Background/Objectives: Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases. This review evaluated PD-L1 and PD-1 expression as potential biomarkers for immunotherapy response in EC, focusing on their relationship with MSI status. Methods: A systematic review, adhering to PRISMA guidelines, analyzed studies from MEDLINE and Embase until February 2023 on PD-1/PD-L1 expression in EC stratified by MSI status, including diverse study designs but excluding conference abstracts, with independent screening, data extraction, and additional reference checks to ensure comprehensive coverage. Results: A systematic analysis of 10 studies found that PD-L1 expression was more frequently expressed in MSI tumors (49%) compared to microsatellite-stable tumors (MSS) (33.5%), while PD-1 was expressed in 58% of MSI cases and 48% of MSS cases. Despite these findings, the prognostic value of PD-L1/PD-1 remains uncertain, with conflicting results regarding their association with survival outcomes. PD-L1 expression varied across molecular subtypes, being highest in POLE-mutated tumors (76.56%) and serous carcinomas (73%). Differences in PD-L1 expression between primary and metastatic sites were also noted, complicating its use as a biomarker. Conclusions: The assessment of PD-L1 expression in EC could represent a valuable option for selecting patients who may benefit from immune checkpoint inhibitors (ICI), including those in the MSS cohort, thereby ensuring a more tailored and personalized treatment strategy.

(1) Background: Endometrial carcinoma (EC) classified as no specific molecular profile (NSMP) represents a heterogeneous group with variable prognoses. This retrospective, single-center study aims to further stratify NSMP ECs to tailor treatment strategies and improve outcomes. (2) Methods: From 2020 to 2023, we collected data on 51 patients diagnosed with NSMP EC following the introduction of molecular profiling at our institution. Patients were retrospectively analyzed for estrogen receptor (ER) status, histotype, and grade to identify potential prognostic subgroups. (3) Results: Our analysis identified two distinct subgroups within NSMP EC: low-risk and high-risk, based on ER status, histotype, and grade. The low-risk NSMP group demonstrated significantly better survival outcomes compared to the high-risk group. With a median follow-up time of 16 moths (IQR 13.0–29.7), the disease-free survival (DFS) and overall survival (OS) for the low-risk group were 100%. For the high-risk group, the DFS and OS were 71.4% and 78.6%, respectively, which showed a statistically significantly difference (Log-Rank Mantel-Cox < 0.001). In the high-risk group, four patients experienced recurrence, and three of these patients died. (4) Conclusions: Stratifying NSMP EC into low-risk and high-risk categories based on ER status, histotype, and grade can lead to more accurate prognostic assessments. In time, it may require tailored adjuvant therapies and a personalized treatment.

Objective: We aimed to compare the clinical utility and diagnostic accuracy of the ADNEX model, ROMA score, RMI I, and RMI IV, as well as two serum markers (CA125 and HE4) in preoperative discrimination between benign and malignant adnexal masses (AMs). Methods: We conducted a retrospective study extracting all consecutive patients with AMs seen at our Institution between January 2015 and December 2020. Accuracy metrics included sensitivity (SE), specificity (SP), and area under the receiver operating characteristic curve (AUC), and their 95% confidence intervals (CI) were calculated for basic discrimination between AMs. Model performance was evaluated in terms of discrimination ability and clinical utility (net benefit, NB). Results: A total of 581 women were included; 481 (82.8%) had a benign ovarian tumor and 100 (17.2%) had a malignant tumor. The SE and SP of CA125, HE4, ROMA score, RMI I, RMI IV, and ADNEX model were 0.60 (0.54–0.66) and 0.80 (0.76–0.83); 0.39 (0.30–0.49) and 0.96 (0.94–0.98); 0.59 (0.50–0.68) and 0.92 (0.88–0.95); 0.56 (0.46–0.65) and 0.98 (0.96–0.99); 0.54 (0.44–0.63) and 0.96 (0.94–0.98); 0.82 (0.73–0.88) and 0.91 (0.89–0.94), respectively. The overall AUC was 0.76 (0.74–0.79) for CA125, 0.81 (0.78–0.83) for HE4, 0.82 (0.80–0.85) for ROMA, 0.86 (0.84–0.88) for RMI I, 0.83 (0.81–0.86) for RMI IV, and 0.92 (0.90–0.94) for ADNEX. The NB for ADNEX was higher than other biomarkers and models across all decision thresholds between 5% and 50%. Conclusions: The ADNEX model showed a better discrimination ability and clinical utility when differentiating malignant from benign Ams, compared to CA125, HE4, ROMA score, RMI I, and RMI IV.

Endometrial cancer of no specific molecular profile (NSMP) represents the most prevalent molecular subtype of endometrial cancer, comprising over 50 % of all diagnoses. Although studies have explored the prevalence of the NSMP subtype, to our knowledge, no systematic review or meta-analysis has specifically targeted grade 3 (G3, high-grade) tumors. We aimed to determine the prevalence of G3 endometrioid endometrial cancer of NSMP and assess regional variations in this prevalence. We also sought to synthesize available data concerning oncologic outcomes, including overall survival, progression-free survival, and disease-specific survival. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No: CRD42024544247). We searched the electronic databases: PubMed/Medline, Scopus, Web of Science, Cochrane Library, and EMBASE. To estimate the overall prevalence of the NSMP subtype, we performed a meta-analysis using the proportions method with the Freeman-Tukey (arcsine) transformation. For estimating oncologic outcomes, we conducted a meta-analysis using hazard ratios (HRs) when available. In the absence of HRs, we utilized Kaplan-Meier curves. All pooled estimates and their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model with the inverse variance method and restricted maximum likelihood estimator. We analyzed 31 studies, encompassing 2,660 patients. The pooled prevalence of NSMP within G3 endometrioid endometrial cancer was 0.29 (95 %CI: 0.23-0.34, I² = 80.8 %). This prevalence was highest in North America (0.43, 95 %CI: 0.17-0.71) and lowest in Europe (0.23, 95 %CI: 0.19-0.28). The random-effects pooled estimate indicated that the NSMP subtype was associated with intermediate oncologic outcomes compared to other molecular subtypes. The pooled prevalence of G3 endometrioid endometrial cancer of NSMP is 29 %. The oncologic outcomes for this molecular subtype seem intermediate, though further refinement and research are needed for a more precise understanding.

Background/Objectives: Ultrasound elastography (UE) is a non-invasive imaging technique that evaluates tissue stiffness and may complement conventional ultrasound in the assessment of uterine diseases. This systematic review aimed to summarize the current evidence on the role of strain elastography (SE) and shear wave elastography (SWE) in the diagnosis and management of benign and malignant uterine pathologies. Methods: A systematic literature search of MEDLINE (PubMed) and Embase was performed to identify studies published between January 2018 and February 2026. Original studies evaluating UE in adenomyosis, uterine fibroids, cervical lesions, and endometrial pathologies were included. Data were qualitatively synthesized according to pathology type and elastographic technique. Results: Twenty studies met the inclusion criteria. In benign myometrial disorders, adenomyosis and uterine fibroids generally showed higher stiffness than normal myometrium, although differentiation between these entities was not always consistent across studies. In cervical disease, malignant and high-grade lesions typically demonstrated increased stiffness compared with benign or low-grade lesions. In endometrial pathology, endometrial carcinoma was generally associated with higher stiffness values than benign lesions and elastography also showed potential in assessing myometrial invasion. Across studies, UE demonstrated promising diagnostic performance, but substantial heterogeneity was observed in acquisition methods, parameters, and reported thresholds. Conclusions: UE appears to be a promising adjunct to conventional ultrasound for the evaluation of uterine pathologies. However, further standardized, large-scale studies are needed to define reproducible protocols and clinically applicable diagnostic thresholds.

Endometrial cancer incidence is markedly rising globally, posing an urgent need to elucidate the molecular mechanisms driving disease characterization and progression. Endometrial cancer evolution is driven by canonical Wnt and p53 pathway alterations, yet the mechanisms orchestrating the transition from localized proliferation to stromal invasion, the proliferation–invasion dichotomy, remain poorly understood. While long non-coding RNAs (lncRNAs) are emerging as critical correlates of divergent tumor phenotypes, their coordination with the broader ubiquitin–proteasome system (UPS), specifically E3 ligase and deubiquitinase (DUB) networks, during endometrial cancer progression is largely unexplored. Whole-transcriptome RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tissue from a clinical cohort of 38 patients, comprising 34 primary endometrial carcinomas across distinct molecular subtypes (MSI, POLE, p53abn, and NSMP) and four pre-cancerous endometrial intraepithelial neoplasia (EIN) lesions. To stringently control for baseline patient-specific confounding, differential gene expression and principal component analyses were executed using a strict, intra-patient, matched-pair design (Tumor vs. Adjacent Normal). A principal component analysis of the batch-corrected transcriptome revealed a profound divergence between tumor and paired adjacent normal phenotypes. This spatial divergence was heavily characterized by lncRNA signatures (including SOCS2-AS1) strongly associated with extracellular matrix (ECM) remodeling. Concurrently, we identified a critical, malignancy-specific transcriptomic dysregulation across the broader UPS network. Within this altered transcriptional landscape, the ubiquitin C-terminal hydrolase (UCHL) family emerged as a highly significant node. UCHL5 displayed robust, global upregulation across the pan-cancer cohort compared with matched controls (log₂FC = 0.83, padj < 0.001). Strikingly, UCHL3 exhibited global upregulation (log₂FC = 1.23, padj = 0.002) that was highly concentrated within the microsatellite instability (MSI) and polymerase epsilon (POLE) hypermutated subtypes, highlighting a potential compensatory transcriptomic response to the predicted cellular stress inherent to high mutational burdens. In an exploratory subset of pre-cancerous EIN lesions (n = 4), neither the invasive lncRNA networks nor profound UPS/UCHL dysregulation were observed, suggesting a preliminary trend that requires validation in larger precursor cohorts. Our paired transcriptomic mapping reveals that endometrial cancer progression is characterized by divergent transcriptomic programs: specific lncRNA networks are tightly coupled to the invasive remodeling of the ECM, while concurrent dysregulation of broad UPS networks reflects the altered proteostasis associated with this phenotypic shift. The pronounced upregulation of critical UPS nodes, such as UCHL3 in MSI/POLE tumors, highlights a landscape of novel, enzymatically targetable vulnerabilities in hypermutated endometrial cancers.