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.

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.

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.

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.

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.

Oncologic, fertility, and obstetric outcomes with MPA therapy in women with endometrial cancer and atypical endometrial hyperplasia.

AIM: Medroxyprogesterone acetate (MPA) is one of the treatments of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) to preserve the fertility. Efficacy of MPA therapy and fertility and obstetric outcomes after remission were evaluated in EC or AEH patients. METHODS: Among patients diagnosed with EC or AEH at Tokushima University Hospital between January 2002 and October 2020, we retrospectively analyzed patients, ages range from 26 to 40, who underwent conservative management using MPA (400-600 mg/day). RESULTS: In total, 19 patients underwent MPA therapy. The 18 (94%) patients achieved complete response (CR), and 1 (5%) patient achieved partial response (PR). Relapse occurred in 6 (32%) patients who had achieved CR. Of the patients who relapsed, 4 patients resumed MPA therapy and were in remission. Among 19 patients, 13 patients attempted pregnancy after CR. All of them underwent ovulation induction or assisted reproductive technology. As a result, 20 pregnancies in 10 (77%) patients and 12 live births in 9 (69%) patients were achieved. Rate of spontaneous abortion was 35% (7/20). CONCLUSIONS: MPA therapy can produce a high remission rate, and be considered an effective treatment for patients who wish fertility preservation. Around 70% patients who attempt to pregnancy can have at least one baby by infertility treatments. Because recurrence rate after MPA therapy is high, it may be desirable to aim for early pregnancy by active intervention.

A multi-centre randomised controlled trial comparing megestrol acetate to levonorgestrel-intrauterine system in fertility sparing treatment of atypical endometrial hyperplasia.

PURPOSE: The objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients. METHODS: The study was a phase II multi-centre randomised controlled trial on the use of MA compared to LNG-IUS in the treatment of AEH conducted from January 2020 to January 2024 in Singapore. Women who were diagnosed with AEH and between 21 and 40 years old were included. The patients were randomised to receive either MA (160 mg orally daily) or LNG-IUS. The primary outcomes assessed were the regression rates at 3 months, 6 months and 9 months of treatment. The secondary outcomes assessed were the side effects, patient acceptability and fertility outcomes. RESULTS: Thirty-six patients completed the trial. The overall regression rate was 88.9% by 9 months. There was no statistically significant difference in the 9-month complete regression rate between MA vs. LNG-IUS. There was also no significant difference in side effects and weight change between both arms. Nineteen patients were actively pursuing fertility after complete regression. There were 8 pregnancies achieved, with resultant 4 live births and 4 miscarriages. CONCLUSION: Our study confirms a high regression rate of AH with medical treatment. LNG-IUS is a non-inferior treatment compared to megestrol acetate. Successful pregnancy outcomes can be achieved after regression of AEH. Long-term studies of sufficient sample-size are needed to assess for fertility and pregnancy outcomes, risk of recurrence and long-term risk of malignancy. TRIAL REGISTRATION NUMBER: The study was registered with the Health Science Authority (HSA) (License No.: CTA1900087) on September 5, 2019: https://eservice.hsa.gov.sg/prism/ct_r/enquiry.do?action=loadSpecificDetail . The trial was registered retrospectively on ClinicalTrials.gov (ID: NCT05492487) on April 7, 2022: https://clinicaltrials.gov/study/NCT05492487 .

Current practice with operative hysteroscopy for fertility preservation in endometrial cancer and endometrial premalignancies.

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

Expression Patterns of Cytokeratins (CK7, CK20, CK19, CK AE1/AE3) in Atypical Endometrial Hyperplasia Coexisting with Endometrial Cancer.

Few studies have evaluated cytokeratin's (CK) staining patterns in atypical endometrial hyperplasia (AEH) coexisting with early-stage endometrial cancer (EC). We aimed to assess the staining patterns of selected CKs (CK7, CK19, CK20, CK AE1/AE3) in 74 patients with coexisting AEH and EC by independently analyzing both morphological variables. Specimens were collected from women with AEH and EC who underwent surgical interventions between 2012 and 2019 at the Department of Obstetrics and Gynecology of Vilnius University Hospital "Santaros Klinikos" in Vilnius, Lithuania. Immunostaining was also qualitatively classified as being heterogeneous or intense. The results revealed heterogeneous CK7 expression in all AEH cases and intense staining in 95.95% cases of AEH. The heterogeneous expression of CK7 was detected in all EC specimens. Intense CK7 expression was observed in 95.09% cases of EC G1 and in all G2 ECs. Heterogenous CK19 expression was present in all AEH specimens with intense staining in 92.42% of cases. Heterogeneous CK19 expression was observed in all EC samples with intense expression in 86.27% cases of EC G1 and 100% cases of EC G2. Interestingly, a significant relationship was found when comparing the heterogeneous expression of CK19 between AEH and well-differentiated EC. A significant difference was reported in the intense expression of CK AE1/AE3 (p = 0.031; p = 0.029) between AEH and G2 ECs and in the intense expression of CK AE1/AE3 between G1 and G2 ECs. CK20 staining was not a characteristic feature for AEH and early-stage EC. CK staining is present either in AEH or in early-stage endometrioid-subtype EC in different manners. Heterogeneous CK19 expression was significantly more common in AEH than in EC. CK20 expression was not associated with either AEH nor early-stage EC. An intense expression of CK AE1/AE3 was mainly present in moderately differentiated ECs, whereas the intense reactivity of AE1/AE3 showed a significant difference in well to moderately differentiated uterine tumors. The clinical implication of CK staining may aid in the more accurate diagnosis of AEH and early-stage EC as well as detect micrometastases leading to better oncological outcomes.

Analysis of CDO1, PITX2, and CDH13 Gene Methylation in Early Endometrial Cancer for Prediction of Medical Treatment Outcomes.

An observational cohort study of patients diagnosed with endometrial cancer (EC) stage IA G1, or atypical endometrial hyperplasia (AEH), undergoing organ-preserving treatment, was conducted. OBJECTIVE OF THE STUDY: To determine CDO1, PITX2, and CDH13 gene methylation levels in early endometrial cancer and atypical hyperplasia specimens obtained before organ-preserving treatment in the patients with adequate response and with insufficient response to hormonal treatment. MATERIALS AND METHODS: A total of 41 endometrial specimens obtained during diagnostic uterine curettage in women with EC (n = 28) and AEH (n = 13), willing to preserve reproductive function, were studied; 18 specimens of uterine cancer IA stage G1 from peri- and early postmenopausal women (comparison group) were included in the study. The control group included 18 endometrial specimens from healthy women obtained by diagnostic curettage for missed abortion and/or intrauterine adhesions. Methylation levels were analyzed using the modified MS-HRM method. RESULTS: All 13 women with AEH had a complete response (CR) to medical treatment. In the group undergoing organ-preserving treatment for uterine cancer IA stage G1 (n = 28), 14 patients had a complete response (EC CR group) and 14 did not (EC non-CR group). It was found that all groups had statistically significant differences in CDO1 gene methylation levels compared to the control group (p < 0.001) except for the EC CR group (p = 0.21). The p-value for the difference between EC CR and EC non-CR groups was <0.001. The differences in PITX2 gene methylation levels between the control and study groups were also significantly different (p < 0.001), except for the AEH group (p = 0.21). For the difference between EC CR and EC non-CR groups, the p-value was 0.43. For CDH13 gene methylation levels, statistically significant differences were found between the control and EC non-CR groups (p < 0.001), and the control and EC comparison groups (p = 0.005). When comparing the EC CR group with EC non-CR group, the p-value for this gene was <0.001. The simultaneous assessment of CDO1 and CDH13 genes methylation allowed for an accurate distinction between EC CR and EC non-CR groups (AUC = 0.96). CONCLUSION: The assessment of CDO1 and CDH13 gene methylation in endometrial specimens from patients with endometrial cancer (IA stage G1), scheduled for medical treatment, can predict the treatment outcome.

Hysteroscopy and weight loss in treatment of endometrial cancer: case report and literature review.

Fertility-sparing treatments have become important for young women with atypical endometrial hyperplasia (AEH) or endometrial carcinoma (EC) who wish to preserve their reproductive potential. Evidence indicates a strong relationship between weight and EC and the effect of weight loss on reducing the risk of EC. We report the case of a young obese woman with a body mass index (BMI) of 46.6 kg/m2, diagnosed with grade 2 endometrial endometrioid adenocarcinoma, who underwent a combined fertility-sparing treatment with hysteroscopic resection followed by insertion of a levonorgestrel intrauterine system. After twelve months of failure to achieve a complete response, bariatric surgery was proposed to lose weight and improve the response to treatment. Histologic regression was achieved three months after surgery, with a weight loss of 30 kg and fifteen months after combined treatment of endometrial cancer. We reviewed the literature to summarize the evidence on the role of bariatric surgery and weight loss in modifying the oncologic and reproductive outcomes of women undergoing fertility-sparing treatment for atypical endometrial lesions.

Comparison of the effect of levonorgestrel-intrauterine system with or without oral megestrol acetate on fertility-preserving treatment in patients with atypical endometrial hyperplasia: A prospective, open-label, randomized controlled phase II study.

OBJECTIVE: To compare the effects of levonorgestrel-intrauterine system (LNG-IUS) with or without oral megestrol acetate (MA) versus MA alone on fertility-preserving treatment in patients with atypical endometrial hyperplasia (AEH). METHODS: This was a single-center phase II study with an open-label, randomized, controlled trial conducted between July 2017 and June 2020 at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. A total of 180 patients (18-45 years) with primary AEH were randomly assigned (1:1:1) to the MA (N = 60), LNG-IUS (N = 60), or MA + LNG-IUS (N = 60) groups, in which the patients received MA (160 mg orally daily), LNG-IUS, or MA + LNG-IUS (MA 160 mg orally daily plus LNG-IUS), respectively. The primary endpoint was complete response (CR) rate at 16 weeks of treatment. The secondary endpoints were CR rate at 32 weeks of treatment, adverse events, and recurrence and pregnancy rates. All analyses were conducted in a modified intention to treat (ITT) population who underwent randomization and in whom treatment was initiated. RESULTS: The Kaplan-Meier estimate of 16-week CR rates (with 95% confidence interval) were 19.2% (9.0-29.4%) in the MA group, 35.0% (22.8-47.2%) in the LNG-IUS group, and 29.4% (17.2-41.6%) in the MA + LNG-IUS groups. Side effects such as weight gain, increased nocturnal urine, night sweat, insomnia and edema face seemed to occur less frequently in LNG-IUS group compared with MA group. No difference was found among groups regarding second endpoints. CONCLUSIONS: LNG-IUS or LNG-IUS plus MA did not show significant therapeutic benefit compared with MA alone. Further studies including sufficient sample-size are needed to validate these findings due to the underpowered design of this trial. FUNDING: This study was supported by the National Key Research and Development Program of China (Grant No 2019YFC1005200 and 2019YFC1005204), Shanghai Medical Centre of Key Programs for Female Reproductive Diseases (Grant No. 2017ZZ010616), Shanghai sailing program (Grant No. 19YF1404200), and Shen Kang clinical project (SHDC22021219). Trial registrationClinicalTrials.govNCT03241888. https://www. CLINICALTRIALS: gov/ct2/show/NCT03241888?term=NCT03241888&draw=2&rank=1.

Molecular subtyping in endometrial cancer: A promising strategy to guide fertility preservation.

OBJECTIVES: To investigate the association of molecular subtype with progesterone response in patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH). METHODS: Premenopausal patients aged ≤48 years with tumor-normal sequencing data who received progesterone for EC/AEH from 1/1/2010-6/30/2021 were identified. Tumors were classified as POLE-ultramutated, microsatellite instability-high (MSI-H), copy number-high (CN-H), or copy number-low (CN-L) molecular subtype. Best response to progesterone was compared by subtype. Appropriate statistical tests were performed. RESULTS: Of 20 patients, 7 (35%) had AEH and 13 (65%) had EC. Sixteen tumors (80%) were CN-L, 3 (15%) were MSI-H, and 1 (5%) was POLE-ultramutated. Median time on progesterone was 22 months (range, 3-115). Ten patients (50%) had complete response (CR); median time to CR was 9 months (range, 3-32). Four patients (20%) had stable disease (SD) and 6 (30%) had progressive disease (PD). For CN-L tumors, 10 patients (62%) had CR, 3 (19%) had SD, and 3 (19%) had PD. For MSI-H tumors, 1 patient (33%) had SD and 2 (66%) had PD. For POLE-ultramutated tumors, 1 patient had PD. Median follow-up was 48 months (range, 12-123). Four of 10 patients (40%) with CR recurred; median time from CR to recurrence was 16 months (range, 5-102). CONCLUSION: Molecular subtype may be associated with progesterone response in patients with EC/AEH. CN-L tumors had the best response, and MSI-H tumors had the poorest. Recurrence after CR is common, and close surveillance is warranted. Larger studies investigating the role of molecular classification in medical management of EC/AEH are needed.

Risk of endometrial cancer in asymptomatic postmenopausal women in relation to ultrasonographic endometrial thickness: systematic review and diagnostic test accuracy meta-analysis.

OBJECTIVE: This study aimed to evaluate the risk of endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women concerning the endometrial thickness measured by stratified threshold categories used for performing subsequent endometrial sampling and histologic evaluation. DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, SciELO, Embase, the Cochrane Central Register of Controlled Trials, LILACS, conference proceedings, and international controlled trials registries were searched without temporal, geographic, or language restrictions. STUDY ELIGIBILITY CRITERIA: Studies were selected if they had a crossover design evaluating the risk of atypical endometrial hyperplasia and endometrial carcinoma in postmenopausal asymptomatic women and calculated the diagnostic accuracy of transvaginal ultrasonography thresholds (at least 3.0 mm) confirmed by histopathologic diagnosis. METHODS: This was a systematic review and diagnostic test accuracy meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy and Synthesizing Evidence from Diagnostic Accuracy Tests guidelines. Endometrial thickness thresholds were grouped as follows: from 3.0 to 5.9 mm; between 6.0 and 9.9 mm; between 10.0 and 13.9 mm; and ≥14.0 mm. Quality assessment was performed using the Quality Assessment Tool for Diagnostic Accuracy Studies 2 tool. Publication bias was quantified using the Deek funnel plot test. Coprimary outcomes were the risk of atypical endometrial hyperplasia or endometrial carcinoma according to the endometrial thickness and diagnostic accuracy of each threshold group. RESULTS: A total of 18 studies provided the data of 10,334 women who were all included in the final analysis. Overall, at an endometrial thickness threshold of at least 3.0 mm, the risk of atypical endometrial hyperplasia or endometrial carcinoma was increased 3-fold relative to women below the cutoff (relative risk, 3.77; 95% confidence interval, 2.26-6.32; I2=74%). Similar degrees of risk were reported for thresholds between 3.0 and 5.9 mm (relative risk, 5.08; 95% confidence interval, 2.26-11.41; I2=0%), 6.0 and 9.9 mm (relative risk, 4.34; 95% confidence interval, 1.68-11.23; I2=0%), 10.0 and 13.9 mm (relative risk, 4.11; 95% confidence interval, 1.55-10.87; I2=86%), and ≥14.0 mm (relative risk, 2.53; 95% confidence interval, 1.04-6.16; I2=78%) with no significant difference among subgroups (P=.885). Regarding diagnostic accuracy, the pooled sensitivity decreased from thresholds below 5.9 mm (relative risk, 0.81; 95% confidence interval, 0.49-0.85) to above 14.0 mm (relative risk, 0.28; 95% confidence interval, 0.18-0.40). Furthermore, the specificity increased from 0.70 (95% confidence interval, 0.61-0.78) for endometrial thickness between 3.0 and 5.9 mm to 0.86 (95% confidence interval, 0.71-0.94) when the endometrial thickness is ≥14.0 mm. For 3.0 to 5.9 mm and 10.0 to 13.9 mm thresholds, the highest diagnostic odds ratios of 10 (95% confidence interval, 3-41) and 11 (95% confidence interval, 2-49), with areas under the curve of 0.81 (95% confidence interval, 0.77-0.84) and 0.82 (95% confidence interval, 0.79-0.86), respectively, were retrieved. The summary point analysis revealed that the 3.0 to 5.9 mm cutoff point was placed higher in the summary receiver operator curve space than the other subgroups, indicating increased endometrial carcinoma or atypical endometrial hyperplasia diagnosis using these cutoffs. CONCLUSION: Both low and high endometrial thickness thresholds in postmenopausal asymptomatic women seem equally effective in detecting endometrial carcinoma and atypical endometrial hyperplasia. However, although using a 3.0 to 5.9 mm cutoff results in a lower specificity, the offsetting improvement in sensitivity may justify using this cutoff for further endometrial evaluation in patients with suspected endometrial malignancy.

Serum HE4 predicts progestin treatment response in endometrial cancer and atypical hyperplasia: A prognostic study.

OBJECTIVE: To investigate serum human epididymis-4 (HE4) as a predictive biomarker of intrauterine progestin response in endometrial cancer and atypical endometrial hyperplasia (AEH). DESIGN: Prospective prognostic factor study. SETTING: Consecutive sample of women attending a tertiary gynaecological oncology centre in northwest England. POPULATION: Women with AEH or early-stage, low-grade endometrial cancer who were unfit for or declined primary surgical management. METHODS: A total of 76 women, 32 with AEH and 44 with endometrial cancer, were treated with a levonorgestrel intrauterine system (LNG-IUS) for 12 months. Endometrial biopsies and imaging were performed to assess treatment response. Pretreatment serum HE4 was analysed by chemiluminescence immunoassay and diagnostic accuracy and logistic regression analyses were performed. MAIN OUTCOME MEASURES: Progestin response at 12 months defined by histology and imaging. RESULTS: The median age and body mass index (BMI) of the final cohort were 52 years (interquartile range [IQR] 33-62 years) and 46 kg/m2 (IQR 38-54 kg/m2 ), respectively. Baseline serum HE4 was significantly higher in non-responders than responders (119.2 pmol/L, IQR 94.0-208.4 pmol/L versus 71.8 pmol/L, IQR 56.1-84.2 pmol/L, p < 0.001). Older age (odds ratio [OR] 0.96, 95% CI 0.93-0.99, p = 0.02), baseline serum HE4 (OR 0.97, 95% CI 0.96-0.99, p = 0.001) and endometrial cancer histology (OR 0.22, 95% CI 0.72-0.68, p = 0.009) were associated with a lower likelihood of progestin treatment response. Serum HE4 remained independently associated with progestin treatment failure when adjusted for age and histology (adjusted hazard ratio 0.97, 95% CI 0.96-0.99, p = 0.008). CONCLUSION: Serum HE4 shows promise as a predictive biomarker of progestin treatment response in endometrial cancer and AEH.

Recent advances in the management of postmenopausal women with non-atypical endometrial hyperplasia.

Non-atypical endometrial hyperplasia is a benign disease without significant somatic genetic changes. Postmenopausal women with non-atypical endometrial hyperplasia have a significant risk of progression to endometrial cancer and persistent endometrial hyperplasia. Most cases of atypical endometrial hyperplasia in postmenopausal women are treated surgically, including hysterectomy. At present, the treatment of postmenopausal women with non-atypical endometrial hyperplasia is still controversial. Correct and timely diagnosis and treatment are of great significance to prevent progression of the lesion. This study mainly provides an updated synthesis of the literature that investigates the etiology, diagnosis and treatment of postmenopausal women with non-atypical endometrial hyperplasia. As of December 2022, a literature search related to postmenopausal non-atypical endometrial hyperplasia was conducted on the PubMed database. For most postmenopausal patients with non-atypical endometrial hyperplasia, regular re-examination should be performed during conservative treatment. For postmenopausal patients with endometrial cancer risk factors, persistent non-atypical endometrial hyperplasia or progesterone contraindications, hysterectomy and bilateral salpingo-oophorectomy should be the first choice.

Obstetric outcomes after medroxyprogesterone acetate treatment for early stage endometrial cancer or atypical endometrial hyperplasia: a single hospital-based study.

BACKGROUND: To investigate perinatal outcomes in pregnancy after high-dose medroxyprogesterone acetate (MPA) therapy for early stage endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) and to determine whether pregnancy after MPA therapy is at a higher risk of placenta accreta. METHODS: Data of 51 pregnancies in 46 women who received MPA therapy for EC or AEH and delivered after 22 weeks of gestation at Keio University Hospital were reviewed. A retrospective matched case-control study was performed to determine the risk of placenta accreta in pregnancy after MPA therapy compared with singleton pregnancies without any history of maternal malignancy treatments. RESULTS: The incidence of placenta accreta was higher in the MPA group than in the control group (15.7 vs. 0%, p = 0.0058). However, no differences in other perinatal outcomes were observed between groups. While gestational weeks at delivery in the MPA group were later than those in the control group (p = 0.0058), no difference in the incidence of preterm delivery was recorded between groups. In the MPA therapy group, the number of patients who underwent ≥ 6 dilation and curettage (D&C) was higher in the placenta accreta group than in the non-placenta accreta group (50.0 vs. 14.0%, p = 0.018). Patients with ≥ 6 D&Cs demonstrated a 6.0-fold increased risk of placenta accreta (p = 0.043, 95% CI 1.05-34.1) than those receiving ≤ 3 D&Cs. CONCLUSION: Pregnancy after MPA therapy is associated with a high risk of placenta accreta. In cases in which the frequency of D&C is high, placenta accreta should be considered.

The role of hysteroscopy in fertility preservation in endometrial cancer and atypical endometrial hyperplasia: a semi-systematic literature review.

PURPOSE: Endometrial premalignancies are among the common reasons for outpatient gynecology visits among women in reproductive ages. Due to the continued increase in global obesity incidence among them, endometrial malignancies are expected to become even further prevalent. Hence, fertility-sparing interventions are essential and needed. In this semi-systematic literature review, we aimed to investigate the role of hysteroscopy in fertility preservation in endometrial cancer and atypical endometrial hyperplasia. Our secondary goal is to analyze the pregnancy outcomes following fertility preservation. METHODS: We conducted a computed search in PubMed. We included original research articles including hysteroscopic interventions in pre-menopausal patients with endometrial malignancies and premalignancies who underwent fertility-preserving treatments. We collected data on medical treatment, response, pregnancy outcomes, and hysteroscopy. RESULTS: Of the query results (n = 364), our final analysis included 24 studies. Overall, 1186 patients with endometrial premalignancies and endometrial cancer (EC) were included. More than half of the studies were retrospective design. They included almost ten different forms of progestins. Of the reported pregnancies (n = 392), the overall pregnancy rate was 33.1%. The majority of the studies used operative hysteroscopy (87.5%). Only three (12.5%) reported their hysteroscopy technique in detail. Although more than half of the studies did not provide any information on adverse effects due to hysteroscopy, there were no serious adverse effects among the reported ones. CONCLUSION: Hysteroscopic resection may increase the success rate of fertility-preserving treatment of EC and atypical endometrial hyperplasia. The clinical significance of the theoretical concern of the dissemination of cancer is not known. Standardization of the use of hysteroscopy in fertility-preserving treatment is needed.