Complex Atypical Endometrial Hyperplasia Research Articles

Evaluation of Sentinel Lymph Nodes in Complex Atypical Endometrial Hyperplasia

Complex atypical endometrial hyperplasia (CAH) carries a high probability of cancer. The intraoperative evaluation of endometrial cancer in cases of CAH has not been reliable. The safety and sensitivity of sentinel lymph node (SLN) sampling has been validated. In our study, we aimed to evaluate the efficacy and safety of SLN sampling in CAH managed by the da Vinci robotic platform. A total of 113 patients with a preoperative diagnosis of CAH were included in this retrospective cohort study. All of them underwent a robot-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, with 69 patients undergoing SLN sampling. A statistical analysis calculated the probability of cancer, the SLN map rate, and surgical complications. The predictors of cancer were evaluated. Descriptive statistics were used to summarize the results; comparative statistics were used to compare the cohorts; and logistical regression analysis was used to predict the risk. Forty-seven percent of the entire cohort was diagnosed with endometrial cancer. The median age was 63 years in the SLN cohort (N = 69) and 61 in the No-SLN cohort (N = 44) (p = 0.363). The median BMI was 34 Kg/m2 in the SLN cohort and 40 in the No-SLN cohort (p = 0.004). The bilateral SLN map was 92.8%, and the unilateral SLN map rate was 7.2%. There were no grade-3–4 complications in the SLN cohort, and four grade-3–4 complications in the No-SLN group (p = 0.021). A preoperative diagnosis of CAH bordering on or unable to rule out cancer was the only predictor of cancer. Sentinel lymph node sampling has a high map rate and low complications in CAH. We recommend a prospective study investigating the clinical benefit of the procedure.

SMARCA4 / BRG1 -deficient Uterine Neoplasm With Hybrid Adenosarcoma and Carcinoma Features: Expanding the Molecular-morphologic Spectrum of SMARCA4 -driven Gynecologic Malignancies.

SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.

Sociocultural influences on dietary behavior and meal timing among Native Hawaiian and Pacific Islander women at risk of endometrial cancer: a qualitative investigation.

PurposeDetermine sociocultural influences on dietary behavior, body image, weight loss, and perceptions of the cultural appropriateness of a meal-timing intervention design and menu among Native Hawaiian and Pacific Islander (NHPI) women at risk of endometrial cancer.MethodsSix 90-min videoconference focus groups among NHPI women (n = 35) recruited by a community champion in Utah. Eligible women were aged ≥ 18 years at risk of endometrial cancer (i.e., BMI ≥ 25 kg/m2, history of non-insulin-dependent diabetes or complex atypical endometrial hyperplasia) had a working cell phone capable of downloading a phone app, could use their cell phone during the day, and were not night-shift workers. Twelve semi-structured questions were posed during the focus groups. Using inductive qualitative methods based on Hatch’s 9-step approach, de-identified transcript data were analyzed.ResultsOverarching themes included economic factors, cultural influences, meal choice and timing, and perceptions of health. Subthemes included affordability, waste avoidance, inundated schedules, and cultural influences. Perceptions of body size and weight loss were influenced by family, community, and social media, whose messages could be conflicting. Important intervention components included satisfying, convenient pre-made meals, while barriers included the need to cook for family members.ConclusionsDietary interventions targeting metabolic health among NHPI women should consider the multitude of sociocultural and economic factors that influence food choices and meal timing in this population, including affordability, hectic schedules, and immigrant adjustment. Promoting the link between physical and mental well-being as opposed to weight loss is a key approach to reaching this population.

Endometrial Cancer Incidence in Patients With Atypical Endometrial Hyperplasia According to Mode of Management.

It is well established that around one-third of patients with atypical endometrial hyperplasia (AEH) go on to develop endometrial cancer (EC). This retrospective cohort study included 119 patients recruited from the University Hospitals of Leicester from 01/01/2015 to 01/01/2020 with a diagnosis of AEH by endometrial biopsy. Patients were divided into two groups according to the management modality: Primary surgery (n=99), and conservative treatment (n=20). The aim of this study was to determine the incidence of EC in patients with AEH in University Hospitals of Leicester, UK, and to explore the reasons why patients with AEH opted for conservative management. EC was diagnosed in 34.4% of patients with AEH managed by primary surgery. Moreover, the incidence of EC in patients with AEH managed conservatively was 25%. The main reason for opting for conservative management was that patients were unfit for surgery when assessed in the high-risk Anaesthetic Clinic (35%). AEH is a pre-malignant lesion that has high risk of EC regardless of the mode of management. Total hysterectomy is the safest first line of treatment in AEH due to the high risk of concurrent EC and progression to EC. Currently, there is no reliable follow-up intervention to distinguish between concurrent EC and progression of AEH. Adequate discussion and counselling are essential when discussing conservative management for women with complex AEH. Patients should be counselled regarding the high risk of developing concurrent EC and risk of progression to EC.

Sociocultural Influences on Dietary Behavior and Meal Timing Among Native Hawaiian and Pacific Islander Women at Risk of Endometrial Cancer: A Qualitative Investigation

ObjectivesDetermine sociocultural influences on dietary behavior, body image, weight loss, and perceptions of the cultural appropriateness of a meal-timing intervention design and menu among Native Hawaiian and Pacific Islander (NHPI) women at risk of endometrial cancer. MethodsSix 90-minute videoconference focus groups among NHPI women (N = 35) recruited by a community champion in Utah. Eligible women were aged ≥18 years at risk of endometrial cancer (i.e., BMI ≥25kg/m2, history of non-insulin dependent diabetes or complex atypical endometrial hyperplasia) had a working cell phone capable of downloading a phone app, could use their cell phone during the day, and were not night-shift workers. Eleven semi-structured questions were posed during the focus groups. De-identified transcript data were analyzed using an inductive qualitative approach based on Hatch’s 9-step approach. ResultsOverarching themes included economic factors, cultural influences, meal choice and timing, and perceptions of health. Subthemes included affordability, waste avoidance, inundated schedules, and cultural influences. Perceptions of body size and weight loss were influenced by family, community, and social media, whose messages could be conflicting. Important intervention components included satisfying, convenient pre-made meals, while barriers included the need to cook for family members. ConclusionsDietary interventions targeting metabolic health among NHPI women should consider the multitude of sociocultural and economic factors that influence food choices and meal timing in this population, including affordability, hectic schedules, and immigrant adjustment. Promoting the link between physical and mental well-being as opposed to weight loss is a key approach to reaching this population. Funding SourcesThis work was supported by 5 For the Fight and the Huntsman Cancer Institute Cancer Control and Population Sciences Pilot Program; Huntsman Cancer Center (P30CA040214); University of Utah’s Clinical and Translational Science Institute; the V Foundation for Cancer Research; the Research Foundation of the American Society of Colon and Rectal Surgeons; and the National Cancer Institute (Grants 5R00CA218694-03 and K01CA234319), an entity of the National Institutes of Health (NIH).

Sentinel Node Biopsy for Endometrial Cancer by Retroperitoneal Transvaginal Natural Orifice Transluminal Endoscopic Surgery: A Preliminary Study.

ObjectiveThe primary objective was to determine the intraoperative and postoperative surgical complications of sentinel lymph node biopsy (SLNB) by retroperitoneal transvaginal natural orifice transluminal endoscopic surgery (vNOTES). The secondary objective was to assess the feasibility of this surgical technique.MethodsThis was a descriptive study realized in a non-university hospital in Switzerland. Seven patients with endometrial cancer or endometrial complex atypical hyperplasia underwent surgical staging with SLNB by retroperitoneal vNOTES using an indocyanine green-based near-infrared fluorescence imaging technique (October 2021–February 2022).ResultsThe median operative time was 113 (81–211) minutes. The median estimated blood loss was 20 (20–400) mL. The overall bilateral detection rate was 100% (7/7). Upon histopathological examination, 5 patients presented an endometrial adenocarcinoma, and we found endometrial complex atypical hyperplasia in 2 cases. We successfully completed all procedures without significant intraoperative complications, but 1 case required conversion to conventional laparoscopy. The median postoperative stay was 2 (2–4) days, and we observed no postoperative complications during this period. We observed 1 case of postoperative deep vein thrombosis and an asymptomatic vaginal vault hematoma in the same patient.ConclusionsOur preliminary study suggests that retroperitoneal vNOTES could be a feasible, safe, and valuable approach to perform SLNB in endometrial cancer. However, strong evidence of its feasibility, the effective benefits, and the long-term oncological outcomes is needed before expanding the use of vNOTES in endometrial cancer outside study settings.

Hysterectomy with a general gynecologist versus gynecologic-oncologist in the setting of complex atypical hyperplasia: a cost-effectiveness analysis

<h3>Objectives:</h3> The standard of care for patients with endometrial complex atypical hyperplasia (CAH) is a total hysterectomy. The underlying risk of finding endometrial cancer at the time of hysterectomy is as high as 43%. Both general gynecologists and gynecologic oncologists perform total hysterectomies. However, some patients with endometrial cancer found at the time of hysterectomy require a lymph node dissection (LND), a procedure typically done only by gynecologic oncologists. Patients who have a hysterectomy for CAH with a general gynecologist and are found to have cancer may require a second surgery with a gynecologic oncologist. In this study, we examined the cost-effectiveness of hysterectomy by general gynecologists versus gynecologic oncologists for CAH patients. <h3>Methods:</h3> We designed a decision-analytic model using TreeAge to compare outcomes between CAH patients who received hysterectomy by a general gynecologist versus a gynecologic oncologist. Our theoretical cohort contained 200,000 patients, the approximate number of patients with new CAH diagnoses per year in the United States. Our outcomes were costs, quality-adjusted life years (QALYs), LND, LND as a second surgery, surgical site infection, and perioperative mortality. We assumed that cancer-related care and outcomes were identical for both groups except for the morbidity and mortality directly related to a second surgery for LND. We applied a cost of frozen section to the gynecologic oncologist branch. Probabilities of perioperative mortality and surgical site infection were the same regardless of surgeon specialty and were applied twice for those who underwent two surgeries. We derived all values from the literature and discounted QALYs at a rate of 3%. To assess the robustness of our model, we performed univariate sensitivity analyses. <h3>Results:</h3> In our one-year theoretical cohort of 200,000 patients with CAH, the hysterectomy with a gynecologic-oncologist strategy was associated with a decrease in 10,744 second surgeries for LND, 546 surgical site infections, and 76 perioperative mortalities (Table 1). The hysterectomy with a general gynecologist strategy was associated with a decrease in 77 LNDs due to perioperative mortalities prior to subsequent LND. Hysterectomy with a gynecologic oncologist was the dominant, cost-effective strategy as it saved $210 million and increased QALYs by 1,138. In our sensitivity analyses, hysterectomy with a gynecologic oncologist was cost-saving and increased QALYs over a wide range of probabilities and costs for LND, surgical site infection, and perioperative mortality. <h3>Conclusions:</h3> In our model, hysterectomy with a gynecologic oncologist for patients with CAH was associated with cost savings and increased QALYs. Our study suggests that patients undergoing hysterectomy for CAH should consider surgery with a gynecologic oncologist rather than a general gynecologist to reduce costs and outcomes associated with a second surgery.

Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy.Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression.Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success.Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.

Uptake and Outcomes of Sentinel Lymph Node Mapping in Women With Atypical Endometrial Hyperplasia.

To examine the utilization, morbidity, and cost of sentinel lymph node mapping in women undergoing hysterectomy for complex atypical endometrial hyperplasia. Women with complex atypical endometrial hyperplasia who underwent hysterectomy from 2012 to 2018 in the Perspective database were examined. Perioperative morbidity, mortality, and cost were examined based on performance of sentinel lymph node mapping, lymph node dissection or no nodal evaluation. Among 10,266 women, sentinel lymph node mapping was performed in 620 (6.0%), lymph node dissection in 538 (5.2%), and no lymphatic evaluation in 9,108 (88.7%). Use of sentinel lymph node mapping increased from 0.8% in 2012 to 14.0% in 2018, and the rate of lymph node dissection rose from 5.7% to 6.4% (P<.001). In an adjusted model, residence in the western United States, treatment by high-volume hospitals and use of robotic-assisted hysterectomy were associated with sentinel lymph node mapping (P<.05 for all). The complication rates were similar between the three groups. The median cost for sentinel lymph node mapping ($9,673) and lymph node dissection ($9,754) were higher than in those who did not undergo nodal assessment ($8,435) (P<.001). Performance of sentinel lymph node mapping is increasing rapidly for women with complex atypical endometrial hyperplasia but is not associated with increased perioperative morbidity or mortality.

Abstract PO019: Identification of differentially expressed genes in primary samples of endometrial hyperplasia and endometrioid endometrial carcinoma responsive to progestin therapy

Abstract One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). This study aims to identify gene expression signatures indicative of the likelihood of successful progestin therapy. Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy. Samples were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach (Illumina), a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression (DE) analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of DE genes to reduce spurious results due to samples with outlier expression. Gene set enrichment was performed using ENRICHR. Analysis of all samples using DESeq2 identified 843 genes significantly associated with outcome, while Noiseq identified 318 genes, with an overlap between the two methods of 137. These 137 genes were largely increased in post-treatment samples from progestin responders and were enriched for the DSigDB terms “progesterone”, “medroxyprogesterone acetate”, and “estradiol”, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. Additionally, a small gene signature (61 genes) was specifically decreased in post-treatment responders compared to all other groups. This gene set is enriched for the GO molecular function “enhancer binding”, BioPlanet 2019 sets “BMP signaling pathway in stem cells” and “Signaling events mediated by the hedgehog family”. The genes in this set may be related to failure on progestin therapies and surprisingly include both ESR1 (estrogen receptor a) and PGR (progesterone receptor). Analysis of RNA-seq data from our cohort of CAH and EEC samples identified a 137 gene signature post-progestin treatment that indicate successful clinical response. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success. Citation Format: Craig M. Rush, Jeffery M. Vahrenkamp, Kathryn Szczotka, Mark K. Dodson, Elke A. Jarboe, Andrew P. Soisson, Jay Gertz. Identification of differentially expressed genes in primary samples of endometrial hyperplasia and endometrioid endometrial carcinoma responsive to progestin therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO019.

THE VALUE OF THE EXPRESSION OF PROGESTERONE RECEPTORS (PR-A AND PR-B) AS PREDICTORS OF RECURRENCE OF ENDOMETRIAL HYPERPLASIA AFTER THERAPY WITH PROGESTINS

The aim of the study. Improving diagnostics and predicting the effectiveness of pathogenetic treatment with progestins of endometrial hyperplasia without atypia, based on the study of the expression of progesterone receptors (PR-A and PR-B) and their ratio in endometrial tissues.Materials and methods. A prospective study was performed in 40 patients of reproductive age with abnormal uterine bleeding, who were diagnosed with endometrial hyperplasia without atypia based on histological examination of endometrial tissue. The control group consisted of 15 patients in whom after treatment there were histological changes to the endometrium of the secretory type. Material for morphological and immunohistochemical studies was obtained by scraping the uterine cavity. The study of progesterone receptors (PRA and PR-B) was performed by immunohistochemistry in the laboratory of immunohistochemistry DDMA. All patients received treatment with micronized progesterone at a dose of 400 mg / day continuously for 6 months. To determine the effect of progestin use, a control study was performed by scraping the uterine cavity after 6 months and the effectiveness of treatment was determined by histological changes of the endometrium.Research results. The treatment showed that 74% of women had histological normalization of the ratio of stromal and epithelial component, 18.7% were diagnosed with simple atypical endometrial hyperplasia (PNGE). Complex atypical endometrial hyperplasia (CNGE) was diagnosed in 7.3% of women. Prior to treatment, low PR-A expression in the endometrial glands (P = 0.013) and stroma (P 1 ratio (19%; P <0.001). According to a study of women with no effect from the therapy, in contrast to women with effective therapy, there was a decrease in the expression of progesterone receptors by 65%, which has a statistically significant relationship with recurrence of endometrial hyperplasia. Conclusions. Treatment of endometrial hyperplasia without atypia with progesterone drugs will be 74% ineffective with low expression of progesterone receptors in endometrial cells. immunohistochemical expression of PR-A and PR-B and their ratio in the stroma and glands during endometrial biopsy before progestin therapy is a valuable prognostic factor for recurrence of endometrial hyperplasia. Therefore, when deciding on the appointment of progestins for the treatment of endometrial hyperplasia without atypia, it is recommended to study the expression of receptors in the endometrium.

Robotic versus laparoscopic hysterectomy in morbidly obese women for endometrial cancer.

Surgery is the mainstay treatment for endometrial cancer and complex atypical endometrial hyperplasia. These conditions are more common in the obese women and as such these patients pose additional risks and challenges to surgery. Laparoscopic hysterectomy (LH) is preferred over open surgery in obese patients as it reduces surgical morbidity. However, more recently, robotic-assisted hysterectomy (RH) has been used in morbidly obese patients to overcome the limitations of conventional laparoscopy. To compare the surgical outcomes of morbidly obese patients undergoing LH or RH for endometrial cancer or complex atypical hyperplasia. A retrospective analysis of morbidly obese patients (BMI > 40kg/m2) who underwent LH or RH for endometrial cancer or complex atypical hyperplasia at the Chris O'Brien Lifehouse Gynaecological Oncology Unit from 2015 to 2019 was performed. Data was collected from the prospectively maintained gynaecology oncology database and descriptive analysis was performed. 33 (51.6%) underwent LH and 31 (48.4%) had RH. More LHs were performed 2015-2017 period, whereas there were more RHs performed in 2018-2019 period (p = 0.01). The difference between theatre time use and operating time for LH surgery compared to RH was significantly shorter (45.7 for LH versus 61.9min for RH, p = 0.009). RH was performed more commonly when BMI was > 50kg/m2 (p = 0.02). There has been an increase in the use of RH in morbidly obese patients, particularly for women with a BMI > 50kg/m2.

Морфологічні особливості ендо- та міометрія у пацієнток з лейоміомою матки і безплідністю

The objective: determination of morphofunctional features of leiomatous nodes and endometrium in women with uterine leiomyoma and infertility to restore reproductive function and prevent recurrence of the underlying disease. Materials and methods. In order to restore reproductive function and prevent recurrence of the underlying disease, morphofunctional features of leiomatous nodes and endometrium in women with uterine leiomyoma and infertility were determined. Thirty samples of leiomyomatous nodes and endometrium were examined, among which 15 were obtained from women with multiple uterine leiomyoma and infertility and 15 samples from women with uterine leiomyoma with isolated uterine leiomyoma. During the study, a general-histological method was used for staining with hematoxylin-eosin and picrofuxin by van Gizon, as well as immunohistochemical methods. Histological examination of the endometrium was performed according to conventional protocol, taking into account the day of the menstrual cycle and R.W. Noyes criteria. Results. In the morphological examination of leiomyomatous nodes in the vast majority of cases the presence of uterine leiomyomas of simple and cell types or their combination was established. In women with multiple uterine leiomyoma, simple-type leiomyoma (53.3%) was predominant, and in patients with isolated leiomyoma the signs of cellular uterine leiomyoma (66.7%) were more frequently found. In 80.0% of women with uterine leiomyoma revealed pathology of the endometrium, such as glandular and glandular-fibrous polyps, simple and complex atypical endometrial hyperplasia, which confirms the theory about the only pathogenetic mechanisms of the emergence of hyperplastic processes of female organs. In 66.7% of women with multiple leiomyomas, signs of chronic endometritis have been found, which exacerbates the pathological process and can have a negative impact on the reproductive function, such as secretory endometrial transformation and impaired blastocyst implantation, and explains a much higher percentage of infertility in the group. Conclusion. In women with impaired reproductive function, patients with uterine leiomyoma, it is necessary to conduct a study of the receptivity of the reproductive organs, namely - the endometrium and leiomatous nodes. This will make it possible to use one or another method of treatment in order to restore reproductive function and prevent recurrence of the underlying disease. Keywords: infertility, uterine leiomyoma, endometrium, receptive apparatus.

Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia

Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.

Proteomic analysis in endometrial cancer and endometrial hyperplasia tissues by 2D-DIGE technique

ObjectiveTo compare the protein expression of complex atypical endometrial hyperplasia, endometrial carcinoma and healthy endometrial tissues, and by this way, to identify proteins that can be used for diagnosis, prognosis and therapeutic targets. MethodsHistopathological examination of the D&C material had reported “benign endometrial changes”, “complex atypical endometrial hyperplasia” and “endometrioid adenocarcinoma” and 30 patients ,who underwent surgery with these diagnosis, were studied.Protein profiles of the study groups were detected using 2D-DIGE technique and compared to the control group. Protein spots which showing different expression, were defined by MALDI TOF/TOF-MS method. ResultsIn the present study, significant elevations were observed in the levels of K2C8, UAP56, ENOA, ACTB, GRP78, GSTP1, PSME1, CALR, PPIA, PDIA3 and IDHc proteins when comparisons were made among the cancer cases and the healthy and complex atypical hyperplasia cases. We determined that the induction of CALR activity may be a factor that progresses apoptosis, thus, may be a hope for postoperative new chemotherapy treatment methods. Moreover, when the expressions of the CAH1 and PPIB proteins are compared to complex atypical hyperplasia and endometrial adenocarcinoma stages, we determined that the CAH1 and PPIB levels increased in more advanced stages. Among these indicators, the proteins that had the closest relation to advanced stage cancer were determined as K2C8, UAP56 and GRP78. ConclusionWe think that it would be useful to determine the diagnosis, prediction of prognosis and identifying therapeutic targets of the highlighted proteins of our study that are K2C8, UAP56, GRP78 and CALR in endometrial cancer.

The role of steroid receptors in the pathogenesis of adenomyosis in the presence of concomitant endometrial pathology in postmenopause

Determining the pathogenesis of adenomyosis in postmenopausal women is promising, as it will allow a more thorough study of the mechanisms of hormonal changes and resolve issues related to adenomyosis in women of reproductive age. The purpose of the study is to establish the role of steroid receptors in the pathogenesis of adenomyosis in the presence of concomitant endometrial pathology in postmenopausal women. Study material is removed uteri with parovaria from 117 patients of 49-76 years old. The cases were divided into 4 groups depending on the presence of adenomyosis (AM) and background pathology (endometrioid carcinoma of the endometrium (ECE) and endometrial hyperplasia (EHP)): 1) 27 women with adenomyosis and EHP; 2) 30 women with adenomyosis and ECE; 3) 30 women with adenomyosis and age-related changes in the endometrium; 4) 30 women with age-related changes without AM (comparison group). The immunohistochemical reaction was carried out using primary antibodies to estrogen (ER), progesterone (PR) and androgen (AR) receptors. Statistical processing was carried out using parametric methods of variation statistics (calculated the arithmetic mean, standard deviation, confidence interval, Student criterion). The predominance of the ER expression in the glandular and stromal components of the eutopic endometrium in the presence of AM and hyperplastic processes was compared with the comparison group (p&lt;0.01). A high level of ER expression is characteristic of the epithelium of the endometrium with EHP (7.333±0.314) and ECE (6.200±0.712) rather than for the endometrium with atrophic changes in the presence of AM (4.433±0.773). In the stroma, a high ER activity was detected with EHP (7.148±0.276) rather than with atrophic changes (4.567±0.738) and ECE (4.167±0.602). It was established that in the epithelium of adenomyosis foci, ER expression indices were lower in atrophy (3.433±1.074) than with AM foci in ECE (4.667±0.526) and EHP (5.148±0.745). In the stroma of adenomyosis foci, ER expression is higher in EHP than in ECE and atrophy. The activity of PR in the eutopic endometrium decreases from simple non-typical to complex atypical EHP and in patients with adenomyosis and ECE, as the degree of differentiation of cells of ECA decreases (from G1 to G3 ECE). A minimal expression of PR was found in the comparison group. In the cells of internal endometriosis there were positive indices of immunohistochemical reaction with PR. There were obtained minimum scores for receptor expression of AR in eu- and ectopic endometria. Conclusion: adenomyosis foci have a regulatory effect on the uterine endometrium, stimulating the expression of ER and, to a lesser extent, PR, and do not affect the level of AR in the eutopic endometrium.

DNA Repair Gene (XPD, XRCC4, and XRCC1) Polymorphisms in Patients with Endometrial Hyperplasia: A Pilot Study.

BackgroundIn this study, we aimed to evaluate the association between endometrial hyperplasia and DNA repair gene (XPD, XRCC4, and XRCC1) polymorphisms.Material/MethodsThere were 114 cases enrolled in the study in 4 groups: simple endometrial hyperplasia (SH) (Group 1), complex endometrial hyperplasia without atypia (CH) (Group 2), complex atypical endometrial hyperplasia (CAH) (Group 3), and normal endometrium (NE) (Group 4). Of these cases, 37 cases had SH, 36 cases had CH, 16 cases had CAH, and 25 cases had NE. To evaluate an association between atypia and DNA repair genes, we consider a group that included both SH and CH, the endometrial hyperplasia without atypia cases (Group 5). Genomic DNA was isolated from paraffin-embedded endometrial tissue collected from the Pathology Department of Gaziantep University Medical School. Polymerase chain reaction (PCR) and/or restriction fragment length polymorphism (RFLP) method was used for evaluating of XPD (−751), XRCC4 (−1394 and a variable number of tandem repeats in intron 3), and XRCC1 (−399) genes.ResultsWe observed a notable distinction in patients having endometrial hyperplasia without atypia (the SH+CH group) and the CAH group in terms of XPD (−751) gene polymorphisms. A notable contrast was observed in patients with endometrial hyperplasia without atypia (the SH+CH group) and the NE group in terms of XRCC4 (VNTR intron 3) polymorphisms (P=0.026, P=0.018, respectively).ConclusionsIt was evident the DNA repair gene XPD and XRCC4 polymorphisms had a role in the pathophysiology of endometrial hyperplasia.

Utility of PTEN, MLH1, ARID1A and β-catenin, biomarkers in endometrial hyperplasia and endometrioid endometrial carcinoma

Objective: Endometrial carcinomas are divided into two groups roughly:Endometrioid (Type I) and Non-endometrioid (Type II). The majority of the endometrial carcinomas are of endometrioid type and, this type of carcinoma is associated with hyperplasia which is formed due to unopposed estrogen.In this study, our purpose is to reveal the expression status of the PTEN, MLH1, ARID1A and β-catenin, biomarkers in all types of endometrial hyperplasia (EH) and endometrioid endometrial carcinoma (EC).Materials and metods: We conducted a retrospective study with 202 cases including 82 EC cases, 71 simple EH cases without atypia, 16 complex EH cases without atypia, 9 simple atypical EH cases, 24 complex atypical EH cases which were diagnosed at Istanbul Civilization University Göztepe Training and Research Hospital. 10 normal endometrial tissues were used for the purpose of control. Resuls: In our study, loss of PTEN ratio was 61%, loss of ARID1A ratio was 52,4%, loss of MLH1 ratio was 40,2% in patients with EC. These ratios were 87,5%, 41,7%, 20,8%, respectively in patients with atypical complex EH and 12,7%; 4,2%; 1,4% in patients with simple EH without atypia. Conclusions: In the light of these findings it has been demonstrated that PTEN, ARID1A and MLH1 have a role in the transition from simple EH to atypical complex EH, and also MLH1 has a role in the transition from aytpical complex EH to EC.

Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives-expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound progesterone receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use.

Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study.

For young women with complex atypical endometrial hyperplasia (CAH) and endometrial cancer (EC) who choose to preserve fertility, progestin therapy is the mainstay of treatment. The objective of this study was to evaluate oncologic and reproductive outcomes associated with progestin therapy among these women from a population-based cancer registry. This was a retrospective population-based cohort study of women under age 45 in British Columbia from 2003 to 2015 with CAH or grade I endometrioid EC who used progestins as initial management. Demographics, treatment type, response to treatment, determinants of definitive surgery (hysterectomy), pathologic findings, and obstetrical outcomes were reviewed. There were 50 women under age 45 with CAH (n = 29) and EC (n = 21). Median age at diagnosis was 36 years (range 25-41), and most were nulliparous (88%) with a median BMI of 32.9 (range 21-70). After 6 months of therapy, 58% of women had persistent disease, and only 35% had full resolution at last follow-up (median 23 months). There were 32 women who had a hysterectomy, including 27 because of persistent/recurrent disease, and 5 who chose surgery despite complete response to progestins. The majority of hysterectomy specimens (85%) had minimal or no residual pathology, even among those with disease on preoperative biopsy. Only 10% of women had successful pregnancies. There is a moderate to high risk of persistence of CAH or EC on progestin therapy. However, for those undergoing hysterectomy, the vast majority has low-risk disease confined to the endometrium, implying the possibility of further conservative management of persistent disease.