Non-atypical Endometrial Hyperplasia Research Articles

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.

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.

Histopathology of endometrium in women presenting with abnormal uterine bleeding in Vindhya region

: Any alteration in frequency, flow duration/blood loss amount of menstruation is known as Abnormal uterine bleeding/AUB. Almost 30% of all patient attending gynaecology OPD are for AUB. This study was conducted in Vindhya region to study endometrial histopathology amongst women complaining of abnormal bleeding pattern: This retrospective study was conducted on 200 women presenting with AUB who undergone endometrial biopsy or hysterectomy in the Obstetrics and Gynaecology Department and sent to Histopathology section of Pathology department, SSMC, Rewa (MP) from Jan 2020 to June 2021. The formalin fixed specimens were received grossing done, followed by processing and then staining with H&amp; E stain, followed by microscopy. Data &amp; history was taken from the patient herself and attenders.: AUB was observed in all age groups. Menorrhagia (105 patients, 52.5%) was commonest bleeding pattern observed in cases of AUB, followed by Metrorrhagia (54 patients, 27%). In our study Proliferative endometrium (71 patients,35.5%) was most common histopathological diagnosis found, followed by Non-Atypical endometrial Hyperplasia (45 patients, 22.5%), Secretory phase (20 patients,10%), DPE (20 patients,10%), Atrophic endometrium (12 patients,6%), Exogenous hormone (pill endometrium 10 patients, 5%), Benign Adenomatous polyp (9 patients, 4.5%), Atypical endometrial Hyperplasia (5 patients, 2.5%), chronic endometritis (5 patients, 2.5%), Endometrial carcinoma (3 patients, 1.5%).Variable Histopathological findings are found in endometrial biopsy and curettage done in AUB patient. This study emphasizes the significance of endometrial biopsy and its histopathological diagnosis for proper patient management.

Levonorgestrel-releasing intrauterine system versus oral progestogens for non-atypical endometrial hyperplasia: predictors for treatment failure

Levonorgestrel-releasing intrauterine system versus oral progestogens for non-atypical endometrial hyperplasia: predictors for treatment failure

Unusual Scenario: Ipsilateral Pelvic Lymph Node Metastasis in High-Grade Serous Ovarian Carcinoma without Peritoneal Extension - A Case Report

Introduction:: Ovarian cancers are the third most common gynecological cancers worldwide with serous carcinomas being the most common subtype with 90% of them as high-grade carcinomas. Case Presentation:: In the present case report a 60 years postmenopausal, nulliparous woman presented with complaints of bleeding per vaginum for 1-2 months with a left-sided solid-cystic ovarian mass of size 4x5 cm and ipsilateral enlarged external iliac and obturator lymph nodes which were diagnosed on histopathological examination as high-grade serous ovarian carcinoma (HGSOCs) with ipsilateral pelvic lymph node metastasis in presence of intact ovarian capsule and no metastatic deposits over the uterus, contralateral ovary and fallopian tubes, omentum, or any other gross peritoneal deposits. There was coexisting non-atypical endometrial hyperplasia. The patient was managed successfully with staging laparotomy with modified radical hysterectomy, and bilateral pelvic lymphadenectomy followed by six cycles of adjuvant chemotherapy with Paclitaxel and Carboplatin injections. Conclusion:: Patients with HGSOCs can have varied presentations with unusual involvement of lymph nodes in the absence of peritoneal spread. Hence, the clinician must be aware of these unusual presentations for the successful management of such cases.

ER and COX2 expression in endometrial hyperplasia processes.

Endometrial hyperplastic processes (EHPs) encompass various morphological changes, characterized by an increased ratio of endometrial glands to stroma. These changes manifest as endometrial hyperplasia (EH) and endometrial polyps. The objective of this study was to investigate the expressions of ER and Cyclooxygenase-2 (COX2) in EH and endometrial polyps, and determine their correlation with histological and anthropometric parameters. Tissue samples were obtained during hysteroresectoscopy and divided into 3 groups: non-atypical EH, glandular EP, and glandular-fibrous EP. We examined the immunoprofile of epithelial and stromal cells using rabbit polyclonal anti-COX2 antibodies and rabbit monoclonal anti-ER antibodies (clone SP1). Our results indicate that there is no association between the expressions of ER and COX2 and the type of EHP. Furthermore, the expression levels of ER and COX2 are not influenced by the patients anthropometric parameters. However, tissues with EHPs exhibited significantly higher COX2 expression compared to intact tissues. We also observed a direct correlation between ER and COX2 expression in the endometrial epithelium. The variability in ER and COX2 expressions observed in hyperplastic processes of the endometrium potentially suggests their synergistic involvement in the initiation and progression of EHPs, as well as their potential role in subsequent tumor transformation.

Abstract CT044: KGOG2031 A phase II trial of repeated high dose luteal hormone therapy for intrauterine recurrence following fertility preserving therapy for atypical endometrial hyperplasia or endometrial cancer

Abstract Background: Atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC) are common disease in menopausal women, however, are gradually increasing in women aged under 40 years. The standard treatment for AEH/EC is hysterectomy, but hormonal therapy is performed for preserving fertility. In general, fertility-preserving treatment is considered for AEH or EEC with well-differentiation and lesions confined to the endometrium without myometrial invasion. According to previous studies, hormonal therapy in these patients responded relatively well. Nevertheless, recurrence was not uncommon, accounting for 26.0% in AEH and 40.6% in EC. The standard treatment for these recurrent patients is hysterectomy, but if there is no myometrial invasion and no extrauterine lesions, repeated hormonal treatment can be considered. However, studies targeting these patients have been very scarce. The purpose of this study was to evaluate the efficacy and safety of high-dose progesterone therapy in recurrence following fertility preserving therapy for AEH or EEC. Methods: KGOG2031 is a multi-center and prospective phase 2 trial. The primary endpoint is a 2-year disease free survival. The secondary endpoints were duration of disease-free survival, overall survival, response rate, adverse events, and infertile rates. Patients with recurrent AEH or EEC without myometrial invasion or extrauterine lesions who underwent high-dose MPA therapy for primary lesions were included. The inclusion criteria are limited to patients with less than two recurrences. The pathologic type for EEC was confined to endometrioid type. The patients should be confirmed histologically at least one complete remission after first treatment. Patients with myometrial invasion, cervical involvement, or extrauterine lesions observed on abdominal/chest computed tomography or pelvic magnetic resonance imaging were excluded. Furthermore, grade 2 or 3 of endometrioid or any grade of other pathologic type of endometrial cancer or non-atypical endometrial hyperplasia were excluded. The enrolled patients should take medroxyprogesterone acetate 500mg every day. D&amp;CB will be performed after anesthesia every 8 weeks to determine the effectiveness, and treatment will be continued for up to 40 weeks until complete remission is achieved. The target number of enrollment is 115 cases, and the recruitment period is 3 years. The follow-up duration is 2 years after the end of treatment, and the total study duration was up to 5 years. Citation Format: Min Kyu Kim, Yung-Taek Ouh. KGOG2031 A phase II trial of repeated high dose luteal hormone therapy for intrauterine recurrence following fertility preserving therapy for atypical endometrial hyperplasia or endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT044.

Molecular mechanisms of resistance of endometrial hyperplasia to progestogen therapy based on the study of the expression of estrogen and progesterone receptors and paracrine cellular markers of cellular interaction

The problem of resistance of non atypical endometrial hyperplasia (NEH) to traditionally accepted, pathogenetically sound therapy with different types of progestins is currently an unsolved problem. In about 17-20% of cases there is a recurrence or even progression of atypical forms of endometrial hyperplasia (AEH), which required the use of surgical treatments. The aim of the study was to investigate the results of hormone therapy with different types of progestins for the treatment of endometrial hyperplasia in women with different types of expression of estrogen and progesterone receptors in combination with the expression of intercellular adhesion molecules E-cadherin and β-catenin to determine the cause of hormonal resistance, formation of groups of women with progestogen-sensitive endometrial hyperplasia (EH) non atypical type NEH (+), which can use progestogens for treatment, and progestogen-resistant forms of endometrial hyperplasia with non atypical NEH (-), which should be offered alternative therapy. The study was performed on the morphological material of the endometrium obtained by diagnostic biopsy in women with abnormal uterine bleeding who were diagnosed with NEH by histological examination. For immunohistochemical study, 80 endometrial samples were taken from women with abnormal uterine bleeding (AUВ) and in the same women after treatment of endometrial hyperplasia without atypia in 3 and 6 months of therapy. The control group (CG) consisted of a group of 20 women who were followed-up without treatment tactics. All women were divided into 3 groups in which different types of progestins were used for treatment: group I – continuous intake of 100 mg of micronized progesterone per os twice a day for 6 months, group II – 20 mg of dihydrogesterone per os twice a day for 6 months, group III – in which LNG-IUD was used. The state of proliferation and differentiation in the studied tissues was assessed by the expression of their key molecular participants – estrogen receptors (ERα) and progesterone (PGR), transmembrane glycoproteins of E-cadherin and β-catenin. ERα and PGR expression were determined by immu­nohistochemistry and calculated by the semi-quantitative H-index method. Evaluation of the expression of E-cadherin and β-catenin was performed by determining the percentage of IHH-positive cells to these antigens depending on the degree of their color. The criterion for the effectiveness of NEH treatment was considered to be a biopsy in 3 and 6 months of treatment in the absence of pathological changes in the endometrium. The results showed that after the use of progestogens in group I there was a change in the endometrium to the secretory type in 45% of cases, in group II with dydrogesterone therapy – in 55% there was a reduction of EH to normal histological picture. The intrauterine system with levonorgestrel (LNG-IUD) showed the greatest efficiency, with the use of which in 75% of cases normalization of the endometrial structure was observed. In the control group in 32% of cases the structure of the endometrium normalized. After 6 months of treatment with gestagens, both oral forms (micronized progesterone, dydrogesterone) and the use of LNG-IUDs showed a positive effect from their use; the therapeutic form of gestagens for therapy is not significant in reducing excessive endometrial proliferation. In the control group of patients who did not receive therapy or discontinued therapy for various reasons, it was shown that 47% of patients had spontaneous regression of EH. The overall percentage of no effect from treatment was 20% in groups I, II and III. Determination of ERα expression in all groups showed a pronounced expression in glands and stroma, which did not differ significantly in the group with NEH (+) and in NEH (-). Analysis of PGR expression of NEH in endometrium (-) showed that in glandular cells (50.82±0.73) and in the stroma (47.34±0.82) it was lower than in the endometrium of women with NEH (+) (gland 187±3.1; stroma 166.4±2.3; p&lt;0.05), as well as in the unchanged endometrium in the proliferative phase (glands 193.2±8.5; stroma 178.7±6.3; p&lt;0.05) and the secretory phase (glands 140.2±4.4; stroma 116.6±3.1; p&lt;0.05). A study of E-cadherin expression in women with EH (-) showed that in 86.4% of cases the expression was absent and in 13.6% it decreased. In NEH (+) women, 49.2% of E-cadherin expression was weak, in 34.4% – moderate, and in 16.4% – negative, indicating an association between PGR and E-cadherin expression. In women with NEH (-) there was marked cytoplasmic expression of β-catenin up to 80%, which can be interpreted as potentially threatening the progression of NEH in atypical forms and relapses. Thus, the study of molecular mechanisms of resistance of endometrial hyperplasia to progestogen therapy will help to develop a differential approach to its diagnosis and treatment.

Massively parallel sequencing of endometrial lavage specimens for the detection of cancer-associated mutations in atypical and non-atypical endometrial hyperplasia.

Endometrial hyperplasia (EH), particularly with atypia, is considered an antecedent of endometrial adenocarcinoma. In this study, we aimed to apply massively parallel sequencing of endometrial lavage specimens for the detection of cancer-associated mutations in atypical (AEH) and non-atypical endometrial hyperplasia (NEH). The identified alterations were compared with those detected in tissue samples. Endometrial lavage specimens and parallel biopsy samples (n = 11 for AEH and n = 9 for NEH) were obtained from 18 women (9 with AEH and 9 with NEH) who received an office hysteroscopy for suspected endometrial lesions. All samples were tested for somatic mutations in hotspot regions of 72 cancer-associated genes by massively parallel sequencing. On analyzing sequencing data, the presence of at least one cancer-associated gene mutation was identified in 72.7 and 44.4% of endometrial lavage specimens obtained from women with AEH and NEH, respectively (p = 0.362, 95% confidence interval = 0.72-3.70). The concordance rates between mutations identified in endometrial lavage specimens and endometrial biopsies were 54.5 and 0% from women with AEH and NEH, respectively (p = 0.014). A patient with NEH harbored mutations in endometrial lavage with the same mutations found in the tissue specimen at low allele frequency below detection cutoff, raising the suspicion of missed focal atypia. Endometrial hyperplasia is characterized by a high burden of cancer-associated mutations, particularly in the presence of atypia. Our study, albeit performed with a relatively small number of samples, indicates that their detection by massively parallel sequencing of endometrial lavage is feasible. Our findings may allow tailoring of endometrial biopsies to the individual risk of AEH; additionally, they can pave the way toward less invasive surveillance protocols in patients with known EH.

Preliminary study of confocal laser endomicroscopy for in vitro specimens of the endometrium

BackgroundThis study observed and described the morphological characteristics of the endometrium of the resected uterus using confocal laser endomicroscopy. This included benign endometrium, non-atypical endometrial hyperplasia, atypical endometrial hyperplasia, and endometrial carcinoma, thereby laying a foundation for finding the precise localization and resection of endometrial lesions, given the feasibility of confocal laser endomicroscopy-assisted hysteroscopy.MethodsThis prospective study included 32 patients who underwent hysterectomy. We used confocal laser endomicroscopy to observe the endometrium of resected uteruses and described the characteristics of endometrium in different states by comparing histopathological findings (primary objects). The secondary objects of observation were the myometrium, endocervical canal, and surface of the external os of the cervix.ResultsA total of 32 patients who underwent hysterectomy for different diseases were included: 9 with endometrial carcinoma (5 with endometrioid carcinoma, 1 with endometrial serous carcinoma, 2 with clear cell carcinoma, and 1 with carcinosarcoma), 2 with atypical endometrial hyperplasia, 9 with benign diseases, 7 with cervical cancer, and 5 with ovarian cancer and borderline tumor. The dynamic images of the endometrium were observed and recorded using probe-based confocal laser endomicroscopy (pCLE). Considering histopathology as the gold standard, the diagnostic concordance rate of pCLE was 96.9% in patients with endometrial carcinoma and precancerous lesions and 100% in patients with endometrial carcinoma.ConclusionConfocal laser endomicroscopy provides real-time high-resolution images of the benign endometrium and endometrial lesions. Compared with histopathology, confocal laser endomicroscopy has high diagnostic accuracy and may become an auxiliary examination tool for hysteroscopy, as it is useful for early identification of endometrial lesions, real-time diagnosis of tumor, and detection of tumor boundaries for complete tumor resection. These findings can lay a foundation for the feasible use of fertility-sparing local excision of tumor lesions by hysteroscopy.

Новая стратегия поиска гормональной терапии пролиферативных процессов эндометрия у пациенток в постменопаузе

The limited efficacy of hormone therapy for endometrial proliferative process (EPP) in postmenopausal patients and its side effects on the immune system functionalities have not been studied in detail. Here we assess the feasibility of hormone therapy for EPP in postmenopausal patients through evaluation of estradiol and progesterone receptor gene expression in endometrial tissue and peripheral blood mononuclear cells (PBMC). The study enrolled 92 postmenopausal patients with EPP, including 37 pts with glandular-fibrous polyps, 7 pts with non-atypical endometrial hyperplasia (EH), 8 pts with atypical endometrial hyperplasia (AEH), 31 pts with moderately differentiated adenocarcinoma and 9 pts with highly differentiated adenocarcinoma. The PBMC isolates and endometrial samples were tested for ER⍺, ERβ, mER, PRA, PRB, mPR and PGRmC1 expression by reverse real time polymerase chain reaction (RT–PCR). Differential changes in PBMC receptor profiles upon in vitro exposure to progesterone or mifepristone were determined for patients with endometrial polyps and healthy women. The results indicate elevated expression of ERα, ERβ, PRA, PRB, mPR and PGRmC1 by endometrial tissues in EH and elevated expression of mER, ER⍺ and PRA by PBMC in AEH, apparently reflecting suppressed functionalities of monocytes, macrophages, Т-cells and natural killer cells. Unaltered expression of the studied genes by PBMC in endometrial adenocarcinoma may reflect the incrementing tumor autonomy. In vitro, mifepristone inhibited ER⍺, ERβ, mPR, PGRmC1, PRA and PRB expression in PBMC isolated from patients with endometrial polyps. We suppose that such effects can mitigate the negative influence of sex steroid hormones on immunocompetent cells.

Risk of atypical hyperplasia and endometrial carcinoma after initial diagnosis of non-atypical endometrial hyperplasia: A long-term follow-up study

ObjectivesThe strong association between atypical endometrial hyperplasia and endometrial carcinoma is well established, but data on the risk of atypical hyperplasia and carcinoma in Danish women with non-atypical endometrial hyperplasia are almost non-existent. This study aimed to investigate the prevalence of atypical hyperplasia and endometrial carcinoma diagnosed within 3 months of initial diagnosis (defined as concurrent disease) and the risk of atypical hyperplasia and carcinoma more than 3 months after initial diagnosis (classified as progressive disease) in Danish women initially diagnosed with non-atypical endometrial hyperplasia.DesignThis cohort study recruited 102 women diagnosed with non-atypical endometrial hyperplasia at Randers Regional Hospital in Randers, Denmark, between 2000 and 2015.MethodsThe endometrium was evaluated by transvaginal ultrasound examination and office mini-hysteroscopy with biopsies in all non-hysterectomized women. Data regarding subsequent hysterectomy or endometrial sampling were obtained from medical records and the Danish Pathology Registry (Patobank).ResultsA total of 15 women were diagnosed with atypical hyperplasia or carcinoma during follow-up. Concurrent atypical hyperplasia or carcinoma was seen in 2.9% (3/102), and among women who remained at risk for more than 3 months after initial diagnosis of non-atypical endometrial hyperplasia (n = 94), progression to atypical hyperplasia or carcinoma was seen in 13% (median follow-up 5.2 years, range 3.6 months to 15.1 years). Sixty-six percent of the women with progressive disease were diagnosed with atypical hyperplasia or carcinoma more than 1 year after initial diagnosis, but only two were diagnosed later than 5 years (5.2 and 9 years).ConclusionsThe risk of being diagnosed with atypical endometrial hyperplasia or endometrial carcinoma more than 5 years after an initial diagnosis of non-atypical endometrial hyperplasia seems to be low in Danish women. Specialized follow-up more than 5 years after diagnosis of non-atypical endometrial hyperplasia may not be warranted.

Restoration of endometrial receptivity and reproductive function in infertile women with excess body weightand complex non-atypical endometrial hyperplasia

To date, there are several approaches to the treatment of endometrial hyperplasia, but it is quite unclear which approach provides a higher clinical response with a lower recurrence rate, in addition to preservation and restoration of fertility in infertile women with complex non-atypical endometrial hyperplasia (NEH) and excess body weight. The purpose of the study was to evaluate the effectiveness of the restoration of reproductive function in patients with infertility, complex NEH and with excess body weight according to the proposed method. Material and methods. 74 women of reproductive age with complex NEH, infertility and excess body weight were under observation, of which 34 patients of the main group after hysteroscopic resection of the lesion at the first stage of treatment, at the second stage of treatment received gonadotropin-releasing hormone agonists (aGnRH) and adjuvant therapy with drugs indole-3-carbinol, metformin, fenofibrate for three months, and then at the third stage of treatment dydrogesterone, metformin, a vitamin-mineral complex that included myo-inositol, banaba leaves, extract of 1% corosolic acid, vitamin D3, methylfolate-quatrafolic, chromium for 6 months. 40 patients of the control group after hysteroscopic resection of the lesion at the first stage of treatment were prescribed aGnRH for 3 months in the second stage of treatment, then methylfolate-mvatrafolic for 6 months. Anthropometric data, echometric and morphofunctional characteristics of the endometrium during the expected window of implantation, hormonal profile and levels of peripheral blood lipokines in the dynamics of treatment were studied. Reproductive results were evaluated within a year after the end of treatment. The results. Treatment of complex NEH in the main group led, compared to the control group, to a decrease in body mass index, improvement in echometric and morphofunctional characteristics of the endometrium, its receptivity during the expected window of implantation, hormonal profile and lipokines level in peripheral blood, a decrease in insulin resistance, and an increase in the frequency of pregnancy. Conclusion. The proposed scheme for the treatment of complex NEH in infertile women with excess body weight allowed to improve their reproductive results, is effective and can be recommended for implementation in wide clinical practice.

Профилактика гиперплазий эндометрия в репродуктивном периоде

Objective. A systemic review of current literature on the efficacy and safety of combined oral contraceptives (COCs) for the prevention of endometrial hyperplasia (EH) in women of reproductive age. The possibilities and perspectives of using COCs for the prevention of EH according to scientific data on the grounds of evidence-based medicine over the past 5 years were considered. It was proven that expanding the range of effective treatment options for EH allows adapting treatment to patients’ needs and offers a personalized approach to their management. Conclusion. Gestodene-containing COCs are an effective and safe method for the prevention of non-atypical EH, carrying a wide range of therapeutic benefits associated with reliable contraceptive capacity and favorable fertility prognosis, especially in young women. Key words: endometrial hyperplasia, COCs, gestodene, polycystic ovary syndrome

Hysteroscopic Endometrial Resection in Women Treated With Tamoxifen for Breast Cancer Provides Definitive Diagnosis and Effective Long-Term Therapy

We evaluated resectoscopic surgery for definitive diagnosis and long-term therapy in 16 symptomatic tamoxifen-treated women with breast cancer who presented with abnormal uterine bleeding and/or intrauterine anomalies. Seven pre-menopausal women had benign pre- and post-operative endometrial biopsy, and 4 had benign polyps. At a median of 7 years of follow-up (range 2–8 y), all remained amenorrheic. Of 9 post-menopausal women, pre-operative biopsy was inadequate in 4, benign endometrium was found in 4, and non-atypical endometrial hyperplasia was found in 1. Post-operatively, all had benign pathology, 8 having polyp and 1 leiomyoma. At a median follow-up of 7 years (range 2–13 y), all were amenorrheic, with no recurrence of breast cancer or uterine pathology.

Risk of More Advanced Lesions at Hysterectomy after Initial Diagnosis of Non-Atypical Endometrial Hyperplasia in Patients with Postmenopausal Bleeding and Oral Anticoagulant Treatment.

Background and Objectives: Endometrial hyperplasia (EH) is a precursor lesion to endometrial cancer (EC), and when cellular atypia is present, in 40% of cases, they are diagnosed with EC on hysterectomy. Usually, EH is clinically manifested by uterine bleeding. In patients with oral anticoagulant therapy (OAT), the uterus is the second most common source of bleeding. The aim of the study was to show that uterine bleeding in postmenopausal patients undergoing OAT may reveal precancerous endometrial lesions with atypia, or neoplastic lesions in patients with an initial diagnosis of endometrial hyperplasia without atypia (non-atypical endometrial hyperplasia, NAEH) on dilation and curettage (D&C). We will be able to estimate the risk of a postmenopausal female patient with uterine bleeding during an OAT to have a precancerous endometrial lesion. Materials and Methods: The subjects of the study were 173 female patients with uterine bleeding, who have had total hysterectomy with bilateral salpingoovarectomy, of whom 99 underwent an OAT. There were 101 female patients initially diagnosed with NAEH, of which 60 did not have anticoagulant treatment (mean age 57.36 ± 6.51) and 41 had anticoagulant treatment (mean age 60.39 ± 7.35) (p = 0.006). From the pathology diagnosis moment, the surgery was performed at 42.09 ± 14.54 days in patients without OAT and after 35.39 ± 11.29 days in those who received such treatment (p = 0.724). Results: Initial diagnosis of NAEH established at D&C was changed at the final diagnosis after hysterectomy in EH with cellular atypia (atypical endometrial hyperplasia AEH) or EC in 18.18% of patients without OAT, and in 40.54% of patients who received this treatment. Conclusions: Based on a logistic regression model, it is estimated that female patients with an initial histopathological diagnosis of NAEH and who underwent OAT have, on average, 4.85 times greater odds (OR = 4.85, 95% CI 1.79–14.06) than the others of being identified postoperatively with more advanced lesions.

Immunohistochemical Expression of “HE4” in Endometrial Hyperplasia versus Endometrial Endometrioid Carcinoma

Aim &#x0D; Endometrial cancer is the most common cancer of the female genital tract. No effective biomarkers currently exist to allow for an efficient risk classification of endometrial carcinoma. Human epididymis protein 4 (HE4) overexpression is first observed in ovarian cancer tissue and subsequent research has shown that the HE4 overexpression has also been observed in patients with endometrial carcinoma. To our knowledge, this marker was evaluated in small number of research studies in cases of endometrial carcinoma versus hyperplasia. This has inspired us to test for immunohistochemical expression of HE4 in endometrial endometrioid carcinoma and hyperplastic endometria and to correlate HE4 expression with various prognostic pathological parameters including International Federation of Gynecology and Obstetrics (FIGO) grading and staging.&#x0D; Methods &#x0D; Immunohistochemical staining for HE4 was performed on paraffin-embedded sections of forty cases of endometrial endometrioid carcinoma and thirty cases of endometrial hyperplasia: including 15 cases of non-atypical hyperplasia and 15 cases of atypical hyperplasia. A histochemical score was used to evaluate HE4 expression by the tumor cells.&#x0D; Results&#x0D; In this study, HE4 overexpression level was significantly higher in endometrial endometrioid carcinoma than endometrial hyperplasia and significantly higher than non-atypical endometrial hyperplasia (P&lt;0.05). HE4 strong expression was detected in 20% of atypical endometrial hyperplasia, but no statistical significance was detected between atypical hyperplasia and endometrial carcinoma. HE4 overexpression showed statistically significant positive correlation with FIGO grading, FIGO staging, and depth of myometrial invasion.&#x0D; Conclusion:&#x0D; During interpretation of endometrial biopsies of atypical hyperplasia, HE4 strong expression might raise the possibility of the presence of coexisting adenocarcinoma not biopsied or even warning of a near future malignant transformation. Also, strong expression of HE4 by tissue biopsy of adenocarcinoma should be reported as this might predict higher grade and stage of the tumor, a point that should be considered by surgeons while performing hysterectomy. These results should be further confirmed by extending the study on a large scale, correlation of HE4 expression with the molecular classification of Tumor Cancer Genome Atlas and long term follow up are required to establish the prognostic significance of HE4 expression in endometrial carcinoma and atypical hyperplasia.&#x0D; Keywords: Endometrial carcinoma, Endometrial hyperplasia, HE4, Immunohistochemistry.

Epigenetic profile of endometrial proliferation in the different morphotypes of endometrial hyperplasia

Research aim: to investigate the proliferative status of endometrium in the different morphotypes of endometrial hyperplasia based upon the identification of key molecular markers of the cell cycle.Materials and methods. Endometrial samples taken from 137 women were investigated: 40 – normal endometrium (NE), 61 – non-atypical endometrial hyperplasia (ЕH), 36 – atypical hyperplasia (AHE). Expression of gene cyclin D1, nuclear antigen Кі-67, glycoproteins Е-cadherin and β-catenin, estradiol receptors (ER) and progesterone receptors (PGR) were investigated. Results. ER expression of NE was high in the proliferative phase and decreased significantly in the secretory phase. PGR expression was high in both phases. ER expression of EH in glandular (180 ± 8.3) and in stromal cells (170.5 ± 4.1) exceed the indicators of the secretory phase. PGR expression in the stromal cells of EH (197.5 ± 9.3) exceed significantly indicators of NE. ER and PGR expression significantly and reliably decreased if there was AHE. ER expression of glandular cells was 2.6 times lower (74.6 ± 3.9) compere to proliferative NE (p &lt;0.05) and 2.4 times lower to EH (р &lt;0.05). ER of stromal AHE cells dropped to 30.3 ± 2.8, which was 5.5–5.6 times lower than in the proliferative NE and EH (p &lt;0.002). PGR expression was 2.5–2.7 times lower (71.1 ± 2.3) in AHE glands than in NE and 2.8 times lower than in EH (p &lt;0.05). Gene cyclin D1 expression was reliably increased in AHE cells compere to NE and EH. Protein Кі-67 expression in the glandular cells of EH was 2.6 times lower (p &lt;0.05) and in AHE 2.9 times lower (p &lt;0.05) than NE proliferative phase. We discovered strong direction to decreasing Е-cadherin expression in EH and it was lowest for AHE. Opposite direction was expression of β-catenin. The highest numbers of positive samples were observed in AHE and it was 100%. The highest numbers of negative β-catenin samples were in the NE cells (32,5–35%).Conclusion. The epigenetic profile investigation of endometrial hyperplasia will be useful for future development of carcinogenesis risk stratification, identifying patients with high risk of endometrial cancer and also for choosing the optimal way to influence the pathological process in the endometrium.

Non-atypical endometrial hyperplasia: risk factors for occult endometrial atypia and malignancy in patients managed with hysterectomy.

ObjectiveTo determine the risk factors for occult endometrial atypia and malignancy in patients diagnosed with non-atypical endometrial hyperplasia (NEH) on endometrial biopsy.MethodsAll new cases of NEH diagnosed between April 2015 and March 2016 at KK Women’s and Children’s Hospital, who underwent hysterectomy as first-line treatment, were included in the study. Patients with a history of endometrial hyperplasia or malignancy were excluded from the study. Patient demographics (e.g., age, parity, body mass index [BMI]), medical history, and clinical presentation were obtained for analysis.ResultsIn total, 262 patients were diagnosed with NEH, of which 18.3% (n=48) underwent hysterectomy as first-line management. The average time to surgery was 77.0±35.7 days. All cases were diagnosed by dilation and curettage, and hysteroscopy. The mean age was 51 years, and the mean BMI was 26.9±5.8 kg/m2. Histology from the hysterectomy specimen showed 9 (18.8%) patients with atypical hyperplasia and 2 (4.2%) with grade 1, stage 1A endometrioid adenocarcinoma. Patients with higher grade final pathology had significantly lower median parity (1 vs. 2, P=0.039), higher mean BMI (30.1±6.5 vs. 25.9±5.3 kg/m2, P=0.033), and BMI ≥30 kg/m2 (54.5% vs. 13.5%, P=0.008, odds ratio 7.68), compared to patients whose final histology showed NEH or no residual hyperplasia.ConclusionOccult endometrial atypia and malignancy were found in 18.8% and 4.2% of patients with an initial diagnosis of NEH, respectively. High BMI and low parity were identified as significant risk factors for high-grade endometrial lesions in patients with NEH.

Histomorphological Patterns of Endometrial Hyperplasia

Background and Aims Endometrial hyperplasia is a pathological condition characterized by an increase in the endometrial gland to stromal ratio when compared to the normal proliferative endometrium. It is the precursor of endometrial carcinomamdashthe most common malignancy of female genital tract. The increased risk of endometrial hyperplasia is found to be more evident in women with abnormal uterine bleeding. Hence we decided to study the histopathological pattern of endometrial hyperplasia in women of different age groups.Methods All the endometrial biopsies with microscopic diagnosis of endometrial hyperplasia over a period of 1 year were retrieved from histopathology records. Information related to age and clinical diagnosis was noted from the accompanying laboratory request forms. Histological typing of endometrial hyperplasia was done depending on the new criteria used in the World Health Organization WHO classification.Results The present study included 40 cases n 40 of endometrial hyperplasia diagnosed by histopathological examination on endometrial biopsies. Age of the patients ranged from 21-70 years. About half of the patients 45 presented with abnormal uterine bleeding and were in the 5th decade of life. Non-atypical endometrial hyperplasia n 34 cases 85 was the most common histological type of endometrial hyperplasia.Conclusions Histopathological examination of endometrium is used for the diagnosis of abnormal uterine bleeding. Endometrial biopsy and curettage are the important sampling methods to detect endometrial hyperplasia. Hence vigilant screening of the endometrial samples plays an important role in the diagnosis and further management.