Molecular classification of endometrial carcinoma on endometrial biopsy: an early prognostic value to guide personalized treatment.

OBJECTIVE: Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the molecular characteristics of the tumor. This study aims to assess the feasibility of obtaining reliable molecular classification status from biopsy specimens collected during hysteroscopy to better modulate the appropriate surgical treatment. METHODS: This monocentric, retrospective, observational study was conducted on 106 patients who underwent a biopsy procedure followed by radical surgery for endometrial cancer, with concurrent molecular investigation. The molecular classification was determined through immunohistochemical staining for p53 and mismatch repair proteins, along with gene sequencing for POLE. RESULTS: Overall, 106 patients underwent molecular investigation, which was finally achieved on 99 patients (93.4%). Among these, the molecular analysis was conducted in 71 patients (67%) on the pre-operative endometrial biopsy and on the final uterine specimen in 28 patients (26.4%). Most of the endometrial biopsies were performed using Bettocchi hysteroscopy (66%). Molecular analysis was not possible in seven patients (6.6%), with six cases due to sample inadequacy and one case attributed to intra-mucosal carcinoma. The molecular results showed that the copy number low sub-group was the most common, and five cases of 'multiple classifiers' were observed in the low-risk category. CONCLUSION: Our experience in obtaining molecular information from biopsy samples underscores the feasibility and efficacy of this technique, even in small tissue samples. This capability helps define the prognostic group of patients, facilitates timely decision-making, and develops a personalized strategy for each patient.

Tumoral programmed cell death 1 (PD1) expression in endometrial carcinoma is a prognostic marker for patient outcome.

OBJECTIVE: Immune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value. METHODS: Tumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded by PDCD1), its ligand (PDL1, encoded by CD274), and interferon gamma (IFNG) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548). RESULTS: PD1, PDL1, and IFNG expression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively. POLE-mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression of PD1 and IFNG. Increased expression of PD1, PDL1, and IFNG was associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance of PD1 for recurrence-free survival (HR 0.39, p=0.009) and PDL1 for overall survival (HR 0.55, p=0.037). The prognostic value of tumoral PD1 on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort. CONCLUSIONS: Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in "hot tumors", predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.

Enhancing Preoperative Assessment of Endometrial Cancer: The Role of Diffusion-Weighted Magnetic Resonance Imaging in Evaluating Myometrial Invasion.

BACKGROUND: Endometrial cancer (EC) is the most common gynecological malignancy. Accurate preoperative staging is essential for guiding treatment. The depth of myometrial invasion is a key prognostic factor. This prospective study aimed to evaluate the added benefit of diffusion-weighted imaging (DWI) compared to T2-weighted imaging (T2WI) and dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative assessment of myometrial invasion in EC. AIM AND OBJECTIVES: The aim of this prospective study was to evaluate the added benefit of DWI in the preoperative assessment of myometrial invasion in EC, in comparison with T2WI and DCE-MRI. The objectives were to assess the imaging characteristics of endometrial carcinoma on T2WI, DCE, and DW MR, to assess the depth of myometrial invasion and overall stage in EC patients, to compare the diagnostic performance of DCE-MRI with that of DW-MRI combined with T2WI, to describe how MR imaging findings can be combined with tumor histologic features and grading to guide treatment planning, and to evaluate the pitfalls and limitations of DCE and DW MR in the assessment of EC. MATERIALS AND METHODS: Thirty-one patients with histologically confirmed EC underwent preoperative pelvic MRI on a 1.5T scanner. T2WI, DWI (b-values 0, 1000 s/mm2), and DCE-MRI were performed. Two radiologists independently assessed myometrial invasion on T2WI, T2WI + DWI, and T2WI + DCE-MRI. Histopathology after hysterectomy was the reference standard. Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each MRI protocol, with separate analyses for superficial (<50%) and deep (≥50%) myometrial invasions. RESULTS: The accuracy for assessing superficial invasion was 61.3% for T2WI, 87.1% for T2WI + DWI, and 87.1% for T2WI + DCE-MRI. For deep invasion, accuracy was 64.5% for T2WI, 90.3% for T2WI + DWI, and 90.3% for T2WI + DCE-MRI. Sensitivity, specificity, PPV, and NPV for T2WI + DWI and T2WI + DCE-MRI were high and comparable (88.9-91.7%) for both superficial and deep invasions. T2WI had markedly lower sensitivity and specificity. The differences between T2WI and the functional MRI protocols were statistically significant (p < 0.01). CONCLUSION: DWI and DCE-MRI significantly improve the diagnostic performance of MRI for the preoperative assessment of myometrial invasion depth in EC compared to T2WI alone. DWI + T2WI and DCE-MRI + T2WI demonstrate comparable high accuracy. DWI may be preferable since it is faster and avoids contrast administration.

Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications.

Ferroptosis, a recently identified type of non-apoptotic cell death, triggers the elimination of cells in the presence of lipid peroxidation and in an iron-dependent manner. Indeed, ferroptosis-stimulating factors have the ability of suppressing antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and the subsequent oxidative death of the cells. Ferroptosis is involved in the pathophysiological basis of different maladies, such as multiple cancers, among which female-oriented malignancies have attracted much attention in recent years. In this context, it has also been unveiled that non-coding RNA transcripts, including microRNAs, long non-coding RNAs, and circular RNAs have regulatory interconnections with the ferroptotic flux, which controls the pathogenic development of diseases. Furthermore, the potential of employing these RNA transcripts as therapeutic targets during the onset of female-specific neoplasms to modulate ferroptosis has become a research hotspot; however, the molecular mechanisms and functional alterations of ferroptosis still require further investigation. The current review comprehensively highlights ferroptosis and its association with non-coding RNAs with a focus on how this crosstalk affects the pathogenesis of female-oriented malignancies, from breast cancer to ovarian, cervical, and endometrial neoplasms, suggesting novel therapeutic targets to decelerate and even block the expansion and development of these tumors.

Fractal Dimension, Circularity, and Solidity of Cell Clusters in Liquid-Based Endometrial Cytology Are Potentially Useful for Endometrial Cancer Detection and Prognosis Prediction.

Endometrial cancer (EC) in women is increasing globally, necessitating improved diagnostic methods and prognosis prediction. While endometrial histology is the conventional approach, liquid-based endometrial cytology may benefit from novel analytical techniques for cell clusters. A clinical study was conducted at the University of Fukui Hospital from 2012 to 2018, involving 210 patients with endometrial cytology. The liquid-based cytology images were analyzed using cell cluster analysis with Image J software. Logistic regression, ROC analysis, and survival analysis were employed to assess the diagnostic accuracy and prognosis between cell cluster analysis and EC/atypical endometrial hyperplasia (AEH). Circularity and fractal dimension demonstrated significant associations with EC and AEH, regardless of age and cytology results. The ROC analysis revealed improved diagnostic accuracy when combining fractal dimension with cytology, particularly in menopausal age groups. Lower circularity and solidity were independently associated with poor overall survival, while higher fractal dimension values correlated with poorer overall survival in Grades 2 and 3 endometrial cancers. The combination of circularity and fractal dimension with cytology improved diagnostic accuracy for both EC and AEH. Moreover, circularity, solidity, and fractal dimension may serve as prognostic indicators for endometrial cancer, contributing to the development of more refined screening and diagnostic strategies.

Survival Difference of Endometrial Cancer Patients with Peritoneal Metastasis Receiving Cytoreductive Surgery (CRS) with and without Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Systematic Review and Meta-Analysis.

Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected additional survival benefits of CRS plus HIPEC over CRS only. Twenty-one and ten studies with a total number of 1116 and 152 cases investigating CRS only and CRS plus HIPEC were identified, respectively. When all articles were analyzed, the 1-year survival rate was 17.60% higher for CRS plus HIPEC (82.28% vs. 64.68%; p = 0.0102). The same tendency was observed for the 2-year (56.07% vs. 36.95%; difference: 19.12%; p = 0.0014), but not for the 5-year (21.88% vs. 16.45%; difference: 5.43%; p = 0.3918) survival rates. The same clinical significance, but statistically less strong observations, could be made if only the studies published after 2010 were investigated (1-year survival rate: 12.08% and p = 0.0648; 2-year survival rate: 10.90% and p = 0.0988). CRS remains one of the core elements of ECPM treatment, but the addition of HIPEC to CRS can increase the positive clinical outcome, especially in the first 2 years.

The Role of Endometrial Sampling before Hysterectomy in Premenopausal Women with Abnormal Uterine Bleeding.

Background/Objectives: An endometrial sampling is recommended for patients experiencing abnormal uterine bleeding above the age of 40 or 45. Valid risk prediction models are needed to accurately assess the risk of endometrial cancer and avoid an unnecessary endometrial biopsy in premenopausal women. We aimed to assess the necessity and usefulness of preoperative endometrial sampling by evaluating premenopausal women who underwent hysterectomy for abnormal uterine bleeding after preoperative endometrial sampling at our clinic. Methods: A retrospective analysis was conducted on 339 patients who underwent preoperative endometrial sampling and subsequently underwent hysterectomy due to abnormal uterine bleeding. Detailed gynecologic examinations, patient histories, and reports of endometrial sampling and hysterectomy were recorded. Cohen's Kappa (κ) statistic was utilized to evaluate the concordance between histopathological results from an endometrial biopsy and hysterectomy. Results: The mean age of the cohort was 47 ± 4 years. Endometrial biopsies predominantly revealed benign findings, with 137 (40.4%) cases showing proliferative endometrium and 2 (0.6%) cases showing endometrial cancer. Following hysterectomy, final pathology indicated proliferative endometrium in 208 (61.4%) cases, with 7 (2.1%) cases showing endometrioid cancer. There was a statistically significant but low level of concordance between histopathological reports of endometrial biopsy and hysterectomy results (Kappa = 0.108; p < 0.001). Significant differences were observed only in the body mass index of patients based on hysterectomy results (p = 0.004). When demographic characteristics were compared with cancer incidence, smoking status and preoperative endometrial biopsy findings showed statistically significant differences (p = 0.042 and p = 0.010, respectively). Conclusions: The concordance between the pathological findings of a preoperative endometrial biopsy and hysterectomy is low. Body mass index is an important differentiating factor between benign histopathologic findings of endometrium and endometrial neoplasia. Moreover, adenomyosis was found to be associated with endometrial cancer cases. The current approach to premenopausal women with abnormal uterine bleeding, which includes a routine endometrial biopsy, warrants re-evaluation by international societies and experts.

Colombian consensus for the molecular diagnosis of endometrial cancer / Consenso colombiano para el diagnóstico molecular del cáncer de endometrio.

Objective: The Cancer Genome Atlas research program (TCGA) developed the molecular classification for endometrial cancer with prognostic and therapeutic utility, which was replaced by the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification by consensus and international guidelines due to its high cost. This article aims to present national recommendations from an expert consensus that allows unification and implementation of the molecular classification for women with endometrial cancer nationwide, with a rational use of resources and technology. Methods: Consensus of 36 experts in clinical oncology, oncological gynecology, pathology, and genetics, with clinical practice in the national territory. The leader group performed a literature review and structuring of questions rated 1 to 9 points. A modified nominal group technique was used. There was a face-to-face meeting with master presentations, deliberative dialogue, and Google Forms (Google LLC, Mountain View, CA, USA) questionnaire voting with analysis and discussion of responses. The non-consensual responses led to a second round of voting. The final manuscript was finally prepared and revised. Results: Seven recommendations were formulated integrating the panelist responses based on evidence, but adjusted to the Colombian context and reality. Recommendation 1. The molecular classification is recommended in all the endometrial cancers using the immunohistochemistry markers as subrogated results from the molecular profile initially proposed in the TCGA classification. Recommendation 2. The sequential test strategy is recommended, starting with the immunohistochemistry markers (p53, MLH1, MSH 2, MSH6, PMS2) simultaneously in all the patients, defining to request POLE (DNA polymerase epsilon) (if available) according to the risk classification based on the surgical piece. Recommendation 3. It is recommended, that the gynecologist oncologist should be the one to request the POLE (if available) according to the final pathology report. This test must be requested for all endometrial cancers stage I-II, except in low risk (stage IA low grade endometrioid histology without linfovascular invasion normal p53) and, stages III-IV without residual disease, without affecting the request of subrogated immunohistochemistry molecular markers upon histology. The consensus proposes that the POLE is requested after the immunohistochemistry and according to the categories in the risk classification established by the 2020 ESGO/ESTRO/ESP guidelines. Recommendation 4. It is recommended to perform immunohistochemistry for hormonal receptors for all women with endometrial cancer and the HER2 in patients with p53abn, simultaneously with the others immunohistochemistry markers. Recommendation 5. It is recommended to perform the immunohistochemistry markers (p53, MLH1, MSH2, MSH6 y PMS2) in an initial endometrial biopsy or curettage when the specimen is adequate and available. In case the initial immunohistochemistry is inconclusive, or there are histological discrepancies between the initial and definitive pathology, it is recommended to repeat the molecular profile in the surgical pathology. The immunohistochemistry markers must be reported in the pathology report according to the CAP (College of American Pathologists) recommendations, independently of the type of sample. Recommendation 6. It is recommended to perform MLH1 promoter methylation testing in patients who exhibit loss of expression of MLH1 in immunohistochemistry whether it is accompanied or not with loss of expression of PMS2. All the patients with deficient MMR (mismatch repair), should be sent for genetic counseling to rule out Lynch syndrome. Recommendation 7. It is recommended to consider the molecular classification in addition to the classical histopathological criteria when making adjuvant judgments, as incorporated by the classification of prognostic groups of the 2020 ESGO/ESTRO/ESP guidelines. Conclusions: It is necessary to implement the molecular classification of endometrial cancer in clinical practice in accordance to the Colombian context, due to its prognostic and probably predictive value. This will enable the characterization of the Colombian population in order to offer individualized guided treatments. This is an academic and nonregulatory document.

Objetivos: el programa Cancer Genome Atlas Research (TCGA) desarrolló la clasificación molecular para cáncer endometrial con utilidad pronóstica y terapéutica, la cual ha sido reemplazada por consensos y guías internacionales por la clasificación ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) debido a su alto costo. El objetivo de este artículo es presentar recomendaciones a nivel nacional derivadas de un consenso de expertos que permitan unificar e implementar la clasificación molecular para mujeres con cáncer endometrial, mediante un uso racional de recursos y tecnología. Materiales y métodos: consenso de 36 expertos en oncología clínica, ginecología oncológica, patología y genética con práctica clínica en el territorio nacional. El grupo líder realizó una revisión de la literatura y estructuración de preguntas calificadas de 1 a 9 puntos. Se utilizó la técnica de grupo nominal modificada. Se efectuaron reuniones presenciales con presentaciones magistrales, diálogo deliberativo y votación de cuestionario Google Forms (Google LLC, Mountain View, CA, USA) con análisis y discusión de respuestas. Las respuestas no consensuadas se llevaron a una segunda ronda de votación. Finalmente, se elaboró y revisó el manuscrito final. Resultados: se formularon siete recomendaciones integrando las respuestas de las panelistas basadas en evidencia, pero ajustadas al contexto y a la realidad colombiana. Recomendación 1. Se recomienda realizar la clasificación molecular en todos los carcinomas endometriales utilizando los marcadores de inmunohistoquímica como resultados subrogados del perfil molecular inicialmente propuesto en la clasificación del TCGA. Recomendación 2. Se recomienda la estrategia secuencial de testeo iniciando por los marcadores de inmunohistoquímica (p53, MLH1, MSH 2, MSH6, PMS2) simultáneamente en todas las pacientes, y definir la solicitud del POLE (polimerasa épsilon del DNA) (si se encuentra disponible) de forma diferida de acuerdo con la clasificación de riesgo basado en la pieza quirúrgica. Recomendación 3. Se recomienda que sea el ginecólogo oncólogo quien solicite el POLE (si se encuentra disponible) de acuerdo con el reporte de patología definitivo. Esta prueba se debe solicitar a todos los cánceres endometriales de estadio I-II, excepto los de bajo riesgo (estadio IA endometrioide de bajo grado sin invasión linfovascular p53 normal) y estadio III-IV sin enfermedad residual, sin afectar la solicitud de los marcadores moleculares subrogados por inmunohistoquímica de acuerdo con la histología. El consenso propone que la solicitud del POLE se realice posterior a la inmunohistoquímica y de acuerdo con la clasificación del riesgo según las categorías establecidas por la guía ESGO/ESTRO/ESP del 2020. Recomendación 4. Se recomienda realizar simultáneamente con los otros marcadores de inmunohistoquímica la prueba para receptores hormonales en todas las pacientes con cáncer endometrial y el HER2 en pacientes con p53abn. Recomendación 5. Se recomienda que los marcadores de inmunohistoquímica (p53, MLH1, MSH2, MSH6 y PMS2) se realicen en la biopsia/legrado endometrial inicial cuando la muestra es adecuada y está disponible. En caso de inmunohistoquímica inicial no concluyente, o discrepancias histológicas entre la patología inicial y definitiva, se recomienda repetir el perfil molecular en la patología quirúrgica. Los marcadores de inmunohistoquímica deben reportarse en el informe de patología de acuerdo con las recomendaciones del CAP (College of American Pathologists), independientemente del tipo de muestra. Recomendación 6. Se recomienda realizar estudio de metilación de promotor de MLH1 en pacientes con pérdida de expresión de MLH1 en la inmunohistoquímica, acompañado o no de pérdida de expresión de PMS2. Todas las pacientes con déficit de MMR (mismatch repair), deben ser enviadas a genética para descartar síndrome de Lynch. Recomendación 7. Se recomienda tener en cuenta la clasificación molecular, además de los criterios histopatológicos clásicos para la toma de decisiones de adyuvancia, tal como los incorpora la clasificación de los grupos pronósticos de la guía ESGO/ ESTRO/ESP del 2020. Conclusiones: es necesario implementar la clasificación molecular de cáncer de endometrio en la práctica clínica acorde al contexto colombiano, dado su valor pronóstico y posiblemente predictivo. Esto permitirá la caracterización de la población colombiana para ofrecer tratamientos guiados de manera individualizada. Se trata de un documento académico y no regulatorio.

Role of Bariatric Surgery in Patients With Endometrial Cancer: A Case Report and Review of Literature.

Objective: The standard surgery for endometrial cancer can be deferred in some situations, including morbid obesity, comorbidities, and the patient's desire for fertility. One of the options to improve patients' circumstances is bariatric surgery. Case report: This study presented two patients with stage IA, grade I endometrioid endometrial adenocarcinoma. Both patients had morbid obesity and had comorbidities. In case 1, because of fertility preservation, and in case 2, because of severe comorbidities, hormone therapy was started, followed by bariatric surgery after counseling patients. Both patients had acceptable changes in body mass index during follow-up, so cancer surgery through laparoscopy was done. Both patients did not need adjuvant therapy; months after cancer surgery, there is no recurrence, and their body mass index is also decreasing. Conclusion: Bariatric surgery can improve outcomes in patients with morbid obesity who suffer endometrial cancer.

Evaluating the quality of radiomics-based studies for endometrial cancer using RQS and METRICS tools.

OBJECTIVE: To assess the methodological quality of radiomics-based models in endometrial cancer using the radiomics quality score (RQS) and METhodological radiomICs score (METRICS). METHODS: We systematically reviewed studies published by October 30th, 2023. Inclusion criteria were original radiomics studies on endometrial cancer using CT, MRI, PET, or ultrasound. Articles underwent a quality assessment by novice and expert radiologists using RQS and METRICS. The inter-rater reliability for RQS and METRICS among radiologists with varying expertise was determined. Subgroup analyses were performed to assess whether scores varied according to study topic, imaging technique, publication year, and journal quartile. RESULTS: Sixty-eight studies were analysed, with a median RQS of 11 (IQR, 9-14) and METRICS score of 67.6% (IQR, 58.8-76.0); two different articles reached maximum RQS of 19 and METRICS of 90.7%, respectively. Most studies utilised MRI (82.3%) and machine learning methods (88.2%). Characterisation and recurrence risk stratification were the most explored outcomes, featured in 35.3% and 19.1% of articles, respectively. High inter-rater reliability was observed for both RQS (ICC: 0.897; 95% CI: 0.821, 0.946) and METRICS (ICC: 0.959; 95% CI: 0.928, 0.979). Methodological limitations such as lack of external validation suggest areas for improvement. At subgroup analyses, no statistically significant difference was noted. CONCLUSIONS: Whilst using RQS, the quality of endometrial cancer radiomics research was apparently unsatisfactory, METRICS depicts a good overall quality. Our study highlights the need for strict compliance with quality metrics. Adhering to these quality measures can increase the consistency of radiomics towards clinical application in the pre-operative management of endometrial cancer. CLINICAL RELEVANCE STATEMENT: Both the RQS and METRICS can function as instrumental tools for identifying different methodological deficiencies in endometrial cancer radiomics research. However, METRICS also reflected a focus on the practical applicability and clarity of documentation. KEY POINTS: The topic of radiomics currently lacks standardisation, limiting clinical implementation. METRICS scores were generally higher than the RQS, reflecting differences in the development process and methodological content. A positive trend in METRICS score may suggest growing attention to methodological aspects in radiomics research.

Lymph node dissection after neoadjuvant chemotherapy improves overall survival in clinical stage III endometrial cancer.

OBJECTIVE: To investigate whether performing a lymph node dissection during hysterectomy improves overall survival in patients with clinical stage III endometrial cancer who received neoadjuvant chemotherapy. METHODS: The National Cancer Database was queried to identify all patients with clinical stage III endometrial cancer who had undergone pre-operative chemotherapy as first course of treatment followed by hysterectomy with or without lymph node dissection between the years 2004 and 2020. Univariable and multivariable models were performed to investigate prognostic factors on overall survival. RESULTS: This study analyzed 2882 patients with clinical stage III endometrial cancer who received upfront chemotherapy. Among those who underwent lymph node dissection, 38% had positive lymph nodes. Factors found to be independently associated with improved survival included lymph node dissection (p<0.001), adjuvant radiation (p<0.001), histology (p<0.001), tumor grade (p<0.001), pathologic node status (p<0.001), age (p<0.001), type of insurance (p=0.027), and race (p<0.001). Patients who underwent lymph node dissection at time of hysterectomy had a significantly better overall survival (107 vs 85 months; p<0.001). Multivariate and propensity score analyses robustly demonstrated that lymph node dissection significantly improved overall survival (HR 0.69, 95% CI 0.57 to 0.84, p<0.001), even among patients with pathologically negative lymph nodes. CONCLUSION: Our study suggests that performing lymph node dissection at the time of hysterectomy is associated with improved overall survival in all patients with stage III endometrial cancer who receive upfront chemotherapy, regardless of age, race, insurance status, histologic subtype, tumor grade, pathologic node status, adjuvant radiation or chemotherapy. Notably, patients with high-risk disease may particularly benefit from this approach.

Predictive factors for adnexal involvement in endometrial cancer FIGO stage IIIA.

OBJECTIVE: Understanding ovarian involvement incidence and risk factors in women with endometrial cancer may inform the decision of ovary preservation. METHODS: Our retrospective study included all consecutive fully surgically staged patients with endometrial cancer who underwent primary surgery between January 2005 and November 2021, assessing the incidence of ovarian metastasis, its role as a prognostic factor for recurrence and death, and evaluated predictors of adnexal involvement. RESULTS: Women with International Federation of Gynecology and Obstetrics (FIGO) 2009 IIIA endometrial cancer comprised 2.3% of the population (36 of 1535 included patients), 23 (63.9%) with endometrioid histology, and a median age of 57.0 years (range 47.7-66.7). A higher body mass index, post-menopausal status, endometrioid histotype, and ß-catenin expression were associated with a lower risk of adnexal involvement. Conversely, dMMR phenotype, p53 expression, myometrial infiltration >50%, lymphovascular space invasion, and cervical stromal invasion were independent predictors of an increased risk of adnexal involvement. A total of 145 (9.5%) patients had adnexal involvement, with an incidence rate of 0.27/100 person-days. Overall survival for FIGO (2009) stage IIIA was 88.9%. CONCLUSIONS: Our study showed that ovarian preservation may be considered for younger patients with low-risk endometrial cancer (G1 and G2 tumors, absence of lymphovascular space invasion, no cervical involvement, and myometrial invasion <50%), adding a favorable predictive role to higher body mass index and high ß-catenin expression.

Immune checkpoint inhibitor combinations for patients with advanced endometrial cancer: a network meta-analysis and cost-utility analysis.

BACKGROUND: Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer. OBJECTIVE: To compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and patient decision-making. METHODS: The PubMed, Embase, Cochrane, and Web of Science Databases were reviewed from January 1, 2010 to October 30, 2023, for phase III randomized controlled trials of first-line immunotherapy combinations in patients with advanced endometrial cancer. Bayesian network meta-analysis was performed to obtain hazard ratios (HRs) of overall survival and progression-free survival, relative risks (RRs) of adverse events, and corresponding p value. The lifetime Markov model of cost-effectiveness analysis was developed to summarize the cost, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios at the US$150 000/QALY of willingness-to-pay of six first-line treatment strategies. RESULTS: Four trials were identified, involving 2577 patients. Dostarlimab plus chemotherapy or durvalumab plus chemotherapy with olaparib was associated with more survival benefits than other immunotherapy regimens and chemotherapy in the mismatch repair-deficient microsatellite instability-high (dMMR/MSI-H) and mismatch repair-proficient microsatellite-stable (pMMR/MSS) population, respectively. Further, pembrolizumab plus chemotherapy versus chemotherapy increased efficacy (cost) by 3.76 QALYs and US$540 817, which yielded incremental cost-effectiveness ratios of US$143 894/QALY in the dMMR/MSI-H population. CONCLUSION: First-line durvalumab plus chemotherapy with olaparib, and dostarlimab plus chemotherapy, were more beneficial for survival in the pMMR/MSS and dMMR/MSI-H populations, respectively. Only pembrolizumab plus chemotherapy versus chemotherapy was cost-effective for patients with dMMR/MSI-H endometrial cancer in the USA.

Influence of Aldehyde Dehydrogenase Inhibition on Stemness of Endometrial Cancer Stem Cells.

Endometrial cancer is one of the most common gynaecological malignancies. Although often diagnosed at an early stage, there is a subset of patients with recurrent and metastatic disease for whom current treatments are not effective. Cancer stem cells (CSCs) play a pivotal role in triggering tumorigenesis, disease progression, recurrence, and metastasis, as high aldehyde dehydrogenase (ALDH) activity is associated with invasiveness and chemotherapy resistance. Therefore, this study aimed to evaluate the effects of ALDH inhibition in endometrial CSCs. ECC-1 and RL95-2 cells were submitted to a sphere-forming protocol to obtain endometrial CSCs. ALDH inhibition was evaluated through ALDH activity and expression, sphere-forming capacity, self-renewal, projection area, and CD133, CD44, CD24, and P53 expression. A mass spectrometry-based proteomic study was performed to determine the proteomic profile of endometrial cancer cells upon N,N-diethylaminobenzaldehyde (DEAB). DEAB reduced ALDH activity and expression, along with a significant decrease in sphere-forming capacity and projection area, with increased CD133 expression. Additionally, DEAB modulated P53 expression. Endometrial cancer cells display a distinct proteomic profile upon DEAB, sharing 75 up-regulated and 30 down-regulated proteins. In conclusion, DEAB inhibits ALDH activity and expression, influencing endometrial CSC phenotype. Furthermore, ALDH18A1, SdhA, and UBAP2L should be explored as novel molecular targets for endometrial cancer.

Notable surgical trials in gynecologic oncology: a 10-year overview.

In the last decade, we have witnessed important advances in novel therapeutics in the management of gynecologic cancers. These studies have built on the findings from preexisting data and have provided incremental contributions leading to changes that have not only impacted the accuracy of cancer detection and its metastatic components but also led to improvements in oncologic outcomes and quality of life. Key landmark trials have changed the standard of care in cervix, uterine, and ovarian cancer. A number of these have been controversial and have generated significant debate among gynecologic oncologists. The main objective of this review was to provide an overview on each of these trials as a reference for immediate and consolidated access to the study aims, methodology, results, and conclusion.

Guideline No. 451: Asymptomatic Endometrial Thickening in Postmenopausal Women.

OBJECTIVE: To formulate strategies for clinical assessments for endometrial thickening on ultrasound in a postmenopausal woman without bleeding. TARGET POPULATION: Postmenopausal women of any age. OUTCOMES: To reduce unnecessary invasive interventions and investigations in women with asymptomatic endometrial thickening while selectively investigating women at risk for endometrial cancer. BENEFITS, HARMS, AND COSTS: It is anticipated that the adoption of these recommendations would save postmenopausal women unnecessary anxiety, pain, and risk of procedural complications. It is also expected to decrease the cost to the health care system by eliminating unnecessary interventions. EVIDENCE: English language articles from Medline, Cochrane, and PubMed databases for relevant peer-reviewed articles dating from 1995 to 2022 (e.g., asymptomatic endometrial thickness, endometrial cancer, postmenopausal bleeding, transvaginal ultrasound, endometrial biopsy, cervical stenosis, hormone therapies and the endometrium, tamoxifen, tibolone, aromatase inhibitors). Results were restricted to systematic reviews and meta-analyses, randomized controlled trials/controlled clinical trials, and observational studies. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Physicians, including gynaecologists, obstetricians, family physicians, radiologists, pathologists, and internists; nurse practitioners and nurses; medical trainees, including medical students, residents, and fellows; and other providers of health care of the postmenopausal population. SOCIAL MEDIA ABSTRACT: Postmenopausal women often have a thickening of the lining of the uterus found during ultrasound. Without bleeding, an endometrium <11 mm is rarely a serious problem but should be evaluated by a health care provider. SUMMARY STATEMENTS: RECOMMENDATIONS.

Optimizing patient selection for secondary cytoreductive surgery in recurrent endometrial cancer.

OBJECTIVE: This retrospective, multicenter, observational study aimed to refine patient selection criteria for secondary cytoreductive surgery in recurrent endometrial cancer. The objective was to identify preoperative predictors of complete cytoreduction, assess surgical complexity, and propose a preoperative predictive scoring system to identify suitable candidates for secondary cytoreductive surgery. METHODS: Data from 331 women with recurrent endometrial cancer were analyzed across three Italian centers from January 2010 to December 2021. Patients were categorized based on treatment received (medical treatment, diagnostic laparoscopy/examination under anesthesia, or secondary cytoreductive surgery). Preoperative predictors, surgical complexity, complications, and a predictive scoring system were assessed. Logistic regression and receiver operating characteristic analysis were used for statistical evaluation. RESULTS: Of the cohort, 56.2% underwent debulking surgery, 17.2% had diagnostic laparoscopy, and 26.6% received medical treatment. Patients undergoing secondary cytoreductive surgery were younger, with a lower body mass index, better performance status, and fewer comorbidities. Single site locoregional relapse was common in secondary cytoreductive surgery patients. Age <65 years, single site relapse, lymph node, and hematogenous relapse were independent predictors of complete cytoreduction. A predictive scoring system demonstrated a clear relationship between the score and the likelihood of complete cytoreduction. CONCLUSION: This study identified age <65 years, single site recurrence, as well as nodal and hematogenous recurrence, as predictive factors for achieving optimal cytoreduction. A predictive scoring system incorporating these factors has been proposed to identify optimal candidates for secondary cytoreductive surgery in recurrent endometrial cancer. The scoring system showed promising predictive accuracy and could aid in refining the decision making process, ensuring appropriate patient selection for secondary cytoreductive surgery. Further prospective studies are warranted to validate and enhance the predictive model.

Are micro-RNA 21 and 143 indicative as prognostic biomarkers in dedifferentiated endometrial adenocarcinoma?

AIM: Dedifferentiated endometrial adenocarcinoma (DEAC) is a rare, aggressive subtype, accounting for 2% of all endometrial cancers. Poor survival in DEAC prompts the need for effective treatment modalities through better prognostic classification. MicroRNAs (miRNA) have essential roles in tumor angiogenesis, which might enable their use as novel biomarkers. In this study, we aimed to reveal the relationship between the expression of miRNA-21 and miRNA-143, which are associated with angiogenesis, and the prognosis of DEAC. METHOD: The study included six cases diagnosed with DEAC. The expression levels of miRNA-21 and miRNA-143 were detected by quantitative real-time PCR. Microvascular density (MVD) was measured by CD34 staining. All data and effects on survival were compared for statistical significance. RESULTS: Six cases diagnosed with DEAC were included in the study. The percentage of undifferentiated components ranged from 50 to 90%. The second component of differentiated carcinoma was detected as endometrioid (3/5 grade I, 1/5 grade II, 1/5 grade III) in five cases and serous in one case. The mean MVD was 27 (range 17-44, SD 9.4). In three cases, miRNA-21 expression was down-regulated in neoplastic areas compared to non-neoplastic areas. On the contrary, it was found to be up-regulated in the remaining three cases. MiRNA-143 expression decreased in four cases and increased in two cases. CONCLUSIONS: Based on these findings, we found a significant irregular expression of miRNA-21 in DEACs. As in other cancers, angiogenesis is significantly associated with survival in DEACs. This study provides initial data for revealing possible implications of miRNAs as prognostic indicators in DEAC.

Prognostic impact of the number of resected pelvic nodes in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis.

OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

Recurrent postmenopausal bleeding: Pathological findings and predictive factors. A multicenter, prospective, observational study.

INTRODUCTION: Recurrent postmenopausal bleeding (PMB) occurs in 6%-25% of postmenopausal women who have experienced a previous episode of PMB. The question of whether recurrent PMB leads to a higher risk of endometrial cancer (EC) in comparison to a single episode of PMB is, however, controversial. Furthermore, little is known about predictive factors for recurrent PMB. MATERIAL AND METHODS: A multicenter prospective cohort study was conducted over a 5-year period in four hospitals in the Netherlands. Women with PMB undergoing endometrial sampling and aged 40 years and older were included. Occurrence of recurrent PMB was retrospectively determined. Primary outcomes included (1) the incidence of recurrent PMB and (2) differences in pathological findings between patients with a single episode vs recurrent PMB. Secondary outcomes included (1) the association between diagnosis of benign polyps at first PMB and pathological findings at recurrent PMB and (2) factors predictive for recurrent PMB. RESULTS: A total of 437 women with PMB were included, of whom 360 were at risk of recurrent PMB. With a median follow-up of 61 months (IQR (Interquartile range) 44-73), 26.4% experienced recurrent PMB. Patients with recurrent PMB were more often diagnosed with benign polyps (34.7% vs. 25.1%, p-value 0.015) and less frequently with a malignancy (5.3% vs. 17.8%, p-value 0.015), compared to patients with a single episode of PMB. Benign polyps at initial PMB were not associated with a (pre)malignancy at recurrence (OR 4.16, 95% CI 0.75-23.03). Predictive factors for recurrent PMB included use of hormone replacement therapy (HRT) (OR 3.32, 95% CI 1.64-6.72), and benign polyps at initial PMB (OR 1.80, 95% CI 1.07-3.04). CONCLUSIONS: Recurrent PMB is common in women with a previous episode of PMB. Compared to patients with a single episode of PMB, patients with recurrent PMB and benign histological outcomes at accurate workup during their first episode were less often diagnosed with malignancies and more frequently with benign polyps. Benign polyps at first PMB are predictive for recurrent PMB, but not for a higher risk of (pre)malignancy.