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

Disparities in endometrial cancer has increased during the past decade with Black women more likely to be diagnosed at a later stage and have higher mortality. The majority of research has been focused on cultural barriers, socioeconomic status, lack of access to care, comorbidities, and tumor histology to explain these disparities. Limited studies have been conducted on the disparity in the treatment of endometrial intraepithelial neoplasia(EIN). We sought to analyze the differences in treatment used in the management of postmenopausal women with EIN to evaluate whether race/ethnicity is a contributing factor. An IRB approved retrospective study was conducted amongst women at a single institution diagnosed with EIN. Ethnicity/race was defined as non-Hispanic White, non-Hispanic Black, Hispanic, and Asian. Demographic and clinical data was extracted. Multivariable logistic regression was used to examine the association between ethnicity/race and treatment, adjusted for age, BMI, and underlying medical conditions such as cardiovascular disease and diabetes. In total, 254 patients were analyzed. A significant association between ethnicity/race and treatment with non-Hispanic Black women less likely to be treated with surgical management compared to non-Hispanic White women (OR = 0.326, 95 %CI 0.129-0.827, p = 0.026). Importantly, after adjusting for clinical risk factors(age, BMI, CVD, diabetes), non-Hispanic Black women remained at an increased risk of not undergoing surgical intervention (OR = 0.333, 95 % CI 0.125-0.882, p = 0.027). Future research is imperative to evaluate the root cause of this disparity in the healthcare system.

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

OBJECTIVE: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning.
METHODS: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python \'sklearn\' library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models.
RESULTS: Of the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%-88%) and a low sensitivity (23%-51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646.
CONCLUSIONS: Even using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology.

Real-world data indicated that some endometrial atypical hyperplasia (EAH) and early endometrial carcinoma (EEC) patients of fertility preservation had a normal ovarian reserve, while some had a decreased ovarian reserve (DOR). This study was designed to investigate the effect of baseline ovarian reserve on the treatment of EAH and EEC patients who ask for preservation of fertility.
This was a prospective cohort study conducted at a single university-affiliated fertility center. A total of 102 EAH and EEC patients who received fertility-preserving treatment between March 2019 and August 2020 were included and divided into a DOR group (n=22) and a non-DOR group (n=80).
The 32-week CR rate of the non-DOR group was significantly higher than that of the DOR group (60.3% vs. 33.3%, P =0.028). The DOR group had a longer treatment duration to achieve CR than the non-DOR group (40.07 vs. 29.71 weeks, P=0.008, HR: 0.54, 95% CI: 0.36-0.86). Multivariate logistic regression analyses demonstrated that DOR (OR: 0.35, 95% CI: 0.13-0.99, P=0.049) and BMI ≥25 kg/m2 (OR: 0.40, 95% CI: 0.17-0.92, P=0.031) were negatively associated with 32-week CR.
Decreased baseline ovarian reserve is negatively correlated with the efficacy of fertility-preserving treatment in EAH and EEC patients, as this group has a lower CR rate and a longer treatment duration to achieve CR than those without DOR.

The purpose of this study was to determine whether utilization of assisted reproductive technology following clearance of endometrial intraepithelial neoplasia (EIN) or early endometrial cancer (EC) shortens time to conception (TTC) and reduces recurrence. Patients aged 18 to 45 with EIN or early EC who achieved pathologic response following progesterone treatment were identified via retrospective chart review. Study groups included patients who pursued ovulation induction (OI), in vitro fertilization (IVF), and spontaneous pregnancy. Primary outcomes were TTC and recurrence rate. Three hundred forty-six charts were reviewed, with 86 patients meeting inclusion criteria and 53 attempting pregnancy. Of those 53 patients, 11 became pregnant and seven had a live birth. Median times to pregnancy were 183 days for IVF, 54 days for OI, and 347 days for spontaneous conception (p < 0.05). No differences were seen in recurrence or progression based on attempted pregnancy method, nor with duration of fertility treatment. Forty-two of 86 patients (49%) were lost to follow-up. For patients with a history of treated EIN or EC, OI may decrease TTC. Larger prospective studies are needed to definitively answer this question. Although no differences in recurrence or progression were identified, the significant loss to follow-up rate in this study is concerning and warrants further investigation.

BACKGROUND: Interpretation of changes and premalignant lesions in endometrial polyps can be challenging. We evaluated the clinical course of patients with focal gland crowdings in endometrial polyps via repeat biopsies and searched for possible morphological findings in the initial biopsy that may foresee a premalignant course.
METHODS: Specimens diagnosed as endometrial polyp and focal gland crowding in patients who had a repeat biopsy in a 1-year period were reexamined. Morphological findings in the initial biopsies were recorded. The group whose repeat biopsies were \"premalignant or malignant\" (Group 1), and the group with \"benign\" repeat biopsies (Group 2) were compared.
RESULTS: \"Endometrial polyp and gland crowdings\" was diagnosed in 115 specimens of which 38 patients had repeat biopsies. Among these 8 (21%) were diagnosed as \"endometrial intraepithelial neoplasia (EIN)\" (Group 1) and 30 (79%) as \"benign\" (Group 2). Morphological features in the initial biopsies were evaluated; PAX2 loss was 6 of 8 (75%) for Group 1 and 7 of 30 (23%) for Group 2 (P = .020), and altered epithelial cytological features were present in 5 of 8 (62%) versus 4 of 30 (13%) (P = .015), both significantly higher in Group 1. Dark intraluminal secretion, intraluminal histiocytes, intraglandular epithelial proliferation, and mean diameter of crowded gland areas were not statistically different between the 2 groups.
CONCLUSIONS: \"Focal gland crowdings\" in endometrial polyps do carry a risk of EIN in subsequent biopsies. We suggest that the loss/decrease of PAX2 and altered epithelial cytological features in these areas in the initial biopsy are indicative of a premalignant course.

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

Elevated body mass index (BMI) is a risk factor for endometrioid endometrial cancer and its precursor, endometrial intraepithelial neoplasia (EIN). Our objective was to describe the association between BMI and age at EIN diagnosis.
We conducted a retrospective study of patients diagnosed with EIN from 2010 to 2020 at a large academic medical center. Patient characteristics were stratified by menopausal status and compared using a chi-square or t-test. We used linear regression to determine the parameter estimate (β) and 95% confidence interval for the association between BMI and age at diagnosis.
We identified 513 patients with EIN; 503 (98%) had complete medical records. Premenopausal patients were more likely to be nulliparous and to have polycystic ovary syndrome than postmenopausal patients (both p ≤ 0.001). Postmenopausal patients were more likely to have hypertension, type 2 diabetes, and hyperlipidemia (all p ≤ 0.02). There was a significant linear association between BMI and age at diagnosis in premenopausal patients (β = -0.19 (95% CI: -0.27, -0.10). In premenopausal patients, for every 1-unit increase in BMI, age at diagnosis decreased by 0.19 years. No association was observed in postmenopausal patients.
In a large cohort of patients with EIN, increasing BMI was associated with an earlier age at diagnosis in premenopausal patients. This data suggests consideration of endometrial sampling in younger patients with known risk factors for excess estrogen exposure.

Gestational endometrium can demonstrate a spectrum of atypical but benign changes. One such lesion is localized endometrial proliferation of pregnancy (LEPP), first described in a series of 11 cases. To understand its biological and clinical importance, we explore the pathologic, immunophenotypic, and molecular features of this entity. Nine cases of LEPP identified in 15 years were retrieved from departmental archives and reviewed. Immunohistochemistry and next-generation sequencing using a comprehensive 446-gene panel were performed when the material was available. Eight cases were identified in curettage specimens performed after first-trimester pregnancy loss, and 1 in the basal plate of a mature placenta. The mean patient age was 35 (range 27-41) years. The mean lesion size was 6.3 (range 2-12) mm. Architectural patterns, often coexisting in the same case, included cribriform (n = 7), solid (n = 5), villoglandular (n = 2), papillary (n = 2), and micropapillary (n = 1). Cytologic atypia was mild in 7 cases and moderate in 2. Mitotic activity was low (up to 3 per 2.4 mm2). All lesions were associated with neutrophils. Background Arias-Stella phenomenon was present in 4 cases. Immunohistochemistry was performed in 7 LEPP, all of which demonstrated wildtype p53, retained MSH6 and PMS2, membranous beta-catenin, and positive estrogen receptor (mean 71%) and progesterone receptor (mean 74%). All were negative for p40 except 1 case (focal weak positivity). PTEN was markedly reduced in background secretory glands in all cases; in 5/7, LEPP foci showed a complete absence of PTEN expression. PIK3CA pathogenic variants were identified in 4/4 cases sequenced; 3/4 had inactivating PTEN mutations. Follow-up, available in 8 patients (mean length = 51 months, range 7-161), was conservative with observation only and showed no persistence or adverse outcomes. LEPP is characterized by intraglandular cribriform/solid architecture, positive estrogen receptor/progesterone receptor, PTEN loss, and PIK3CA and PTEN mutations. Although our findings indicate that LEPP is neoplastic, for now, we advise against diagnosing LEPP as endometrial carcinoma or hyperplasia because LEPP has a particular clinicopathologic context (concurrent gestation), distinct morphology (purely intraepithelial complex growth), and indolent outcome. Thus, it should be distinguished from endometrial intraepithelial neoplasia and carcinoma for which therapeutic interventions are indicated.