Classification Of Endometrial Carcinoma Research Articles

Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

Background: Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations between molecular classification of EC and DTCs. Methods: Patients treated for primary EC at Tuebingen University women's hospital between 2003 and 2016 were identified. A total of 402 patients with a complete set of BM cytology, molecular, and clinical data were evaluable. Results: DTC occurrence was distributed equally among all four molecular groups (p = 0.651). DTC positivity was associated with a less favorable disease-free survival (HR: 1.86, 95% CI: 1.03-3.36, p = 0.036) and progression-free survival (HR: 1.86, 95% CI: 1.01-3.44, p = 0.045). Presence of DTCs was associated with a higher frequency of distant disease recurrence (p = 0.017). Conclusions: In line with our previous findings, tumor cell dissemination is not associated with molecular features in our large cohort of primary EC patients. Since DTCs seem to be associated with survival and location of disease recurrence, further studies are needed to decisively define their role in EC survival.

Unsolved Issues in the Integrated Histo-Molecular Classification of Endometrial Carcinoma and Therapeutic Implications.

Endometrial carcinoma (EC) is the most frequent gynecological cancer, with an increasing incidence and mortality in recent times. The last decade has represented a true revolution with the development of the integrated histo-molecular classification of EC, which allows for the stratification of patients with morphologically indistinguishable disease into groups with different prognoses. Particularly, the POLE-mutated subgroup exhibits outstanding survival. Nevertheless, the indiscriminate application of molecular classification appears premature. Its prognostic significance has been proven mainly in endometrioid EC, the most common histotype, but it has yet to be convincingly confirmed in the other minor histotypes, which indeed account for a relevant proportion of EC mortality. Moreover, its daily use both requires a mindful pathologist who is able to correctly evaluate and unambiguously report immunohistochemical staining used as a surrogated diagnostic tool and is hampered by the unavailability of POLE mutation analysis. Further molecular characterization of ECs is needed to allow for the identification of better-tailored therapies in different settings, as well as the safe avoidance of surgery for fertility preservation. Hopefully, the numerous ongoing clinical trials in the adjuvant and metastatic settings of EC will likely produce evidence to refine the histo-molecular classification and therapeutic guidelines. Our review aims to retrace the origin and evolution of the molecular classification for EC, reveal its strengths and limitations, show clinical relevance, and uncover the desired future developments.

Integration of the Molecular Classification of Endometrial Carcinoma to Select Patients for Fertility Sparing Strategies.

Fertility-sparing treatment (FST) for endometrial carcinoma (EC) is an option for a subgroup of young women with low-risk disease. The low-risk group comprises patients with endometrioid EC stage IA, grade 1, with or without focal lymphovascular invasion. In the era of molecular subtyping, treatment de-escalation for some EC subtypes is recommended. Recommendations for fertility-preserving treatments were developed regardless of the molecular classification of EC. However, few studies have focused on this topic. In this review, we summarize the actual data available in the literature and discuss the impact of some molecular subtypes of FST.

Advantages of next-generation sequencing (NGS) in the molecular classifi cation of endometrial carcinomas - our experience with 270 cases.

Molecular classification of endometrial carcinomas (EC) divides these neoplasms into four distinct subgroups defined by a molecular background. Given its proven clinical significance, genetic examination is becoming an integral component of the diagnostic procedure. Recommended diagnostic algorithms comprise molecular genetic testing of the POLE gene, whereas the remaining parameters are examined solely by immunohistochemistry. The aim of this study is to share our experiences with the molecular classification of EC, which has been conducted using immunohistochemistry and next-generation sequencing (NGS) at our department. This study includes all cases of EC diagnosed at Šikl's Department of Pathology and Biopticka Laboratory Ltd. from 2020 to the present. All ECs were prospectively examined by immunohistochemistry (MMR, p53), fol lowed by NGS examination using a customized Gyncore panel (including genes POLE, POLD1, MSH2, MSH6, MLH1, PMS2, TP53, PTEN, ARID1A, PIK3CA, PIK3R1, CTNNB1, KRAS, NRAS, BRCA1, BRCA2, BCOR, ERBB2), based on which the ECs were classified into four molecularly distinct groups [POLE mutated EC (type 1), hypermutated (MMR deficient, type 2), EC with no specific molecular profile (type 3), and TP53 mutated ("copy number high", type 4)]. The cohort comprised a total of 270 molecularly classified ECs. Eighteen cases (6.6%) were classified as POLE mutated EC, 85 cases (31.5%) as hypermutated EC (MMR deficient), 137 cases (50.7%) as EC of no specific molecular profile, and 30 cases (11.1%) as TP53 mutated EC. Twelve cases (4.4%) were classified as "multiple classifier" endometrial carcinoma. ECs of no specific molecular profile showed multiple genetic alterations, with the most common mutations being PTEN (44% within the group of NSMP), fol lowed by PIK3CA (30%), ARID1A (21%), and KRAS (9%). In comparison with recommended diagnostic algorithms, NGS provides a more reliable classification of EC into particular molecular subgroups. Furthermore, NGS reveals the complex molecular genetic background in individual ECs, which is especially significant within ECs with no specific molecular profile. These data can serve as a springboard for the research of therapeutic programs committed to targeted therapy in this type of tumor.

Molecular classification of endometrial carcinoma-ashort summary for clinical use

Histopathological examination is still the backbone for the diagnosis and treatment decision making in endometrial carcinoma (EC). The binary classification of EC into type1 (mostly endometrioid) and type2 (mostly serous), although still helpful, showed overlapping clinical, morphological and molecular features and was not very prognostic discriminatory for all subtypes of EC. Analysing the most recent studies dealing with the molecular classification of EC and the recommendations of the German S3-guidelines for EC. Based on the comprehensive molecular study of The Cancer Genome Atlas Project (TCGA) four distinct molecular subtypes have been identified: EC with POLE mutation (POLEmut), with loss of mismatch repair proteins (MMR deficiency; dMMR), or with TP53 mutation (p53mut) and without any of these alterations, termed NSMP (no specific molecular profile). The molecular classification of EC presents amorphomolecular approach, based on histopathological evaluation (tumor diagnosis, subtyping, grading), immunohistochemistry (MMR, p53) and molecular analyses for POLE. The incorporation of this molecular classification is recommended for clinical use by the World Health Organisation (WHO) as well as many national guidelines and international societies. Due to the heterogeneity of NSMP-EC, which is the largest molecular group, additional research is indicated to further characterise these tumors.

The importance of molecular classification of endometrial carcinomas in clinical practice: how to apply it and difficulties in application

Classification of endometrial carcinomas (EC) based solely on histological features is not sufficient for the prognostic and therapeutic guidance of patients. Furthermore, the existence of EC in which the histological type cannot be determined clearly and the poor reproducibility of histological typing have led to difficulties in clinical management. However, molecular classification of EC is very promising because of the high reproducibility and good correlation with clinical outcome. Within the scope of “the Cancer Genome Atlas Project”, EC were divided into four different genomic subtypes, and molecular classification models for EC were developed based on these molecular subcategories. The prognostic differences between these molecular subgroups and the benefit for guidance for adjuvant therapy have been clearly demonstrated in studies. In this article, the importance of molecular classification for EC is discussed and its use in clinical practice is reviewed.

The value of T2 mapping for evaluating the pathological type, grade and depth of myometrial invasion in endometrial carcinoma

Objective: To investigate the value of T2 map and synthetic T2WI generated by T2 mapping in evaluating the histological type, pathological classification and depth of myometrial invasion of endometrial carcinoma (EC). Methods: Seventy-three patients with pathologically proven EC diagnosed at the First Affiliated Hospital of Zhengzhou University from December 2019 to December 2021 and 42 healthy volunteers were enrolled in the study. All subjects underwent conventional MRI, diffusion weighted imaging (DWI) and T2 mapping sequence for the pelvic cavity to test the T2 values and the apparent diffusion coefficient (ADC) of the focus nidus of the patients and the normal endometrium of the volunteers. The T2 and ADC values of EC vs normal endometrium, and those of different histological types and pathological grades were compared. The receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of T2 and ADC values in determining the pathological type and classification of EC. In addition, two radiologists used synthetic T2WI combined with T2 map and conventional T2WI combined with DWI, respectively, to evaluate the depth of myometrial invasion, and compared the imaging results with the results of pathological diagnosis to evaluate the diagnostic efficacy of the two methods in determining the depth of myometrial invasion. Results: The T2 and ADC values of endometrial carcinoma were 85.0 (80.8, 92.5) ms and 0.71 (0.64, 0.77) ×10(-3) mm(2)/s, respectively, which were significantly lower than those of normal endometrium [147.4 (123.4, 176.7) ms and 1.46 (1.26, 1.76)×10(-3) mm(2)/s, respectively; both P<0.05]. The T2 values of endometrioid carcinoma (EA) [84.1 (79.5, 88.7) ms] were significantly lower than those of non-EA [98.8 (92.1, 102.8) ms; P<0.05]. There was no significant difference in ADC values between EA and non-EA (P=0.075). The T2 values of G1, G2 and G3 groups in EA were 89.1 (84.4, 94.4) ms, 83.6 (80.9, 86.2) ms, and 76.5 (71.4, 80.3) ms, respectively. There were significant differences in the T2 values between G1 vs G2, G1 vs G3, and G2 vs G3 groups, respectively (all P<0.017). Significant difference was also found in the ADC values between the G1 and G3 groups (P<0.017). The area under the ROC curve (AUC) of T2 values in distinguishing EA from non-EA was 0.867. The AUC of T2 values, ADC values and their combination in predicting high-grade EA was 0.888, 0.730 and 0.895, respectively. The accuracy of synthetic T2WI+ T2 map and conventional T2WI+ DWI in the diagnosis of deep myometrial invasion was 78.1% and 79.5%, respectively, with no significant difference (P>0.05). Conclusions: T2 mapping has great potential in preoperative evaluation of EC. The quantitative T2 value can be used in the diagnosis, pathological classification and grading of EC. The combination of synthetic T2WI and T2 map may be helpful to determine the depth of myometrial invasion.

Fast and reliable Sanger POLE sequencing protocol in FFPE tissues of endometrial cancer.

The new classification of endometrial carcinoma (EC) requires molecular interpretation of somatic polymerase epsilon (POLE) exonuclease domain mutations. The identification of pathogenic mutations within the POLE gene defines the important subtype of ultramutated tumours ("POLE-ultramutated") with specified prognostic and predictive utility. POLE somatic mutations are present in 7-12% of ECs, usually high-grade tumours with aggressive appearance. Molecular analysis of the POLE gene can be performed using a qPCR test, the Sanger sequencing method, a next generation sequencing (NGS) panel test and also in situ hybridisation (IHC) assay. We describe our current approach of identification of POLE mutations using Sanger sequencing technology, which is still the most robust, accurate and fast technique to sequence DNA. We present a reliable protocol for Sanger sequencing of the entire sequence coding exonuclease domain of POLE - exons 9, 10, 11, 12, 13 and 14 (codons 268-491) with 5-10 nucleotides in exon/intron boundaries (reference sequences: NM_006231.4, NP_006222.2). The protocol has been optimized for formalin-fixed, paraffin-embedded (FFPE) EC tissues. The method developed in our laboratory allows better diagnosis of patients with EC according to current standards.

Classification of high-grade endometrium carcinomas using molecular and immunohistochemical methods.

As a result of the integration of molecular changes into the histological classification of cancers, which increases diagnostic repeatability, the differences between the groups become more prominent and targeted therapies gain significance. The most comprehensive molecular study regarding endometrial carcinomas (EC) is The Cancer Genome Atlas (TCGA) project. According to TCGA, endometrial carcinomas are classified into four molecular prognostic subgroups: copy-number-low/p53-wild-type (p53wt), DNA polymerase epsilon (POLE)-mutated/ultramutated (POLEmt), microsatellite-instability/hypermutated (MSI), and copy-number-high/p53-mutated (p53mt). In this study, we aim to apply the molecular classification to our high-grade endometrial cancer patients, and particularly, to identify our overtreated patients. Ninety-seven patients diagnosed with high-grade EC in Selcuk University, Faculty of Medicine between 2009-2018 were retrospectively evaluated and classified into four subgroups. Primary outcomes of overall and progression-free survival were evaluated for clinical, pathological, and molecular features. Further, all molecular groups were divided into endometroid and non-endometrioid groups, and disease-free survival (DFS) and overall survival (OS) were investigated across groups. According to molecular classification, 23 patients (23.7%) were assigned to the MSI group, 21 (21.6%) to the POLEmt group, 40 (41.2%) to the p53mt group, and 13 (13.4%) to the p53wt group. Patients' DFS (p = 0.001) and OS rates (p = 0.001) were significantly different according to their molecular classification. The results of our analyses determined that, in the molecular classification of high-grade ECs, the p53mt group had the poorest prognosis and the POLEmt group had the best prognosis. Tumor size, myometrial invasion, lymphovascular space invasion (LVSI), lymph node metastasis, cervical invasion, ovarian invasion and stage showed statistically significant differences based on molecular classification (p < 0.05). The use of molecular classification in the clinical practice will allow more accurate prognostic prediction and more appropriate treatment planning, particularly as high-grade ECs constitute a heterogenous group with poor prognosis.

576P Genome instability index used for the optimization of molecular classification of endometrial carcinoma

The molecular classification of endometrial carcinoma (EC) has divided patients into four distinct prognostic subtypes based on the genomic abnormalities. However, in clinical application, the genomic copy number index lacks a simple and accurate detection method, and the method of using p53 immunohistochemistry or TP53 mutation as a surrogate for copy number status needs to be optimized. Here, we explored the application of genome instability (GI) index in molecular classification of EC. We assessed a retrospective cohort of EC from Beijing Cancer Hospital between 2011 and 2020. Genomic profiling of tumor tissues from EC patients was sequenced by OncoScreen Plus Panel of 520 cancer-related genes, and tumor immune microenvironment was evaluated using multiplex immunofluorescence staining. GI index was calculated as the sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. 143 patients were enrolled in this study, with the median follow-up time of 38.77 months. Molecular analysis firstly identified four different prognostic subgroups: POLE mutations (mut), MSI-H, TP53 wildtype, and TP53 mut. We also divided patients into two groups based on GI index: GI-high and GI-low, and patients with GI-high were found in three subgroups except for POLE mut. Further analysis showed that GI status had a more important effect on prognosis than TP53 mutation. Therefore, we proposed a three-group molecular classification based on POLE mutation and GI index: POLE mut (n=9, 6.5%), GI-low (n=116, 82.9%), and GI-high (n=15, 10.7%). Patients with GI-high had much poorer survival than those with GI-low [disease-free survival: hazard ratio (HR), 17.87, 95% CI, 6.67-50.00, P < 0.001; overall survival: HR, 16.75, 95% CI, 4.76-50.00, P < 0.001]. The application in TCGA-UCEC cohort containing 481 EC patients confirmed that this new method worked well for risk stratification of EC. Further analysis showed that patients in GI-high group had higher tumor grade, aneuploidy and lower T cell infiltrations. The one-stop method of GI index combined with POLE mutation offers more accurate and stable disease risk stratification and demonstrates the potential for guiding therapy for EC patients.

Optimized molecular classification of endometrial carcinoma-based on the combination of POLE mutations with homologous recombination deficiency (HRD).

e17628 Background: Molecular analysis of endometrial carcinoma (EC) has identified four clinically significant molecular subgroups with different prognoses: POLE mutations, microsatellite instability-high (MSI-H/dMMR), copy number low (CN-L/p53-normal), and copy number high (CN-H/p53-aberrant). However, the convenience and repeatability of detection methods for molecular classification, as well as the evaluation of their prognostic significance, need to be further explored. Recently, homologous recombination deficiency (HRD) has been studied to show the prognostic value in EC. Here, we aimed to establish a next-generation sequencing (NGS)-based one-stop method with the combination of HRD and POLE mutations for molecular classification of EC. Methods: Paraffin-embedded tissues of 143 eligible EC patients were collected from Beijing Cancer Hospital between 2011 and 2020 and sequenced using a panel of 520 cancer-related genes which could also detect MSI status (OncoScreen Plus, Burning Rock Biotech). HRD score was calculated as the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores based on the sequencing data. Results: The median follow-up time in this cohort was 38.77 months. We firstly classified EC patients into four subgroups: POLE mutations (mut) (n = 9, 6.3%), MSI-H (n = 45, 31.5%), TP53 wildtype (wt) (n = 67, 46.9%), and TP53 mut (n = 22, 15.4%). POLE mut subgroup had the excellent prognosis as no patient in this subgroup relapsed after surgical resection. Compared with TP53 mut subgroup, the other two subgroups had better prognosis [disease free survival (DFS): TP53 wt: hazard ratio (HR), 0.2, 95% CI, 0.07-0.57, P = 0.003; MSI-H: HR, 0.2, 95% CI, 0.06-0.68, P = 0.01; overall survival (OS): TP53 wt: HR; 0.11, 95% CI, 0.02-0.56, P = 0.008; MSI-H: HR, 0.25, 95% CI, 0.06-1.03, P = 0.055]. Except for the patients with POLE mut, the others were then further optimized and divided into two groups based on HRD score with the cutoff of 13: HRD-high (n = 15, 11.5%) and HRD-low (n = 116, 88.5%). Patients in HRD-low subgroup showed much improved survival than those in HRD-high subgroup (DFS: HR, 0.06, 95% CI, 0.02-0.15, P &lt; 0.001; OS: HR, 0.06, 95% CI, 0.02-0.21, P &lt; 0.001). Most notably, the postoperative recurrence rate was 36.4% in the TP53 mut subgroup with the worst prognosis in the traditional classification, and 66.7% in the HRD-high subgroup with the worst prognosis in the optimized classification. Conclusions: The method of classifying EC patients into four subgroups by NGS large panel provides similar clinical features to previous reports classified by other methods but is more convenient and stable. Furthermore, the method of combination of POLE mutations with HRD offers more accurate disease risk stratification and demonstrates the potential for directing therapy for EC patients.

Molecular classification of endometrial carcinoma applied to endometrial atypical hyperplasia biopsy specimens.

e17622 Background: 50% of endometrial atypical hyperplasia (AH) cases on endometrial sampling have concurrent endometrial cancer (EC) on hysterectomy. Little data exists regarding molecular signatures that can predict the presence of concurrent endometrial cancer in patients with AH on biopsy. Therefore, we set to characterize molecular landscapes of endometrial samples diagnosed with AH with EC on the final hysterectomy specimen, using matched controls. Methods: Karmanos Cancer Institute pathology database was searched for patients with AH on endometrial curettage or biopsy who had a hysterectomy within 6 months. Only samples with adequate tissue for next generation sequencing were included. In total, 59 tissue samples from 34 patients were included: there were 15 AH endometrial biopsy samples, 18 AH final hysterectomy samples (13 matched pairs), 13 EC endometrial biopsies and 13 samples that were EC on final hysterectomy samples (12 matched pairs) that were analyzed using next-generation sequencing (WES) and/or whole transcriptome sequencing (WTS) (NovaSeq). TMB was measured by counting all somatic mutations found per tumor (TMB-high: &gt;10 mutations per MB). Immune cell infiltrates were calculated by Quantiseq. Significance was determined using Fisher exact, Chi-square and Mann-Whitney U test and adjusted for multiple comparisons: p &lt; 0.05 but q &gt; 0.05 was considered a trend. Results: Clinical analysis demonstrated 15/34 patients with endometrial AH on initial sampling and EC on the final hysterectomy. 2 out of 15 patients were &gt; stage II at time of surgery. Molecularly, fewer PTEN mutations were found between AH (2/8) and EC (14/17) on final hysterectomy (25% vs 82.4%, p = 0.01). Samples of EC origin were MSI-H by NGS-MSI (3/18) and had no mutations in PPP2R1A (0/16). Comparing hysterectomy samples, EC trended toward increased CTLA4 (FC: 6.97-fold) expression and immune cell infiltration of Macrophage M1 (+1.19%), NK cells (+2.13%), CD8+ T Cells (+1.27%), regulatory T cells (+2.17%) and Dendritic cells (+2.87%) compared to AH samples (all p &lt; 0.05). Similarly, when comparing endometrial biopsies, EC samples trended toward increased expression of CTLA4 (12.6-fold), HAVCR2/TIM3 (FC: 2.59-fold) and IFNG (FC: 17.8-fold) immune checkpoint genes, as well as increased immune cell infiltration of Neutrophils (+11.7%), CD8+ T cells (+2.39%) and regulatory T cells (+2.43%) compared to AH samples (all p &lt; 0.05). Conclusions: There are molecular and tumor microenvironment differences seen between AH endometrial biopsies that have concurrent EC compared to those that do not on the final hysterectomy specimens. These differences may lead to advances in identifying appropriate patients for fertility sparing treatments, versus those that can be managed surgically by a benign gynecologist or a gynecologic oncologist. Analyses with larger sample sizes are needed and are ongoing.

Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience

The comprehensive genomic analysis of endometrial carcinoma (EC) by The Cancer Genome Atlas (TCGA) led to the discovery of four distinct and prognostically significant molecular subgroups. Molecular classification has the potential to improve risk-stratification when integrated with clinicopathologic features and has recently been included in national and international patient management EC guidelines. Thus, the adoption of molecular classification into routine pathologic and clinical practice is likely to grow significantly in the upcoming years. Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Here we describe our effort to implement rapid and routine molecular classification on all ECs diagnosed at our institution. To this effect, we performed immunohistochemistry as a surrogate marker for identifying genetic and/or epigenetic alterations in DNA mismatch repair (e.g., MLH1, PMS2, MSH6, MSH2), and TP53 genes. In addition, we have developed and employed a single-gene POLE SNaPshot assay, which is a rapid and analytically sensitive method for detecting select POLE exonuclease domain mutations (EDMs). We report our molecular testing workflow and integrative reporting system as well as the clinicopathologic and molecular features of 310 ECs that underwent routine molecular classification at our institution. The 310 ECs were molecularly classified as follows: 15 (5%) POLE mutant (POLEmut), 79 (25%) mismatch repair-deficient (MMRd), 135 (44%) no specific molecular profile (NSMP), and 81 (26%) p53 abnormal (p53abnl). This work provides an initial framework for implementing routine molecular classification of ECs.

Clinicopathologic vs. Molecular Integrated Prognostication of Endometrial Carcinoma by European Guidelines.

Simple SummaryThe European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) published joint guidelines in January 2021 that provide recommendations on all relevant issues of diagnosis and treatment in endometrial carcinoma. Assessment of prognosis and adjuvant therapy decisions are based on classification of endometrial carcinomas into five risk groups with specific clinicopathologic features. Integration of molecular classification, originally described by The Cancer Genome Atlas, is encouraged for a more personalized risk assessment when molecular tools are available. We found that clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses. The p53 abnormal molecular subgroup and mismatch repair deficient molecular subgroup were associated with poor survival within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. Molecular classification caused a risk-group shift in 6–7% of patients. Comprehensive molecular classification was needed in 40% of patients for molecularly directed adjuvant therapy.This was a retrospective study of 604 patients with endometrial carcinoma, classified into ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and Leiden classifier were employed for molecular classification. Median follow-up time was 81 months. Clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses (p < 0.001). Disease-specific survival was similar for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, the p53 abnormal subgroup (hazard ratio 9.1, 95% confidence interval 2.0–41; p = 0.004) and mismatch repair deficient subgroup (hazard ratio 3.5, 95% confidence interval 1.2–10; p = 0.024) were associated with disease-related death within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. A risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (p = 0.341). Of the 36 patients shifted in the ProMisE cohort, 27 were upshifted and 9 downshifted. Based on the Leiden classifier, polymerase-ϵ sequencing could be omitted in 60% (311/515) of patients without affecting the risk-group assessment. ESGO-ESTRO-ESP 2021 guidelines provide a platform for risk classification in future trials on molecularly directed treatment of endometrial carcinoma.

Karcinom endometrijuma - angiogeneza i osvrt na uloge vaskularnog endotelnog faktora rasta

Endometrial carcinomas (EC) represent the most common malignant tumors of the female reproductive system and the sixth most common in the female population with an increased incidence of morbidity and mortality over the past three decades. In addition to stage, grade and type of tumor, these are the most significant prognostic factors of the biological behavior of EC and in current clinical practice are based on pathohistological examination. The shortcomings of the current histological classification are cited as one of the key limiting factors in further research, as well as in the understanding of EC carcinogenesis and improving therapeutic protocols. A new molecular classification of EC was formulated, based on the analysis of molecular biological features, recognized as highly related to the specific clinical course. Considerable efforts have been made to understand the process of angiogenesis as one of the key processes in tumor growth. The vascular endothelial growth factor (VEGF) family is a group of proangiogenic ligands that play a central role in the process of physiological and pathological angiogenesis. This factor is the most widely investigated angiogenic one as a potential biomarker and target for targeted therapy. After vast research, clinical studies have shown significant advances in the development of anti-angiogenic therapy directed at VEGF, predominantly in the form of combined therapy. In defining therapeutic groups, this therapy relies on the molecular classification of EC. Antiangiogenic therapy is limited to small specific groups of patients, associated with side effects, and numeorus patients who initially responded to targeted therapy develop resistance over time, which indicates the further need for a better understanding of the mechanisms and factors involved in the angiogenic process of EC. Potentially promising advances in the development of targeted therapeutic options for EC can be expected within the integration of molecular features of EC as a factor in the context of histological classification.

Activation of oxidative phosphorylation in TP53-inactive endometrial carcinomas with a poor prognosis

ObjectiveWe aimed to identify pathways for potential therapeutic targets by conducting molecular profiling of endometrial carcinomas in patients with poor prognosis.MethodsThe classification of endometrial carcinomas has undergone a paradigm shift...

Progress in the pathological arena of gynecological cancers.

This review covers the significant new developments in the pathological classification of gynecological tumors. Many of these were included in the updated World Health Organization Classification of Female Genital Tract Tumours, published in 2020. Topics include the compelling evidence that a large majority of extrauterine high‐grade serous carcinomas arise from the fallopian tube; the Cancer Genome Atlas (TCGA) Classification of endometrial carcinomas; the discovery that most so‐called synchronous endometrial and ovarian endometrioid carcinomas represent metastasis from the endometrium to the ovary; and the division of cervical, vaginal, and vulval carcinomas into clinically meaningful HPV‐associated and HPV‐independent types. Newly described tumor types are covered, including endometrial and ovarian mesonephric‐like adenocarcinoma, uterine sarcoma types associated with specific molecular abnormalities, and gastric (gastrointestinal)‐type adenocarcinomas of the endometrium and vagina. Important molecular events in ovarian sex cord–stromal tumors are also discussed.

Molecular testing in endometrial carcinoma - joint recommendation of Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists.

Molecular classification of endometrial carcinoma is becoming an important part of the dia-gnostic process with direct therapeutic implications. Recent international guidelines, including the joint recommendation of the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology and the European Society of Pathology include the molecular classification into standard dia-gnostic algorithms. Molecular testing of endometrial carcinomas is also recommended in the latest (5th edition) of the World Health Organization classification of female genital tumors. Due to the need to implement these recommendations in practice, representatives of four professional societies of the Czech Medical Association of J. E. Purkyn&#283; (the Czech Oncological Society, the Oncogynecological Section of the Czech Gynecological and Obstetrical Society, the Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists) organized a meeting focused on this topic. Recommendation for molecular testing of endometrial carcinoma in routine dia-gnostic practice in the Czech Republic.

Abstract IA002: Histopathological classification of endometrial cancers and surrogate markers of genomic subtypes

Abstract Endometrial carcinoma has been subclassified based on tumor cell-type morphology i.e. the resemblance of the tumor cells to their normal counterparts based on microscopic examination. The main histotypes of endometrial carcinoma, endometrioid and serous carcinoma, correspond roughly to Type I and Type II endometrial carcinoma, as described by Bokhman in 1983. Although these histotypes are associated with different patient outcomes and are associated with different mutations, with endometrioid carcinomas having a more favorable prognosis than serous carcinomas, there are a significant number of endometrial carcinomas that are difficult to classify based on histopathological examination. This results in there being only moderate inter-observer reproducibility in the histopathological classification of endometrial carcinoma and this, in turn, compromises the ability to use histotype as a basis for treatment decisions. The Cancer Genome Atlas identified 4 molecular subtypes of endometrial carcinoma based on genomic architecture: ultramutated, hypermutated, low numbers of somatic copy number abnormalities, and high numbers of somatic copy number abnormalities. These correlate with patient outcome and, increasingly, have been show to be correlated with response to treatment. In this presentation the current subclassification of endometrial carcinoma, the development of surrogate markers of genomic molecular subtype and the correlation between molecular subtype and histotype will be discussed,Endometrial carcinoma has been subclassified based on tumor cell-type morphology i.e. the resemblance of the tumor cells to their normal counterparts based on microscopic examination. The main histotypes of endometrial carcinoma, endometrioid and serous carcinoma, correspond roughly to Type I and Type II endometrial carcinoma, as described by Bokhman in 1983. Although these histotypes are associated with different patient outcomes and are associated with different mutations, with endometrioid carcinomas having a more favorable prognosis than serous carcinomas, there are a significant number of endometrial carcinomas that are difficult to classify based on histopathological examination. This results in there being only moderate inter-observer reproducibility in the histopathological classification of endometrial carcinoma and this, in turn, compromises the ability to use histotype as a basis for treatment decisions. The Cancer Genome Atlas identified 4 molecular subtypes of endometrial carcinoma based on genomic architecture: ultramutated, hypermutated, low numbers of somatic copy number abnormalities, and high numbers of somatic copy number abnormalities. These correlate with patient outcome and, increasingly, have been show to be correlated with response to treatment. In this presentation the current subclassification of endometrial carcinoma, the development of surrogate markers of genomic molecular subtype and the correlation between molecular subtype and histotype will be discussed. Citation Format: C. Blake Gilks. Histopathological classification of endometrial cancers and surrogate markers of genomic subtypes [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA002.

POLE, MMR, and MSI Testing in Endometrial Cancer: Proceedings of the ISGyP Companion Society Session at the USCAP 2020 Annual Meeting.

Subclassification of endometrial carcinoma (EC) based on morphologic features alone has been shown to have suboptimal reproducibility, both in regard to biopsy versus hysterectomy findings, as well as interobserver agreement. This restricts the role of morphologic classification of EC as a tool for risk prediction and therefore treatment planning. A diagnostic algorithm based on The Cancer Genome Atlas (TCGA) classification of EC holds promise for improving accuracy in risk prediction. This classifies EC into 4 groups: those harbouring mutations in the exonuclease domain of DNA polymerase epsilon, POLE (POLEmut), those showing a mismatch repair defect, those showing mutations in TP53 (p53abn) and a heterogenous group showing none of these 3 abnormalities (currently termed no specific molecular profile). These groups can be accurately and reproducibly diagnosed on biopsy samples using a limited panel of tests, namely immunohistochemistry for mismatch repair proteins and p53, and testing for POLE exonuclease domain pathogenic variants. In this article we briefly review the biology, testing and interpretation of POLE and mismatch repair defects in EC.