Atypical Endometrial Hyperplasia Research Articles

Diaphragmatic clear cell carcinoma with Lynch syndrome after surgery for atypical endometrial hyperplasia and ovarian endometriosis: A case report

Diaphragmatic clear cell carcinoma with Lynch syndrome after surgery for atypical endometrial hyperplasia and ovarian endometriosis: A case report

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.

Chinese guidelines on the management of endometrial hyperplasia

• Endometrial hyperplasia can be classified as either hyperplasia without atypia or atypical hyperplasia.• Abnormal uterine bleeding is the most common symptom of endometrial hyperplasia. Transvaginal ultrasound is recommended for initial imaging to evaluate endometrial hyperplasia (evidence level 2+), while transrectal ultrasound is recommended for virgo patients (evidence level 3).• Endometrial biopsy should be used to confirm diagnosis in patients where endometrial lesions are suspected. Effective histological approaches to make definite diagnoses include diagnostic curettage (evidence level 2++), hysteroscopic-guided biopsy (evidence level 2+) and endometrial aspiration biopsy (evidence level 2-).• Progesterone is the preferred medication for the treatment of endometrial hyperplasia without atypia. Compared to oral progestins, placement of a levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with higher regression rates, lower recurrence rates and fewer adverse events which can be the initial treatment method. (Meta evidence level 1-, RCT evidence level 2+). Ultrasound and endometrial biopsies should be performed every 6 months during treatment to evaluate its effect and treatment should continue until no pathological changes are observed in two consecutive endometrial biopsies. Hysterectomy is not the preferred choice of treatment for patients with endometrial hyperplasia without atypia.• Minimally invasive hysterectomy is indicated for patients with endometrial atypical hyperplasia (evidence level 1+), bilateral fallopian tubes should also be removed (evidence level 2+). In cases where surgery cannot be tolerated, fertility is desired or the patient is younger than 45 years old, medical therapy is recommended (evidence level 3). LNG-IUS is the preferred medical therapy method (evidence level 2+). Endometrial pathologic evaluation should be performed every 3 months during conservative treatments, with adjustments made to dosages or approaches based on observed response to medication. Treatment should continue until no pathological changes are detected in two consecutive endometrial biopsies (evidence level 2++). There is no indication of sentinel lymph nodes biopsy and/or lymphadenectomy for hyperplasia with or without atypia.• Total hysterectomy is recommended to treat patients with recurrent endometrial atypical hyperplasia (evidence level 3); however, medical conservative therapy may be considered for patients hoping to become pregnant in the future.• Patients with fully regressed disease who would like to become pregnant should be advised to seek assistance through assisted reproductive technologies (evidence level 3).• Long-term follow-up is suggested for patients after endometrial hyperplasia treatment (evidence level 2+). Patient education is imperative for improving medication adherence, increasing regression rates and lowering recurrence rates (evidence level 3).

Pregnancy and obstetric outcomes after fertility-sparing management of endometrial cancer and atypical hyperplasia: a multicentre cohort study.

What are the pregnancy and obstetric outcomes in women with atypical hyperplasia (AH) or early-stage endometrial cancer (EC) managed conservatively for fertility preservation? The study found a live birth rate of 62% in patients with AH or EC after conservative treatment, with higher level of labour induction, caesarean section, and post-partum haemorrhage. Fertility-sparing treatment is a viable option for women with AH or EC during childbearing years, but the outcomes of such treatments, especially regarding pregnancy and obstetrics, need further exploration. This retrospective cohort study analysed data from January 2010 to October 2022, involving 269 patients from the French national register of patients with fertility-sparing management of AH/EC. Women above 18 years of age, previously diagnosed with AH/EC, and approved for fertility preservation were included. Patients were excluded if they were registered before 2010, if their treatment began <6 months before the study, or if no medical record on the pregnancy was available. In total, 95 pregnancies in 67 women were observed. Pregnancy was achieved using ART in 63 cases (66%) and the live birth rate was 62%, with early and late pregnancy loss at 26% and 5%, respectively. In the 59 cases resulting in a live birth, a full-term delivery occurred in 90% of cases; 36% of cases required labour induction and 39% of cases required a caesarean section. The most common maternal complications included gestational diabetes (17%) and post-partum haemorrhaging (20%). The average (±SD) birthweight was 3110 ± 736 g; there were no significant foetal malformations in the sample. No significant difference was found in pregnancy or obstetric outcomes between ART-obtained and spontaneous pregnancies. However, the incidence of induction of labour, caesarean section, and post-partum haemorrhage appears higher than in the general population. The retrospective nature of the study may introduce bias, and the sample size might be insufficient for assessing rare obstetric complications. This study offers valuable insights for healthcare providers to guide patients who received fertility-sparing treatments for AH/EC. These pregnancies can be successful and with an acceptable live birth rate, but they seem to be managed with caution, leading to possible tendency for more caesarean sections and labour inductions. No increase in adverse obstetric outcomes was observed, with the exception of suspicion of a higher risk of post-partum haemorrhaging, to be confirmed. No funding was received for this study. There are no conflicts of interest to declare. N/A.

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

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. 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. 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). 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.

Proliferation activity and hormonal status of atypical hyperplasia and endometrioid adenocarcinoma of the endometrium

Atypical hyperplasia of the endometrium is a precancerous condition for endometrioid adenocarcinoma of the endometrium, which is the largest group among malignant neoplasms of the uterine body, according to the Cancer Registry, the mortality rate from which took the 3rd place in 2021. The absence of specific clinical manifestations complicates diagnostics at the early stages of the process, which necessitates the study of histological and immunohistochemical criteria to verify the diagnosis. The aim of the study. To improve the differential diagnostic morphological and immunohistochemical criteria for the diagnosis of atypical hyperplasia and endometrioid adenocarcinoma of the endometrium, using the latest international classification data. Materials and methods. Retrospective analysis of 76 cases of postoperative material of women for the period from 2020 to 2022 with a diagnosis of “endometrioid adenocarcinoma of the endometrium” – 61 cases and “endometrial hyperplasia with atypia” – 15 included an assessment of histological, immunohistochemical features, followed by statistical processing of the obtained results. Results. The incidence of endometrioid adenocarcinoma of the endometrium and atypical endometrial hyperplasia occurs in the premenopausal and menopausal periods. The expression level of the Ki-67 marker is directly proportional to the degree of tumor malignancy (p &lt; 0.05). Estrogen receptors decrease as the degree of tumor malignancy increases. Progesterone receptors are equally present in endometrioid adenocarcinomas and atypical endometrial hyperplasia (p &lt; 0.05). Conclusions. The necessity of using the Ki-67 marker and determining the hormonal status in endometrioid adenocarcinomas of the endometrium and atypical hyperplasia of the endometrium is argued.

Correlation between steroid receptor expression and response to progestational therapy in patients with atypical endometrial hyperplasia or cancer

BackgroundConservative management of atypical endometrial hyperplasia (AEH) or endometrial cancer (EMCA) often relies on the treatment of synthetic progestins, which show varied success and response rates. We evaluate the correlation between steroid receptor expression and response to progestin therapy in patients with AEH and EMCA. MethodsRetrospective cohort study collected data for patients with AEH or EMCA who had an endometrial sample after receiving conservative therapy utilizing either Megestrol acetate or Levonorgestrel Intrauterine device (IUD). Immunohistochemistry (IHC) was performed on pre- and post- treatment biopsy samples to assess androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) expression. IHC scores (1–12) were calculated based on staining intensity and percentage of positive cells. Results and analysisWe identified 15 patients with AEH and EMCA between 2015 and 2023 with the majority of African American ethnicity (53 %). Fourteen patients (93 %) received Megestrol acetate, and 1 patient received Levonorgestrel IUD alone. Three patients ultimately underwent hysterectomy. Seven (46.6 %) endometrial samples had strong positivity for AR, PR and ER expression on pre-treatment biopsies, and only 3 (20 %) of them maintained strong positivity for the 3 receptors in the post-treatment. Patients who successfully responded to the treatment demonstrated a significantly greater decrease in IHC scores after the treatment compared to those who did not respond (p = 0.009). ConclusionSteroid receptor expression could be used as a possible biomarker for response to progestin therapy in patients undergoing conservative management for AEH and EMCA.

A Rare Case Report: Atypical Endometrial Hyperplasia and Combination of Placental Site Nodule and Treatment Follow-up

A Rare Case Report: Atypical Endometrial Hyperplasia and Combination of Placental Site Nodule and Treatment Follow-up

Treatment of Chronic Endometritis with Vague Symptoms in Patients with Endometrial Hyperplasia

Aim. To develop new therapeutic approaches for chronic endometritis with vague symptoms, which is frequently diagnosed in patients with endometrial hyperplasia.Materials and Methods. We collected the material from uterine scrapings in patients (age 25-63 years) with endometrial hyperplasia (diagnosed by ultrasound examination) and abnormal uterine bleeding which occurred during hysteroscopic dilation and curettage. Among the exclusion criteria were intraepithelial neoplasia and atypical endometrial hyperplasia, cancer, systemic inflammation, and hormonal therapy. To verify the diagnosis, we employed immunohistochemistry, digital slide scanning, and morphometry.Results. This study confirmed the value of immunohistochemical diagnosis underlying the pathogenetic therapy of endometrial hyperplasia using non-steroidal anti-inflammatory drugs. Inflammatory markers indicating the distribution and quantitative alterations in cell populations had the highest diagnostic value.Conclusion. We developed a molecularly oriented algorithm for the treatment of patients with endometrial hyperplasia. This algorithm improves existing preventive, diagnostic and therapeutic approaches using immunohistochemical techniques. Such molecular testing can help in making correct therapeutic decisions.

A Comprehensive Approach: Correlating Ultrasound Imaging with Endometrial Histopathological Analysis in Perimenopausal Women with Heavy MenstrualBleeding.

Abnormal uterine bleeding (AUB) is a common troublesome symptom in the perimenopausal age group. The most common type of AUB in this age group is heavy menstrual bleeding. There is a risk of endometrial carcinoma and atypical endometrial hyperplasia in women with AUB in the age group of 40-50 years. Hence early evaluation is of paramount importance in managing women with perimenopausal heavy menstrual bleeding. The current study was undertaken to study the correlation between ultrasound findings and various benign and malignant endometrial histologies in perimenopausal women with heavy menstrual bleeding. Women aged 40-55 years presenting with heavy menstrual bleeding at the gynaecology outpatient department at Sree Balaji Medical College and Hospital, Chennai, India, were included in the study. Patients on anti-platelet and anti-coagulation therapy and patients already on hormonal treatment for heavy menstrual bleeding were excluded from the study. The demographic factors, symptom profiles, ultrasound findings, and histopathological reports were tabulated and analysed. Of the 147 women included in the study, 75 (51%) were aged 45-50 years and 107 (73%) had two or more pregnancies. Fibroid was the common non-endometrial cause of heavy menstrual bleeding in 52 (35%) cases. The proliferative pattern was the most common non-pathological histology identified in 46 (31%) cases. Endometrial hyperplasia without atypia was the most common pathological histology observed in the study population. Endometrial thickness of more than 8 mm was strongly associated with premalignant or malignant endometrial lesions. Our study has attempted to identify the correlation between ultrasound evaluation of perimenopausal women with heavy menstrual bleeding and endometrial pathology. Ultrasound, being cost-effective and widely available, is proven to be a tool for first-line investigation of perimenopausal women with heavy menstrual bleeding that guides further evaluation and management.

Diagnostic, prognostic, and predictive importance of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and CA125 in endometrial hyperplasia and carcinoma.

Inflammation has an important role in the progression of endometrial carcinoma. The aim of this study is to find the association between neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and CA125 in endometrial hyperplasia and endometrial carcinoma. The study also focuses on the association of CA125, NLR, and PLR with histopathological parameters in endometrial carcinoma that are of prognostic importance. This is a prospective cross-sectional study on 57 biopsy-proven cases of endometrial hyperplasia and carcinoma conducted over a period of two years. The NLR, PLR, and CA125 were calculated and recorded in all the 57 cases. The 57 cases were divided into three groups: endometrial hyperplasia without atypia group which included 36 cases, endometrial atypical hyperplasia group which included 10 cases, and the endometrial carcinoma group which included 11 cases. Comparison was done between the groups, and parity, NLR, PLR, and CA125 were found to be significant, but patient age and postmenopausal status were not significant. NLR, PLR, and CA125 were found to increase with higher grade, pT-stage, and nodal stage for the endometrial carcinoma cases. NLR, PLR, and CA125 were marginally increased or normal in the case of endometrial hyperplasia without atypia and endometrial atypical hyperplasia, while they were significantly increased in endometrial carcinoma, and also correlated with an increase in grade, pT-stage, and nodal stage. Hence, these can be considered for additional screening as diagnostic, prognostic, and predictive markers in case of abnormal uterine bleeding with endometrial pathology.

Metformin and progestins in women with atypical hyperplasia or endometrial cancer: systematic review and meta-analysis.

To assess metformin's effectiveness in adding it to progestin-based hormone therapy for treating atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC). We conducted a systematic review and meta-analysis following PRISMA guidelines (registration number CRD42023399094). We searched databases for studies up to March 2023, including randomized and non-randomized clinical trials in English. Out of 280 studies, 9 studies (1104 patients) were eligible. A total of 408 patients were allocated to receive metformin, and 696 patients entered the control group. Primary analysis focused on evaluating the CR showed a significant difference in patients with AEH treated with metformin (RR = 1.10, 95% CI 1.02-1.20, p = 0.02). Relapse rate (RR = 0.62, 95% CI 0.33-1.17, p = 0.14) was also evaluated. Secondary analysis indicated higher pregnancy rates (RR = 1.28, 95% CI 1.04-1.57, p = 0.02) with no significant difference in live birth rates (RR = 0.56, 95% CI 0.29-1.10, p = 0.09). Combined therapy is effective. Metformin shows superiority to the standard regimen in achieving better CR rate in patients with AEH and benefits pregnancy rates but not recurrence or live birth rates. Therefore, the ideal fertility-sparing treatment for EC has not yet been determined and further clinical trials are needed.

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

ObjectiveThis 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...

Abstract PR003: The combination of the glucagon like peptide-1 receptor agonist semaglutide and the progestin levonorgestrel is highly effective in preclinical studies of endometrial cancer

Abstract Obesity is a major risk factor for endometrial cancer (EC), and glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss during conservative treatment or for EC prevention. Progestins such as levonorgestrel are effective in preventing or treating early-stage EC. However, better and more durable response rates could be achieved using combinatorial therapeutic regimens of well tolerated agents with the potential to enhance progestin effectiveness. We theorized that the combination of semaglutide and levonorgestrel would be useful as a novel treatment or prevention regimen and tested this hypothesis using EC cell lines, patient-derived organoids, and RNA-sequencing from patient samples. From the molecular perspective, EC cell lines, organoids, and tissues express GLP-1R as determined by both qPCR and Western blotting, and GLP-1R agonist treatment induces GLP-1R mRNA transcription through positive feedback mechanisms in EC cell models. Preclinical studies in 6 patient-derived organoid models of EC demonstrated the promising therapeutic effects of the combination of semaglutide and levonorgestrel on endometrial cell viability. Specifically, patient-derived organoids from grade 1 endometrial carcinomas were treated with progesterone, levonorgestrel, semaglutide, or levonorgestrel + semaglutide at drug concentrations of 100 nM for 72 hours. Multiple models demonstrated a significant reduction in viability in response to combinatorial treatment. Most interesting was the induction of not only the membrane GLP-1 receptor with treatment, but also the significant upregulation of nuclear and membrane progesterone receptors, PR and PGRMC1/2, respectively, indicating a positive feedback loop between semaglutide and progestins such as levonorgestrel. In addition, other steroid hormone receptor mRNAs such as the estrogen, androgen and mineralocorticoid receptors (ER, AR, and MR) were similarly upregulated. In these studies, we identify synergistic molecular crosstalk between the GLP-1R and steroid hormone receptor pathways with the potential to enhance the anti-cancer activity of semaglutide and levonorgestrel when combined. Future studies are aimed at testing this regimen in patients conservatively managed for atypical endometrial hyperplasia or low-grade endometrial cancers. Citation Format: Kimberly K. Leslie, Andrea Hagemann, Kristina Thiel, Ian Hagemann, David Mutch, Eric Devor, Paige Malmrose. The combination of the glucagon like peptide-1 receptor agonist semaglutide and the progestin levonorgestrel is highly effective in preclinical studies of endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr PR003.

Diagnosis and management of endometrial hyperplasia: A UK national audit of adherence to national guidance 2012-2020.

Endometrial hyperplasia (EH) is a precusor lesion for endometrial cancer (EC), the commonest gynaecological malignancy in high-income countries. EH is a proliferation of glandular tissue, classified as either non-atypical endometrial hyperplasia (NEH) or, if the cytological features are abnormal, atypical endometrial hyperplasia (AEH). The clinical significance of AEH is that patients face both a high risk of having occult EC and a high risk of progression to EC if untreated. Recommendations on the care of women with EH were introduced by United Kingdom-wide guidance (Green-top Guide No. 67, 2016). National adherence to guidance is unknown. We aimed to describe the care of patients with EH; to compare the patterns of care for those with EH with national guidance to identify opportunities for quality improvement; and to compare patterns of care prior to and following the introduction of national guidance to understand its impact. In this UK-wide patient-level clinical audit, we included 3,307 women who received a new histological diagnosis of EH through a gynaecology service between 1 January 2012 and 30 June 2020. We described first-line management, management at 2 years, and surgical characteristics prior to and following national guidance for EH using proportions and 95% confidence intervals (CIs) and compared process measures between time periods using multilevel Poisson regression. Of the 3,307 patients, 1,570 had NEH and 1,511 had AEH between 2012 and 2019. An additional 85 patients had NEH and 141 had AEH during 2020. Prior to national guidance, 9% (95% CI [6%, 15%]) received no initial treatment for NEH compared with 3% (95% CI [1%, 5%]) post-guidance; 31% (95% CI [26%, 36%]) and 48% (95% CI [43% 53%]) received an intrauterine progestogen, respectively, in the same periods. The predominant management of women with AEH did not differ, with 68% (95% CI [61%, 74%]) and 67% (95 CI [63%, 71%]) receiving first-line hysterectomy, respectively. By 2 years, follow-up to histological regression without hysterectomy increased from 38% (95% CI [33%, 43%]) to 52% (95% CI [47%, 58%]) for those with NEH (rate ratio (RR) 1.38, 95% CI [1.18, 1.63] p < 0.001). We observed an increase in the use of total laparoscopic hysterectomy among those with AEH (RR 1.26, 95% CI [1.04, 1.52]). In the later period, 37% (95% CI [29%, 44%]) of women initially diagnosed with AEH who underwent a first-line hysterectomy, received an upgraded diagnosis of EC. Study limitations included retrospective data collection from routine clinical documentation and the inability to comprehensively understand the shared decision-making process where care differed from guidance. The care of patients with EH has changed in accordance with national guidance. More women received first-line medical management of NEH and were followed up to histological regression. The follow-up of those with AEH who do not undergo hysterectomy must be improved, given their very high risk of coexistent cancer and high risk of developing cancer.

Analysis of clinical data of different endometrial pathological types in perimenopausal women with abnormal uterine bleeding.

Early detection and diagnosis are important for improving the therapeutic effect and quality of life in patients with endometrial cancer (EC). This study aimed to analyze the clinical data of different endometrial pathological types in perimenopausal women with abnormal uterine bleeding (AUB) in order to provide evidence for the prevention and early diagnosis of EC. A total of 462 perimenopausal women with AUB were enrolled in this prospective observational study. Endometrial biopsy was performed in patients with suspected endometrial lesions. According to the pathological examination results, the patients were divided into endometrial polyp group (EP) (n = 71), endometrial hyperplasia without atypia group (EH) (n = 59), atypical endometrial hyperplasia (AEH) (n = 36), and EC group (n = 27). The history risk factors and ultrasonic imaging characteristics of endometrium among the four groups were compared. Twenty-seven women were diagnosed with EC (5.84%). The prevalence rate of AEH and EC in the group of 51- to 55-year-old women was significantly higher than that in the groups of 40- to 45-year-old women and of 46- to 50-year-old women (P < 0.05). The age, body mass index, and history of diabetes gradually increased with the development of endometrial pathological types. In addition, the correlation index of endometrial blood flow increased gradually, and the proportion of uneven endometrial echo, unclear endometrial-myometrial junction (EMJ), and ovarian cyst also increased gradually. However, no statistically significant difference was found when comparing endometrial thickness (ET) and endometrial volume (EV) among endometrial pathological groups (P > 0.05). The ET, EV, endometrial vascularization index, endometrial flow index, and vascularization flow index in the ovarian cyst group were significantly higher (P < 0.05), and the proportion of uneven endometrium echo and unclear EMJ were significantly higher compared with that in the non-ovarian cyst group (P < 0.05). The most common cause of perimenopausal women with AUB was benign endometrial lesions. However, women aged 51-55 years old with endometrial high risk factors and ovarian cyst should be alert to AEH and EC. Endometrial biopsy needs to be performed to determine endometrial malignancy in necessity.

Atypical Endometrial Hyperplasia and Concurrent Cancer: A Comprehensive Overview on a Challenging Clinical Condition.

The present review regarding atypical endometrial hyperplasia (AEH) focused on the main debated factors regarding this challenging clinical condition: (i) predictive variables of occult endometrial cancer (EC); (ii) the rate of EC underestimation according to different endometrial sampling methods; and (iii) the appropriateness of lymph node status assessment. When cancer is detected, approximately 90% of cases include low-risk EC, although intermediate/high-risk cases have been found in 10-13% of women with cancer. Older age, diabetes, high BMI, and increased endometrial thickness are the most recurrent factors in women with EC. However, the predictive power of these independent variables measured on internal validation sets showed disappointing results. Relative to endometrial sampling methods, hysteroscopic endometrial resection (Hys-res) provided the lowest EC underestimation, ranging between 6 and 11%. Further studies, including larger sample sizes of women undergoing Hys-res, are needed to confirm these findings. These data are urgently needed, especially for female candidates for conservative treatment. Finally, the evaluation of lymph node status measured on 660 of over 20,000 women showed a lymph node positivity of 2.3%. Although there has been an increase in the use of this procedure in AEH in recent years, the present data cannot recommend this option in AEH based on a cost/risk/benefit ratio.

Oncological and reproductive outcomes of endometrial atypical hyperplasia and endometrial cancer patients undergoing conservative therapy with hysteroscopic resection: A systematic review and meta-analysis.

Our objective was to conduct a systematic review and meta-analysis of studies evaluating the oncological and reproductive outcomes of patients with endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC) undergoing conservative therapy with hysteroscopic resection (HR). This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for systematic reviews and meta-analyses. The study strictly followed the methodological framework proposed by the Cochrane Handbook and was retrospectively registered in PROSPERO (CRD42023469986). Searches were conducted in PubMed, Embase, and the Cochrane Library, from inception to October 10, 2023. A checklist based on items of the Newcastle-Ottawa Scale and the Methodological Index for Non-randomized Studies was used for quality assessment. The primary end points for this meta-analysis were complete response (CR), pregnancy, and live birth rates following HR-based therapy in patients with EEC or AH. The secondary end point was the recurrence rate (RR). Twenty-one articles involving 407 patients with clinical stage IA, low or intermediate grade, EEC, and 444 patients with AH managed with HR-based conservative treatment were included for this systematic review. CR to HR-based conservative therapy was achieved in 88.6% of patients with EEC and 97.0% of patients with AH. Of these, 30.6% and 24.2%, respectively, had live births. The overall pooled disease RR was 18.3% and 10.8% in patients with EEC and AH, respectively. Further subset analyses revealed that EEC patients with body mass index (BMI) ≤28 kg/m2 had higher CR rates as well as higher chances of pregnancy and live birth (91.6% CR, 32.9% pregnancy, 31.1% live birth) compared with patients with BMI >28 kg/m2 (86.4% CR, 28.4% pregnancy, 23.0% live birth). The HR followed by oral progestogen subgroup had higher CR rates and higher chances of pregnancy and live birth (91.8% CR, 36.3% pregnancy, 28.2% live birth) than the HR followed by the levonorgestrel intrauterine system subgroup (82.5% CR, 25.3% pregnancy, 16.3% live birth). Hysteroscopic resection followed by progestins appears to be a promising choice for fertility-sparing treatment in young patients with AH and EEC, with effective and safe responses. The live birth rate remains to be improved by providing medical guidance and encouragement.

Novel FOXL2 Mutation in an Ovarian Adult Granulosa Cell Tumor: Report of a Case With Diagnostic and Clinicopathologic Implications.

Adult granulosa cell tumor, the most common malignant ovarian sex cord-stromal tumor, harbors the characteristic mutation c.402C>G (p.C134W) in the FOXL2 gene in ~90% to 95% of cases. To date, no other variants of FOXL2 mutations have been identified in these tumors. Here we report the first case of an adult granulosa cell tumor with a novel FOXL2 point mutation c.398C>T (p.A133V) presenting in a 64-year-old postmenopausal woman. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy for atypical endometrial hyperplasia and gross examination revealed an incidental 3.2cm right ovarian mass with a solid, bright yellow, homogeneous cut surface. Microscopically, ~30% of the tumor showed a nested growth pattern composed of uniform tumor cells with oval nuclei and a moderate amount of pale cytoplasm, while the remaining areas consisted of a bland storiform fibromatous stroma. Reticulin stain demonstrated loss of the individual pericellular network within the nested areas, while the pericellular staining pattern was retained in the background stromal component. FOXL2 sequencing analysis was performed in both components and revealed a c.398C>T (p.A133V) mutation in the nested component, whereas wild-type FOXL2 sequence was identified in the fibromatous stroma. Sections from the uterus showed a low-grade endometrioid endometrial adenocarcinoma with superficial myometrial invasion. The patient underwent adjuvant vaginal cuff brachytherapy for the endometrial carcinoma and is alive and well at 8 months follow-up. This case illustrates that new FOXL2 mutations may be detected in ovarian sex cord-stromal tumors with increasing use of routine molecular testing, adding to the complexity of the pathologic diagnosis. In the right morphologic and clinical context, a FOXL2 mutation-even if it is different from the dominant hotspot mutation c.402C>G (p.C134W)-can support the diagnosis of adult granulosa cell tumor.

End-to-end deep learning method for predicting hormonal treatment response in women with atypical endometrial hyperplasia or endometrial cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and atypical endometrial hyperplasia (AEH) is considered a high-risk precursor to EC. Hormone therapies and hysterectomy are practical treatment options for AEH and early-stage EC. Some patients prefer hormone therapies for reasons such as fertility preservation or being poor surgical candidates. However, accurate prediction of an individual patient's response to hormonal treatment would allow for personalized and potentially improved recommendations for these conditions. This study aims to explore the feasibility of using deep learning models on whole slide images (WSI) of endometrial tissue samples to predict the patient's response to hormonal treatment. We curated a clinical WSI dataset of 112 patients from two clinical sites. An expert pathologist annotated these images by outlining AEH/EC regions. We developed an end-to-end machine learning model with mixed supervision. The model is based on image patches extracted from pathologist-annotated AEH/EC regions. Either an unsupervised deep learning architecture (Autoencoder or ResNet50), or non-deep learning (radiomics feature extraction) is used to embed the images into a low-dimensional space, followed by fully connected layers for binary prediction, which was trained with binary responder/non-responder labels established by pathologists. We used stratified sampling to partition the dataset into a development set and a test set for internal validation of the performance of our models. The autoencoder model yielded an AUROC of 0.80 with 95% CI [0.63, 0.95] on the independent test set for the task of predicting a patient with AEH/EC as a responder vs non-responder to hormonal treatment. These findings demonstrate the potential of using mixed supervised machine learning models on WSIs for predicting the response to hormonal treatment in AEH/EC patients.