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International Journal of Gynecological... Jan 2021A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large...
A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.
Topics: Endometrial Neoplasms; Europe; Female; Genital Neoplasms, Female; Humans; Medical Oncology; Preoperative Care; Risk Factors
PubMed: 33397713
DOI: 10.1136/ijgc-2020-002230 -
International Journal of Molecular... Oct 2022The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific... (Review)
Review
The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.
Topics: Biomarkers, Tumor; Carcinoma, Endometrioid; Endometrial Neoplasms; Female; Humans; Mutation; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Tumor Suppressor Protein p53
PubMed: 36232987
DOI: 10.3390/ijms231911684 -
Histopathology Jan 2020Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with... (Review)
Review
Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high-grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair-deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non-specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this 'histomolecular' approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios.
Topics: Biomarkers, Tumor; Carcinoma, Endometrioid; Endometrial Neoplasms; Female; Humans; Mutation; Prognosis; Tumor Suppressor Protein p53
PubMed: 31846532
DOI: 10.1111/his.14015 -
Virchows Archiv : An International... Feb 2021A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large...
A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
Topics: Biomarkers, Tumor; Biopsy; Carcinoma; Endometrial Neoplasms; Evidence-Based Medicine; Female; Humans; Medical Oncology; Molecular Diagnostic Techniques; Neoplasm Staging; Predictive Value of Tests; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 33604759
DOI: 10.1007/s00428-020-03007-z -
Nature Communications Oct 2022Endometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect...
Endometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect oncogenic origin and pathological progression in patients. Here we use single-cell RNA sequencing to profile cells from normal endometrium, atypical endometrial hyperplasia, and endometrioid endometrial cancer (EEC), which altogether represent the step-by-step development of endometrial cancer. We find that EEC originates from endometrial epithelial cells but not stromal cells, and unciliated glandular epithelium is the source of EEC. We also identify LCN2 + /SAA1/2 + cells as a featured subpopulation of endometrial tumorigenesis. Finally, the stromal niche and immune environment changes during EEC progression are described. This study elucidates the evolution of cell populations in EEC development at single-cell resolution, which would provide a direction to facilitate EEC research and diagnosis.
Topics: Female; Humans; Transcriptome; Ecosystem; Carcinoma, Endometrioid; Endometrial Hyperplasia; Endometrial Neoplasms
PubMed: 36273006
DOI: 10.1038/s41467-022-33982-7 -
Acta Bio-medica : Atenei Parmensis Dec 2019Endometrial Cancer (EC) is the commonest gynecological cancer and its incidence is increasing. The diagnosis of endometrial carcinoma in young women of childbearing age... (Review)
Review
Endometrial Cancer (EC) is the commonest gynecological cancer and its incidence is increasing. The diagnosis of endometrial carcinoma in young women of childbearing age is rare. Indeed, only 4% of patients with endometrial carcinoma are <40 years of age. It's typically diagnosed in postmenopausal women. The standard approach for the management of endometrial cancer in young women of childbearing age is hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy but is not ideal for women interested in future fertility. We reviewed the published literature to clarify in fertile women who have not yet fulfilled their desire for motherhood, what are the strategies, the risks of a conservative treatment of early stage of Endometrial Cancer and what are the obstetric outcomes in this patients. Recently, several studies have reported encouraging results on fertility-sparing management of EC with high dose of progestins in selected women associated or not with hysteroscopic resection.
Topics: Aftercare; Conservative Treatment; Endometrial Neoplasms; Female; Humans; Neoplasm Staging
PubMed: 31910163
DOI: 10.23750/abm.v90i4.7800 -
The New England Journal of Medicine Jun 2019Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.
METHODS
In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.
RESULTS
Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.
CONCLUSIONS
Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Disease-Free Survival; Endometrial Neoplasms; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm, Residual; Prognosis; Quality of Life; Recurrence; Statistics, Nonparametric; Treatment Outcome
PubMed: 31189035
DOI: 10.1056/NEJMoa1813181 -
Current Oncology (Toronto, Ont.) Jan 2022Endometrial carcinoma (EC) is traditionally treated with surgery and adjuvant treatment depending on clinicopathological risk factors. The genomic analysis of EC in 2013... (Review)
Review
Endometrial carcinoma (EC) is traditionally treated with surgery and adjuvant treatment depending on clinicopathological risk factors. The genomic analysis of EC in 2013 and subsequent studies using immunohistochemistry have led to the current EC molecular classification into: polymerase epsilon mutated (POLEmut), p53 abnormal (p53abn), mismatch repair deficient (MMRd), and no specific molecular profile (NSMP). The four groups have prognostic value and represent a promising tool for clinical decision-making regarding adjuvant treatment. Molecular classification was integrated into the recent European Society of Gynecologic Oncology (ESGO) management guidelines. POLEmut EC has favorable outcomes and retrospective studies found that omitting adjuvant treatment is safe in this group; two prospective clinical trials, PORTEC-4 and TAPER, are ongoing to assess this. p53 abn is associated with increased recurrence, decreased survival, and benefitted from chemotherapy in the PORTEC-3 subgroup molecular analysis. The clinical trials PORTEC-4a and CANSTAMP will prospectively assess this. MMRd and NSMP groups have intermediate prognosis and will likely continue to rely closely on clinicopathological features for adjuvant treatment decisions. In addition, the molecular classification has led to exploring novel treatments such as checkpoint inhibitors. Overall, the molecular perspective on EC and associated clinical trials will likely refine EC risk stratification to optimize care and avoid overtreatment.
Topics: Biomarkers, Tumor; Endometrial Neoplasms; Female; Genomics; Humans; Mutation; Prospective Studies; Retrospective Studies
PubMed: 35200562
DOI: 10.3390/curroncol29020063 -
International Journal of Gynecological... Jan 2019In this review, we sought to address 2 important issues in the diagnosis of endometrial carcinoma: how to grade endometrial endometrioid carcinomas and how to... (Review)
Review
Endometrial Carcinoma Diagnosis: Use of FIGO Grading and Genomic Subcategories in Clinical Practice: Recommendations of the International Society of Gynecological Pathologists.
In this review, we sought to address 2 important issues in the diagnosis of endometrial carcinoma: how to grade endometrial endometrioid carcinomas and how to incorporate the 4 genomic subcategories of endometrial carcinoma, as identified through The Cancer Genome Atlas, into clinical practice. The current International Federation of Gynecology and Obstetrics grading scheme provides prognostic information that can be used to guide the extent of surgery and use of adjuvant chemotherapy or radiation therapy. We recommend moving toward a binary scheme to grade endometrial endometrioid carcinomas by considering International Federation of Gynecology and Obstetrics defined grades 1 and 2 tumors as "low grade" and grade 3 tumors as "high grade." The current evidence base does not support the use of a 3-tiered grading system, although this is considered standard by International Federation of Gynecology and Obstetrics, the American College of Obstetricians and Gynecologists, and the College of American Pathologists. As for the 4 genomic subtypes of endometrial carcinoma (copy number low/p53 wild-type, copy number high/p53 abnormal, polymerase E mutant, and mismatch repair deficient), which only recently have been identified, there is accumulating evidence showing these categories can be reproducibly diagnosed and accurately assessed based on biopsy/curettage specimens as well as hysterectomy specimens. Furthermore, this subclassification system can be adapted for current clinical practice and is of prognostic significance independent of conventional variables used for risk assessment in patients with endometrial carcinoma (eg, stage). It is too soon to recommend the routine use of genomic classification in this setting; however, with further evidence, this system may become the basis for the subclassification of all endometrial carcinomas, supplanting (partially or completely) histotype, and grade. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.
Topics: Carcinoma, Endometrioid; Endometrial Neoplasms; Female; Genomics; Gynecology; Humans; Neoplasm Grading; Neoplasm Staging; Pathologists; Practice Guidelines as Topic; Prognosis; Societies, Medical
PubMed: 30550484
DOI: 10.1097/PGP.0000000000000518 -
British Journal of Cancer Jul 2015Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for...
BACKGROUND
Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.
METHODS
Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.
RESULTS
Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.
CONCLUSIONS
Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.
Topics: Aged; DNA Polymerase II; Endometrial Neoplasms; Female; Genes, p53; Humans; Middle Aged; Mutation; PTEN Phosphohydrolase; Poly-ADP-Ribose Binding Proteins; Retrospective Studies
PubMed: 26172027
DOI: 10.1038/bjc.2015.190