node assessment. The incidence of positive lymph nodes among those who had undergone any LN evaluation was found to be 1.1% (95% CI 0.3%-2%). The rate of positive LNs was 1.4% (95% CI 0.2%-1.9%) among those who had undergone specifically SLN. 319 (44.3%, 95% CI 34%-54.7%) patients of the patients initially diagnosed with EIN/AH (n = 699), were finally upgraded to EC diagnosis. Fifteen percent of the final EC diagnosed patients were treated with adjuvant treatment. No significant difference regarding complication rates was noticed. CONCLUSIONS: Our review indicates that the rate of metastatic LNs is <2% in patients undergoing surgical nodal evaluation for EIN/AH. However, the rate of complication for SLN mapping is low and may have an impact on postoperative therapy decisions in those diagnosed with malignancy.

Weight-loss therapy in patients with obesity with endometrial intraepithelial neoplasia and uterine cancer.

OBJECTIVE: Although obesity is an important risk factor for endometrial intraepithelial neoplasia (EIN) and uterine cancer, little is known about the trends in use of weight-loss therapy for patients with obesity with EIN and uterine cancer. We examined the use of weight-loss therapy among patients with obesity with EIN and uterine cancer. METHODS: The Merative MarketScan Database was used to identify patients aged 18-70 years who were obese and diagnosed with EIN or uterine cancer. The primary treatment for EIN or uterine cancer was categorized as either primary hysterectomy or hormonal therapy. Nutrition counseling, bariatric surgeries, and weight-management medications were identified as weight-loss therapy. We analyzed trends in the use of any weight-loss therapies with Cochran-Armitage tests. A multivariable logistic regression model was developed to examine factors associated with weight-loss therapy use. RESULTS: Overall, 15,374 patients were identified, including 5561 (36.2%) patients with EIN and obesity, and 9813 (63.8%) patients with uterine cancer and obesity. Weight-loss therapy was utilized within 1 year after diagnosis in 480 (8.6%) patients with EIN and in 802 (8.2%) patients with uterine cancer. Use of any weight-loss therapy after diagnosis of EIN increased from 4.1% in 2009 to 12.6% in 2020 (P < .001), and the use of any weight-loss therapy after diagnosis of uterine cancer increased from 4.9% in 2009 to 11.4% in 2020 (P < .001). In a multivariable regression model, younger age and patients with high comorbidity score were associated with a higher likelihood of using any weight-loss therapy. CONCLUSIONS: Use of weight-loss therapy has increased, however there is still a significant underuse of this adjunctive therapy in patients with obesity with EIN or uterine cancer.

Treatment outcomes according to various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia - Multicenter retrospective study (KGOG2033).

OBJECTIVE: To investigate pathologic complete response (pCR) and recurrence outcomes using various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN). METHODS: Medical records of patients diagnosed with AH/EIN and undergoing follow-up endometrial biopsy after progestin treatment between 2011 and 2020 were retrospectively reviewed. Clinical factors and treatment outcomes were analyzed according to initial progestin treatment (oral progestin [OP], levonorgestrel-releasing intrauterine device [LNG-IUD], and combination), OP dose, and maintenance treatment using Pearson's χ2, Fisher's exact test, and Kaplan-Meier analysis. RESULTS: Of 124 patients included, 74, 37, and 13 were in the OP, LNG-IUD, and combination groups, respectively. The pCR rate was 79.8% and recurrence rate was 21.2%. The pCR rates within 3 and 6 months were significantly higher in the OP group than in the LNG-IUD group, but were not significantly different within 12 and 24 months. Recurrence rate was significantly higher in the OP group than in the LNG-IUD group. The pCR rate and recurrence rate had no significant differences between the combination group and the other groups. Excluding the LNG-IUD group, 53 and 34 patients received low- and high-dose OP, respectively. The pCR and recurrence rates were comparable between the low- and high-dose OP groups. Maintenance therapy was significantly associated with lower recurrence rate. CONCLUSIONS: Although OP alone achieved more short-term pCR than the other groups, more recurrences occurred after pCR than LNG-IUD alone. High-dose OP as well as combination of OP and LNG-IUD did not increase pCR or reduce recurrence. Maintenance therapy may reduce the recurrence rate after pCR.

Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.

Gallic acid ameliorates endometrial hyperplasia through the inhibition of the PI3K/AKT pathway and the down-regulation of cyclin D1 expression.

BACKGROUND: Gallic acid (GA) is an organic compound with phenolic properties that occurs naturally and can be found in Guizhi Fuling capsules, showcasing a wide range of biological functionalities. PURPOSE: The objective of this study was to examine the influence of GA on endometrial hyperplasia (EH) and elucidate its underlying mechanism. METHODS: Initially, the induction of EH was achieved by administering estradiol to mice via continuous subcutaneous injection for a duration of 21 days. Concurrently, GA treatment was administered, and subsequently, the uterine tissue structure was assessed using hematoxylin and eosin (H&E) staining. Following this, the proliferation of human endometrial cells treated by GA was determined utilizing the CCK-8 method. Furthermore, network pharmacology and single-cell-RNA-seq data were employed to identify the target of GA action. In addition, we will employ immunofluorescence (IF), immunohistochemistry (IHC), flow cytometry, western blot and RT-qPCR methodologies to investigate the impact of GA on the expression level of cyclin D1, PI3K, p-PI3K, AKT, p-AKT. RESULTS: GA treatment ameliorated histopathological alterations in the uterus and suppress proliferation. Estradiol stimulation can activate the PI3K/AKT pathway, leading to up-regulation of cyclin D1 expression, whereas GA treatment results in down-regulation of its expression. CONCLUSIONS: The expression of cyclin D1 is down-regulated by GA through the inhibition of the PI3K/AKT pathway, effectively mitigating estradiol-induced EH in mice.

Uterine-Conserving Treatment Options for Atypical Endometrial Hyperplasia and Early Endometrial Cancer.

PURPOSE OF REVIEW: This review aims to synthesize available literature on uterine-conserving treatment options for atypical endometrial hyperplasia and grade 1 endometrial carcinoma while highlighting remaining unanswered questions. RECENT FINDINGS: The need for uterine-conserving treatment options for atypical endometrial hyperplasia and grade 1 endometrial carcinoma is growing with the increasing number of cases in younger patients or those who cannot undergo surgery. We reviewed the oncological and reproductive outcomes associated with endocrine therapies used for atypical endometrial hyperplasia and grade 1 endometrial carcinoma. The rising prevalence of delayed childbearing, obesity, and diabetes in reproductive-age individuals and of medical comorbidities associated with high surgical risk continues to amplify the demand for uterine-conserving therapies. Appropriate patient selection for such therapies is imperative to maximize likelihood of treatment response. The ideal candidates are patients with atypical endometrial hyperplasia or early-stage, low-grade endometrial cancer with no evidence of myometrial invasion or extrauterine disease. The most accepted conservative therapeutic approach is hormonal therapy with close surveillance, with or without eventual hysterectomy following childbearing or failure of treatment. Further prospective and randomized trials are needed to address optimal patient and treatment selection, as well as the use of molecular profiling for treatment individualization and prognostication.

Predicting the Risk of nOdal disease with histological and Molecular features in Endometrial cancer: the prospective PROME trial.

OBJECTIVE: To assess the role of histopathological and molecular features in predicting the risk of nodal metastases in apparent early-stage endometrial cancer patients undergoing sentinel node mapping. METHODS: This is a prospective trial. Consecutive patients with apparent early-stage endometrial cancer, undergoing laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and sentinel node mapping, were enrolled. Histological and molecular features were used to predict the node positivity. RESULTS: Charts of 223 apparent early-stage endometrial cancer patients were included in this study. Four (1.8%) patients were excluded from this study due to the lack of data about molecular features. Additionally, nine (4%) patients did not meet the inclusion criteria (due to the presence of peritoneal carcinomatosis or bulky nodes (the presence of p53 abnormality correlated with the presence of advanced stage disease (p<0.001)). The study population included 178 (84.8%) and 32 (15.2%) patients with endometrioid and non-endometrioid endometrial cancer, respectively. According to pathological uterine risk factors, 93 (44.3%), 45 (21.4%), 40 (19.1%), and 32 (15.2%) were classified as low, intermediate, intermediate-high, and high-risk, respectively. Using the surrogate molecular classification, 10 (4.8%), 42 (20%), 57 (27.1%), and 101 (48.1%) were included in the POLE mutated, p53 abnormal, MMRd/MSI-H, and NSMP, respectively. Overall, 41 (19.5%) patients were detected with positive nodes. Molecular features were not associated with the risk of having nodal metastases (OR 1.03, 95% CI 0.21 to 5.05, p=0.969 for POLE mutated; OR 0.788, 95% CI 0.32 to 1.98, p=0.602 for p53 abnormal; OR 1.14, 95% CI 0.53 to 2.42, p=0.733 for MMRd/MSI-H). At multivariable analysis, only deep myometrial invasion (OR 3.318, 95% CI 1.357 to 8.150, p=0.009) and lymphovascular space invasion (OR 6.584, 95% CI 2.663 to 16.279, p<0.001) correlated with the increased risk of positive nodes. CONCLUSION: Our data suggest that molecular classification does not seem useful to tailor the need of nodal dissection in apparent early-stage endometrial cancer. p53 abnormality predicts the risk of having advanced disease at presentation. Further external validation is needed. CLINICAL TRIAL REGISTRATION: NCT05793333.

Hysterectomy with sentinel lymph node dissection in the setting of preoperative endometrial intraepithelial neoplasia and an endometrial stripe ≥20 mm: a cost-effectiveness analysis .

OBJECTIVES: Routine lymph node assessment in patients with endometrial intraepithelial neoplasia is institution and surgeon-dependent without clear guidelines. We sought to determine if routine sentinel lymph node (SLN) dissection at the time of laparoscopic hysterectomy for patients with a preoperative diagnosis of endometrial intraepithelial neoplasia and a preoperative ultrasound with endometrial stripe ≥20 mm is cost-effective. METHODS: A decision model was created to perform two cost-effectiveness analyses: (1) hysterectomy with frozen section versus hysterectomy with SLN dissection in patients with a preoperative diagnosis of endometrial intraepithelial neoplasia and an endometrial stripe of 20 mm or greater, and (2) the same options in all patients with a preoperative diagnosis of endometrial intraepithelial neoplasia. Costs obtained from Centers for Medicare and Medicaid Services and event probabilities and quality of life utility values were obtained through literature review. RESULTS: In the case of preoperative endometrial stripe ≥20 mm, hysterectomy with SLN dissection cost $2469 more than hysterectomy with frozen section and gained 0.010 quality adjusted life years, or $44,997/quality-adjusted life years gained. In one-way sensitivity analyses, SLN dissection remained the favored strategy at a willingness to pay threshold of $100,000/quality-adjusted life years unless chronic lower extremity lymphedema after full lymphadenectomy had a likelihood <13.1% (base case value 18.1%); otherwise, SLN dissection was favored with individual variation of all other parameters over plausible ranges. When considering all patients with endometrial intraepithelial neoplasia, hysterectomy with frozen section was favored, with results most sensitive to variation of lymphedema risk after full lymphadenectomy. CONCLUSION: Hysterectomy with SLN dissection in patients with a preoperative endometrial stripe ≥20mm on ultrasound is cost-effective when compared with hysterectomy with frozen section.

Integrated histological parameters define prognostically relevant groups in atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia.

OBJECTIVE: To assess the risk of endometrial carcinoma following a diagnosis of atypical hyperplasia/endometrioid intraepithelial neoplasia by endometrial biopsy, stratified based on integrated histological parameters. METHODS: All women with atypical hyperplasia/endometrioid intraepithelial neoplasia undergoing hysterectomy within 1 year of diagnosis without progestin treatment were included. Patients were subdivided into three study groups, based on two criteria: (a) grade of nuclear atypia and (b) foci (<2 mm) of confluent glands with no intervening stroma: low-grade, high-grade, and confluent glands. The rate of endometrial carcinoma on the subsequent hysterectomy was assessed in each study group, and differences between study groups were assessed using Fisher's exact test, with a significant p value <0.05. Reproducibility was assessed by using Cohen's κ. RESULTS: Ninety-six patients were included. Overall, 36 of 96 patients (37.5%) had endometrial carcinoma on the subsequent hysterectomy. The number of endometrial carcinomas was 4 of 42 (9.5%) in the low-grade group, 14 of 28 (50.0%) in the high-grade group, and 18 of 26 (69.2%) in the confluent glands group. The rate of endometrial carcinoma was significantly higher in the high-grade group than in the low-grade group (p<0.001), whereas it did not significantly differ between the high-grade group and the confluent glands group (p=0.176). The reproducibility among pathologists was moderate for low-grade versus high-grade (κ=0.58) and substantial for confluent glands versus low-grade (κ=0.63) and high-grade (κ=0.63). CONCLUSION: Atypical hyperplasia/endometrioid intraepithelial neoplasia can be stratified into prognostically relevant groups based on integrated histological parameters, with a possible major impact on patient management.

Artificial intelligence model for enhancing the accuracy of transvaginal ultrasound in detecting endometrial cancer and endometrial atypical hyperplasia.

OBJECTIVES: Transvaginal ultrasound is typically the initial diagnostic approach in patients with postmenopausal bleeding for detecting endometrial atypical hyperplasia/cancer. Although transvaginal ultrasound demonstrates notable sensitivity, its specificity remains limited. The objective of this study was to enhance the diagnostic accuracy of transvaginal ultrasound through the integration of artificial intelligence. By using transvaginal ultrasound images, we aimed to develop an artificial intelligence based automated segmentation model and an artificial intelligence based classifier model. METHODS: Patients with postmenopausal bleeding undergoing transvaginal ultrasound and endometrial sampling at Mayo Clinic between 2016 and 2021 were retrospectively included. Manual segmentation of images was performed by four physicians (readers). Patients were classified into cohort A (atypical hyperplasia/cancer) and cohort B (benign) based on the pathologic report of endometrial sampling. A fully automated segmentation model was developed, and the performance of the model in correctly identifying the endometrium was compared with physician made segmentation using similarity metrics. To develop the classifier model, radiomic features were calculated from the manually segmented regions-of-interest. These features were used to train a wide range of machine learning based classifiers. The top performing machine learning classifier was evaluated using a threefold approach, and diagnostic accuracy was assessed through the F1 score and area under the receiver operating characteristic curve (AUC-ROC). RESULTS: 302 patients were included. Automated segmentation-reader agreement was 0.79±0.21 using the Dice coefficient. For the classification task, 92 radiomic features related to pixel texture/shape/intensity were found to be significantly different between cohort A and B. The threefold evaluation of the top performing classifier model showed an AUC-ROC of 0.90 (range 0.88-0.92) on the validation set and 0.88 (range 0.86-0.91) on the hold-out test set. Sensitivity and specificity were 0.87 (range 0.77-0.94) and 0.86 (range 0.81-0.94), respectively. CONCLUSIONS: We trained an artificial intelligence based algorithm to differentiate endometrial atypical hyperplasia/cancer from benign conditions on transvaginal ultrasound images in a population of patients with postmenopausal bleeding.

Concurrent endometrial cancer in atypical endometrial hyperplasia and the role of sentinel lymph nodes: clinical insights from a multicenter experience.

OBJECTIVE: This study aimed to evaluate the prevalence of concurrent endometrial cancer in patients pre-operatively diagnosed with atypical endometrial hyperplasia undergoing hysterectomy. Additionally, we assessed the occurrence of high to intermediate-risk and high-risk tumors according to the ESGO-ESTRO-ESP classification. The study also compared surgical outcomes and complications between patients undergoing simple hysterectomy and those undergoing hysterectomy with sentinel lymph node biopsy. METHODS: In this multicenter retrospective study, patients with a pre-operative diagnosis of atypical endometrial hyperplasia were identified and divided into two groups: Group 1, which included patients treated with total hysterectomy with or without bilateral salpingo-oophorectomy, and Group 2, where sentinel lymph node biopsy was incorporated into the standard surgical treatment. RESULTS: Among 460 patients with atypical endometrial hyperplasia, 192 received standard surgical management (Group 1) and 268 underwent sentinel lymph node biopsy (Group 2). A total of 47.2% (95% CI 42.6% to 51.7%) of patients were upgraded to endometrial cancer on final histopathological examination. High to intermediate-risk and high-risk tumors constituted 12.3% and 9.2% in Group 2 and 7.4% and 3.7% in Group 1. Lymph node metastases were identified in 7.6% of patients with concurrent endometrial cancer who underwent nodal assessment with at least unilateral mapping. Of the 12 sentinel lymph node metastases, 75.0% were micrometastases, 16.7% macrometastases, and 8.3% isolated tumor cells. No significant differences were found in estimated blood loss, operative time, and intra-operative and post-operative complications between the two groups. The rate of patients undergoing sentinel lymph node biopsy doubled every 2 years (OR 2.010, p<0.001), reaching 79.1% in the last 2 years. CONCLUSION: This study found a prevalence of concurrent endometrial cancer of 47.2%, and sentinel lymph node biopsy provided prognostic and therapeutic information in 60.8% of cases. It also allowed for the adjustment of adjuvant therapy in 12.3% of high to intermediate-risk patients without increasing operative time or complication rates.

Risk of endometrial malignancy in women treated for breast cancer: the BLUSH prediction model - evidence from a comprehensive multicentric retrospective cohort study.

OBJECTIVE: This study aimed to evaluate characteristics of endometrial surveillance in women treated for breast cancer to build a clinical prediction model. DESIGN: A multicentric retrospective cohort study was conducted at two tertiary-care university hospitals from January 2020 to June 2023. Perimenopausal and postmenopausal women treated for breast cancer were categorized into two groups: patients with and without diagnosis of endometrial malignancy (endometrial carcinoma) or premalignancy (atypical endometrial hyperplasia). Characteristics of breast cancer and ultrasonographic and hysteroscopic examinations were compared. A prediction model for endometrial malignancy was built using logistic regression. Predictive accuracy was assessed using the receiver operating characteristic (ROC) curve and goodness of fit using the Hosmer-Lemeshow test. RESULTS: One hundred and thirty-two (28 with premalignancy or malignancy and 104 without malignancy) women were analyzed. A nomogram was produced for prediction model development utilizing the presence and duration in months of abnormal uterine (BL)eeding, ultrasound (US) vascular pattern and echogenicity and (H)ysteroscopic appearance of endometrium (BLUSH) as determined by logistic regression. Sensitivity and specificity were 79.17% and 95.19%, respectively, with an area under ROC curve of 0.965, indicating good accuracy. Good goodness of fit and prediction stability were indicated by the calibration curve and Hosmer-Lemeshow test (χ2 = 26.36; p = 0.999). CONCLUSIONS: Breast cancer survivors undergoing endometrial surveillance might benefit from a potentially useful prediction model based on hysteroscopic appearance, ultrasonographic uniformity of endometrium, Doppler flow and presence of abnormal uterine bleeding.

Guideline No. 451: Asymptomatic Endometrial Thickening in Postmenopausal Women.

OBJECTIVE: To formulate strategies for clinical assessments for endometrial thickening on ultrasound in a postmenopausal woman without bleeding. TARGET POPULATION: Postmenopausal women of any age. OUTCOMES: To reduce unnecessary invasive interventions and investigations in women with asymptomatic endometrial thickening while selectively investigating women at risk for endometrial cancer. BENEFITS, HARMS, AND COSTS: It is anticipated that the adoption of these recommendations would save postmenopausal women unnecessary anxiety, pain, and risk of procedural complications. It is also expected to decrease the cost to the health care system by eliminating unnecessary interventions. EVIDENCE: English language articles from Medline, Cochrane, and PubMed databases for relevant peer-reviewed articles dating from 1995 to 2022 (e.g., asymptomatic endometrial thickness, endometrial cancer, postmenopausal bleeding, transvaginal ultrasound, endometrial biopsy, cervical stenosis, hormone therapies and the endometrium, tamoxifen, tibolone, aromatase inhibitors). Results were restricted to systematic reviews and meta-analyses, randomized controlled trials/controlled clinical trials, and observational studies. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Physicians, including gynaecologists, obstetricians, family physicians, radiologists, pathologists, and internists; nurse practitioners and nurses; medical trainees, including medical students, residents, and fellows; and other providers of health care of the postmenopausal population. SOCIAL MEDIA ABSTRACT: Postmenopausal women often have a thickening of the lining of the uterus found during ultrasound. Without bleeding, an endometrium <11 mm is rarely a serious problem but should be evaluated by a health care provider. SUMMARY STATEMENTS: RECOMMENDATIONS.

Fertility-sparing re-treatment for endometrial cancer and atypical endometrial hyperplasia patients with progestin-resistance: a retrospective analysis of 61 cases.

OBJECTIVE: This study aimed to evaluate the oncological and reproductive outcomes of fertility-preserving re-treatment in progestin-resistant endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) women who desire to maintain their fertility. METHODS: Our study included 61 progestin-resistant EC/AEH patients. These patients underwent treatment with gonadotropin-releasing hormone agonist (GnRHa) solely or a combination of GnRHa with levonorgestrel-releasing intrauterine system (LNG-IUD) or aromatase inhibitor (AI). Histological evaluations were performed every 3-4 months. Upon achieving complete remission (CR), we recommended maintenance treatments including LNG-IUD, cyclical oral contraceptives, or low-dose cyclic progestin until they began attempting conception. Regular follow-up was conducted for all patients. The chi-square method was utilized to compare oncological and fertility outcomes, while the Cox proportional hazards regression analysis helped identify risk factors for CR, recurrence, and pregnancy. RESULTS: Overall, 55 (90.2%) patients achieved CR, including 90.9% of AEH patients and 89.7% of EC patients. The median re-treatment time was 6 months (ranging from 3 to 12 months). The CR rate for GnRHa alone, GnRHa + LNG-IUD and GnRHa + AI were 80.0%, 91.7% and 93.3%, respectively. After a median follow-up period of 36 months (ranging from 3 to 96 months), 19 women (34.5%) experienced recurrence, 40.0% in AEH and 31.4% in EC patients, with the median recurrence time of 23 months (ranging from 6 to 77 months). Among the patients who achieved CR, 39 expressed a desire to conceive, 20 (51.3%) became pregnant, 11 (28.2%) had successfully deliveries, 1 (5.1%) was still pregnant, while 8 (20.5%) suffered miscarriages. CONCLUSION: GnRHa-based fertility-sparing treatment exhibited promising oncological and reproductive outcomes for progestin-resistant patients. Future larger multi-institutional studies are necessary to confirm these findings.

The Analysis of in vitro Fertilization Outcomes after Fertility-Preserving Therapy for Endometrial Hyperplasia or Carcinoma.

OBJECTIVES: This study aimed to evaluate the clinical efficacy of fertility-preserving therapy through in vitro fertilization (IVF) procedures in women who were pathologically diagnosed with endometrial hyperplasia or carcinoma. DESIGN: A retrospective cohort study on fertility-preserving therapy was conducted. Participants/Materials, Setting: A total of 82 women were enrolled who had simple endometrial hyperplasia (SH), complex hyperplasia (CH), complex atypical hyperplasia (CAH), and endometrioid endometrial carcinoma stage IA (EC IA) and underwent IVF at Gangnam CHA fertility center between January 2008 and December 2020. METHODS: The primary endpoints were oncologic outcomes and subsequent reproductive outcomes of patients who underwent fertility-preserving treatments analyzed by χ2 test or Fisher's exact test. RESULTS: Of the 82 patients, 33 had a cumulative clinical pregnancy (40.2%), and 25 had a cumulative live birth (30.5%) through IVF procedures following pathologic confirmation of complete remission or non-progressive status. The cumulative clinical pregnancy rates and live birth rates for SH were 50.0% and 30.0%, for CH were 37.8% and 28.9%, for CAH were 25.0% and 25.0%, and for EC were 38.5% and 38.5%, respectively. There were no significant differences in cumulative clinical pregnancy rates or live birth rates when comparing the four groups. There was a difference in endometrial thickness between medroxyprogesterone acetate (MPA) treatment group and intrauterine device (IUD) group (p = 0.036); however, there were no significant differences in clinical pregnancy rates among MPA, IUD, and MPA+IUD groups. LIMITATIONS: Because of the retrospective nature of the study, many factors relevant to the treatment decision were not strictly controlled. CONCLUSIONS: All endometrial hyperplasia and carcinoma groups had competent cumulative live birth rates by IVF procedures. There may be differences in endometrial thickness depending on the treatment methods, but this does not affect clinical pregnancy rates. Therefore, the fertility-preserving treatment for endometrial hyperplasia and carcinoma is a safe and feasible method that results in good IVF outcomes.

Characteristic hysteroscopy appearance considerations for detecting uterine endometrial malignancies.

AIM: The effectiveness of hysteroscopy in diagnosing endometrial lesions has been demonstrated, showing high diagnostic accuracy for malignant endometrial lesions. Although the characteristic appearances of atypical and malignant endometria have been reported, they are not definitive and sometimes complicated. This study aimed to identify a small number of characteristic features to detect endometrial abnormalities using a simple judgment system and analyze the diagnostic characteristics and their accuracy in endometrial malignancy diagnosis. METHODS: We performed a retrospective analysis of hysteroscopy video data of 250 patients, of which we selected for analysis based on pathology examination 152 cases with benign changes, 16 with atypical endometrium, and 18 with carcinoma in situ or endometrial cancer. Endometrial characteristics assessed included protrusion, desquamation, extended vessel, atypical vessel, and white/yellow lesion. RESULTS: Multivariable analysis revealed that desquamation (p = 0.001, odds ratio [OR] 5.28), atypical vessels (p < 0.001, OR 8.50), and white/yellow lesions (p = 0.011, OR 1.37) were significant predictors for endometrial malignancy. From their contribution status, scoring points of 4, 6, and 1 were settled according to the odds ratio proportions. When scores ≥5 (at least both desquamation and white/yellow lesions or only atypical vessels) were used to define endometrial malignancy, sensitivity and specificity were 100% and 92%, respectively. When detecting cancer, atypical, and benign cases, sensitivity and specificity were 88% and 90%, respectively. CONCLUSION: Our characteristics hysteroscopic findings showed a higher predictive ability in detecting endometrial malignancies. However, further examination with more cases would be needed to accurately diagnose endometrial malignancy by hysteroscopy.

Update on the oncologic and obstetric outcomes of medroxyprogesterone acetate treatment for atypical endometrial hyperplasia and endometrial cancer.

AIMS: To evaluate the safety and effectiveness of high-dose oral medroxyprogesterone acetate (MPA) therapy as a fertility-sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. METHODS: We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post-MPA therapy pregnancies were examined. RESULTS: MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post-CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. CONCLUSIONS: High-dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.