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Introduction: Endometrial carcinoma (EC) is the commonest gynecological cancer affecting women in Western populations. To predict patient risk, the 2020 edition of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract stressed the importance of integrated histo-molecular classification of the disease. This survey analysis poses attention on the most frequently used immunohistochemical and molecular markers adopted in daily categorization of ECs in European laboratories., Methods: We analyzed data collected through questionnaires administered to 40 Italian, 20 Spanish, 3 Swiss and 6 United Kingdom (UK) laboratories. We collected information regarding daily practice in EC evaluation, specifically concerning mismatch repair status (MMR) and microsatellite instability (MSI). Summary and descriptive statistical analyses were carried out to evaluate the current practice of each laboratory., Results: The results show that MMR status is mainly evaluated by using immunohistochemistry (IHC) on most EC samples. The most frequent approach for the analysis of MMR status is IHC of four proteins (PMS2, MSH6, MSH2, MLH1). MSI analysis by molecular methods is uncommon but useful as a supplemental tool in specific conditions. MLH1 promoter hypermethylation and BRAF V600 mutations analysis are performed in case of negative expression of MLH1/PMS2. Other markers (mainly p53 followed by POLE and PTEN) are investigated in particular in Spain and Switzerland in a consistent number of cases., Conclusion: Guidelines consultation and standardization of laboratory procedures are efficient means for EC prognostic risk stratification and improving the quality of care., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: The incidence of endometrial cancer is increasing worldwide. While delays in diagnosis reduce survival, case molecular misclassification might be associated with under- and over-treatment. The objective of this study was to evaluate genetic alterations to detect and molecularly classify cases of endometrial cancer using non-invasive samples., Methods: Consecutive patients with incident endometrial cancer (N = 139) and controls (N = 107) from a recent Spanish case-control study were included in this analysis. Overall, 339 cervicovaginal samples (out of which 228 were clinician-collected and 111 were self-collected) were analysed using a test based on next-generation sequencing (NGS), which targets 47 genes. Immunohistochemical markers were evaluated in 133 tumour samples. A total of 159 samples were used to train the detection algorithm and 180 samples were used for validation., Findings: Overall, 73% (N = 94 out of 129 clinician-collected samples, and N = 66 out of 90 self-collected samples) of endometrial cancer cases had detectable mutations in clinician-collected and self-collected samples, while the specificity was 80% (79/99) for clinician-collected samples and 90% (19/21) for self-collected samples. The molecular classifications obtained using tumour samples and non-invasive gynaecologic samples in our study showed moderate-to-good agreement. The molecular classification of cases of endometrial cancer into four groups using NGS of both clinician-collected and self-collected cervicovaginal samples yielded significant differences in disease-free survival. The cases with mutations in POLE had an excellent prognosis, whereas the cases with TP53 mutations had the poorest clinical outcome, which is consistent with the data on tumour samples., Interpretation: This study classified endometrial cancer cases into four molecular groups based on the analysis of cervicovaginal samples that showed significant differences in disease-free survival. The molecular classification of endometrial cancer in non-invasive samples may improve patient care and survival by indicating the early need for aggressive surgery, as well as reducing referrals to highly specialized hospitals in cancers with good prognosis. Validation in independent sets will confirm the potential for molecular classification in non-invasive samples., Funding: This study was funded by a competitive grant from Instituto de Salud Carlos III through the projects PI19/01835, PI23/00790, and FI20/00031, CIBERESP CB06/02/0073 and CIBERONC CB16/12/00231, CB16/12/00234 (Co-funded by European Regional Development Fund. ERDF: A way to build Europe). Samples and data were provided by Biobank HUB-ICO-IDIBELL, integrated into the Spanish Biobank Network, and funded by the Instituto de Salud Carlos III (PT20/00171) and by Xarxa de Bancs de Tumors de Catalunya (XBTC) sponsored by Pla Director d'Oncologia de Catalunya. This work was supported in part by the AECC, Grupos estables (GCTRA18014MATI). It also counts with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Generalitat de Catalunya, and grants to support the activities of research groups 2021SGR01354 and 2021SGR1112., Competing Interests: Declaration of interests L.C. received supplies from Integrated DNA Technologies (IDT) and Roche Diagnostics at a 50% discount for the pilot study of this project and received a speaker's honoraria from Roche. Idibell and Roche signed a contract to collaborate in the development of the bioinformatics pipeline. L.C. has received Colli-Pee® devices (Novosanis) for a research project free of charge. X.B. and L.A. received funds from Merck & Co, Elsevier, Hologic, GlaxoSmithKline (GSK) and SP received funds to attend a meeting from Seegene. P.P.T received funds from Merck & Co and Werfen. JHcispoly and IDIBELL signed a service agreement for another project on endometrial cancer., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC., Methods: Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome., Results: A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the 'high and advanced/metastatic' risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO 'high and advanced/metastatic' were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression., Conclusion: The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification., Competing Interests: Declaration of Competing Interest The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: NCon: advisory boards for Seattle Genetics, AstraZeneca and Mersana, education fees from Medscape Oncology, and grants for travelling from Roche, Genmab and Amgen. IV: advisory boards for Amgen, AstraZeneca, Clovis Oncology, Carrick Therapeutics, Debiopharm International, F Hoffmann-La Roche, Genmab, GSK, Immunogen, Millenium Pharmaceuticals, MSD Belgium, Octimet Oncology, Oncoinvent, Pharmamar-Doctaforum Servicios, Roche, Sotio, Tesaro, Deciphera Pharmaceuticals and Verastem Oncology (fees for consulting to his university), contracted research (KU Leuven) for Oncoinvent AS and Genmab, corporate sponsored research for Amgen and Roche, and grants for travelling from Amgen, MSD/Merck, Roche, AstraZeneca and Tesaro. DC: advisory boards for AstraZeneca, Roche, Sotio and Novocure. MRM: personal financial interests for AstraZeneca, Biocard, Clovis Oncology, Geneos, Genmab, Karyopharm Therapeutics, Merck, Mersana, MSD, Oncology Venture, Pfizer, Roche, SeatleGenetics, SeraPrognostics, Sotio, Tesaro-GSK, ZaiLab; leadership role for Karyopharm Therapeutics, Sera Prognostics; institutional financial interests (study grants) for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Tesaro-GSK, Ultimovacs. JL: advisory boards for AstraZeneca, Pfizer, GSK, Eisai, MSD/Merck, Artios Pharma, Regeneron, Amgen and Clovis Oncology, and grants for travelling from Clovis Oncology. CC: advisory boards for MSD, Takeda and GSK, conducting research for TherAguiX and Roche, and grants for travelling from Takeda. AF: advisory boards for GSK and Johnson & Johnson SpA, and grants for travelling from Pharmmar and MSD Italia. CF: advisory boards for AstraZeneca, Clovis, Ethicon, Roche, MSD, GSK and Tesaro, and grants for travelling from Sequana. AGM: speakers’ bureau activities for AstraZeneca, Pharmamar, Roche and GSK, advisory boards for Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, Pharmamar, Roche and Sotio, and grants for travelling from AstraZeneca, Pharmamar Roche and Tesaro. DL: advisory boards for Roche, Amgen, MSD, GSK, Clovis, AstraZeneca, Immunogen, Genmab, Pharmamar and Merck, and grants for travelling from Pharmamar, GSK, Roche and AstraZeneca. CM: consulting/advisory boards for Roche, Novartis, Amgen, MSD, AstraZeneca, Pfizer, Pharmamar, Cerulean, Vertex and Tesaro, funded research from EU, FWF, AstraZeneca and Roche, and honoraria/expenses from Roche, Novartis, Amgen, MSD, Pharmamar, AstraZeneca and Tesaro. JS: advisory boards for Roche, Eisei, MSD, AstraZeneca, Clovis, GSK and Tesaro. AT: advisory boards for Genmab; PW: advisory boards for Amgen, AstraZeneca, MSD, Novartis, Pfizer, Pharmamar, Lilly, Roche Pharma GmbH, TEVA, Eisai, Clovis and Tesaro, and grants for travelling from Roche Pharma GmbH, AstraZeneca, MSD, Amgen and Pfizer. NC: consulting and advisory services, speaking or writing engagements, public presentations for Roche, AstraZeneca, MSD, Pharmamar, Tesaro, GSK, Clovis, Advaxis, Pfizer, Takeda, Immunogen, Biocad, Amgen, Novartis and Ellipses, institutional financial interests for Roche, Pharmamar and AstraZeneca, and non-financial interests for ESMO clinical Guidelines (subject editor for gynecological cancer). XMG, SM, TB, SL, PM, RN, DOD, DQ, MRR, AS, AW, FP, and CLC: no conflicts of interest., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2021 International Gynecologic Cancer Society and European Society of Gynecological Oncology [Published by BMJ]; Springer Verlag GmbH Berlin Heidelberg, part of Springer Nature. Published by Elsevier B.V. All rights reserved.)

Molecular pathology is an essential part of pathology complementing conventional morphological tools to obtain a correct integrated diagnosis with appropriate assessment of prognosis and prediction of response to therapy, particularly in cancer. There is a concern about the situation of molecular pathology in some areas of Europe, namely, regarding the central role of pathologists in assessing somatic genomic alterations in cancer. In some countries, there are attempts that other laboratory medicine specialists perform the molecular analysis of somatic alterations in cancer, particularly now when next generation sequencing (NGS) is incorporated into clinical practice. In this scenario, pathologists may play just the role of "tissue providers," and other specialists may take the lead in molecular analysis. Geneticists and laboratory medicine specialists have all background and skills to perform genetic analysis of germline alterations in hereditary disorders, including familial forms of cancers. However, interpretation of somatic alterations of cancer belongs to the specific scientific domain of pathology. Pathologists are necessary to guarantee the quality of the results, for several reasons: (1) The identified molecular alterations should be interpreted in the appropriate morphologic context, since most of them are context-specific; (2) pre-analytical issues must be taken into consideration; (3) it is crucial to check the proportion of tumor cells in the sample subjected to analysis and presence of inflammatory infiltrate and necrosis should be monitored; and 4) the role of pathologists is crucial to select the most appropriate methods and to control the turnaround time in which the molecular results are delivered in the context of an integrated diagnosis. Obviously, there is the possibility of having core facilities for NGS in a hospital to perform the sequence analysis that are open to other specialties (microbiologists, geneticists), but also in this scenario, pathologists should have the lead in assessing somatic alterations of cancer. In this article, we emphasize the importance of interpreting somatic molecular alterations of the tumors in the context of morphology. In this Position Paper of the European Society of Pathology, we strongly support a central role of pathology departments in the process of analysis and interpretation of somatic molecular alterations in cancer.

Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.

Background: Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in ∼20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA., Methods: Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations., Results: In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes., Conclusions: OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.