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Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific—(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC.

Item does not contain fulltext External beam radiotherapy (EBRT) is an important cornerstone in the treatment of localized prostate cancer. Current image-guided radiotherapy (IGRT) techniques allow for more accurate and precise delivery of radiation treatment by the use of imaging before each fraction. Magnetic resonance guided radiotherapy (MRgRT) is the next step in IGRT with hybrid systems combining linear accelerators with MRI-scanners. With MRgRT, it is possible to visualize pelvic anatomy in great detail and subsequently perform replanning of the radiation dose distribution before each radiotherapy fraction. This technique has the potential to increase the therapeutic window of EBRT, by improved normal tissue sparing due to margin reduction and more accurate target dose delivery. This is particularly promising for prostate cancer, with its biology lending itself to ultra-hypofractionation, reducing radiotherapy treatment to as little as five fractions. Also, recent studies have shown that focal dose escalation to the intraprostatic tumor to high ablative doses can substantially increase disease-free survival. In this article, we discuss these unique opportunities as well as the potential future benefits of MRgRT in prostate cancer treatment.

External beam radiotherapy (EBRT) is an important cornerstone in the treatment of localized prostate cancer. Current image-guided radiotherapy (IGRT) techniques allow for more accurate and precise delivery of radiation treatment by the use of imaging before each fraction. Magnetic resonance guided radiotherapy (MRgRT) is the next step in IGRT with hybrid systems combining linear accelerators with MRI-scanners. With MRgRT, it is possible to visualize pelvic anatomy in great detail and subsequently perform replanning of the radiation dose distribution before each radiotherapy fraction. This technique has the potential to increase the therapeutic window of EBRT, by improved normal tissue sparing due to margin reduction and more accurate target dose delivery. This is particularly promising for prostate cancer, with its biology lending itself to ultra-hypofractionation, reducing radiotherapy treatment to as little as five fractions. Also, recent studies have shown that focal dose escalation to the intraprostatic tumor to high ablative doses can substantially increase disease-free survival. In this article, we discuss these unique opportunities as well as the potential future benefits of MRgRT in prostate cancer treatment.

Purpose Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. Methods ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model’s overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). Results A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761–0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595–0.800) as Brier score has been calculated 0.09. Conclusions We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC.

Contains fulltext : 251438.pdf (Publisher’s version ) (Open Access) For high-risk endometrial cancer (EC) patients, adjuvant chemotherapy is recommended to improve outcome. Yet, predictive biomarkers for response to platinum-based chemotherapy (Pt-aCT) are currently lacking. We tested expression of L1 cell-adhesion molecule (L1CAM), a well-recognised marker of poor prognosis in EC, in tumour samples from high-risk EC patients, to explore its role as a predictive marker of Pt-aCT response. L1CAM expression was determined using RT-qPCR and immunohistochemistry in a cohort of high-risk EC patients treated with Pt-aCT and validated in a multicentric independent cohort. The association between L1CAM and clinicopathologic features and L1CAM additive value in predicting platinum response were determined. The effect of L1CAM gene silencing on response to carboplatin was functionally tested on primary L1CAM-expressing cells. Increased L1CAM expression at both genetic and protein level correlated with high-grade, non-endometrioid histology and poor response to platinum treatment. A predictive model adding L1CAM to prognostic clinical variables significantly improved platinum response prediction (C-index 78.1%, P = .012). In multivariate survival analysis, L1CAM expression was significantly associated with poor outcome (HR: 2.03, P = .019), potentially through an indirect effect, mediated by its influence on response to chemotherapy. In vitro, inhibition of L1CAM significantly increased cell sensitivity to carboplatin, supporting a mechanistic link between L1CAM expression and response to platinum in EC cells. In conclusion, we have demonstrated the role of L1CAM in the prediction of response to Pt-aCT in two independent cohorts of high-risk EC patients. L1CAM is a promising candidate biomarker to optimise decision making in high-risk patients who are eligible for Pt-aCT.

ObjectiveOvarian cancer is known for its poor prognosis, which is mainly due to the lack of early symptoms and adequate screening options. In this study we evaluated whether mutational analysis in cervicovaginal and endometrial samples could assist in the detection of ovarian cancer.MethodsIn this prospective multicenter study, we included patients surgically treated for either (suspicion of) ovarian cancer or for a benign gynecological condition (control group). A cervicovaginal self-sample, a Papanicolaou (Pap) smear, a pipelle endometrial biopsy, and the surgical specimen were analyzed for (potentially) pathogenic variants in eight genes (ARID1A,CTNNB1,KRAS,MTOR,PIK3CA,POLE,PTEN, andTP53) using single-molecule molecular inversion probes. Sensitivity and specificity were calculated to assess diagnostic accuracy.ResultsBased on surgical histology, our dataset comprised 29 patients with ovarian cancer and 32 controls. In 83% of the patients with ovarian cancer, somatic (potentially) pathogenic variants could be detected in the final surgical specimen, of which 71% included at least aTP53variant. In 52% of the ovarian cancer patients, such variants could be detected in either the self-sample, Pap smear, or pipelle. The Pap smear yielded the highest diagnostic accuracy with 26% sensitivity (95% CI 10% to 48%). Overall diagnostic accuracy was low and was not improved when includingTP53variants only.ConclusionsMutational analysis in cervicovaginal and endometrial samples has limited accuracy in the detection of ovarian cancer. Future research with cytologic samples analyzed on methylation status or the vaginal microbiome may be relevant.

Introduction/Background* Patients with high-grade endometrial carcinoma (EC) have an increased risk of lymph node metastasis (LNM). Preoperative serum CA125 and imaging findings have been incorporated in multiple risk stratification models to predict LNM and advanced disease in EC and are widely used in clinical practice. However, data on their predictive value in high-grade EC are limited. We therefore aim to determine the predictive value of CA125 combined with preoperative computed tomography (CT) imaging in high-grade EC for LNM. Methodology Retrospective multicentre cohort study including patients (n=334) with preoperative high-grade EC and available CA125. Clinical data including imaging results, primary surgical treatment and final International Federation of Gynaecology and Obstetrics (FIGO) stage were recorded. CA125 was considered elevated at >35 IU/L. Result(s)* Patients with high-grade EC (n=334) and elevated CA125 more often presented with advanced FIGO stage (III-IV), 64.2% (95/148) versus 18.8% (35/186) in patients with normal CA125 (p Multivariate analysis (table 2) showed that elevated CA125, histological deep (>50%) myometrial invasion, and cervical involvement independently predict histological LNM (p Conclusion* This study demonstrates that elevated CA125 in patients with high-grade EC is an important prognostic marker for the predication of LNM and advanced stage disease. In patients with preoperative normal CA125, the additional value of CT imaging was limited with respect to the prediction of LNM. We therefore recommend to incorporate CA125 in routine preoperative work-up for risk stratification in high-grade EC.

Contains fulltext : 218296.pdf (Publisher’s version ) (Closed access) Endometrial carcinoma (EC) is traditionally diagnosed by a histopathological assessment of an endometrial biopsy, leaving up to 30% of patients undiagnosed due to technical failure or an inadequate amount of tissue. The aim of the current study is to assess whether mutational analysis of cervical cytology or pipelle endometrial biopsies improves the diagnostic accuracy of traditional histopathological diagnosis of EC. This prospective multicentre cohort study included patients surgically treated for EC or a benign gynaecological condition (control group). A Pap brush sample, cervicovaginal self-sample, pipelle endometrial biopsy and surgical specimen of either the EC or normal endometrium were obtained. A targeted next-generation sequencing panel was used to analyse these samples for mutations in eight genes. Sensitivity, specificity and predictive values were calculated. Fifty-nine EC patients and 31 control patients were included. In these patients, traditional histopathological diagnosis by pipelle had a sensitivity of 79% and a specificity of 100%. For EC patients, 97% of surgical specimens contained at least one mutation. Mutational analysis of Pap brush samples, self-samples and pipelle endometrial biopsies yielded a sensitivity of 78, 67 and 96% with a specificity of 97, 97 and 94%, respectively. Combining one of these three methods with histopathological pipelle endometrial biopsy evaluations yielded a sensitivity of 96, 93 and 96%, respectively. Our study has shown that mutational analysis of either cervical cytology or pipelle endometrial biopsies improves diagnosis of EC. Prospective validation will support implementation in clinical practice. 8 p.

Summary Preoperative histopathological classification determines the primary surgical approach in endometrial carcinoma (EC) patients but has only moderate agreement between preoperative and postoperative diagnosis. The aim of the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study is to determine whether histopathological assessment and a small panel of diagnostic biomarkers decreases discrepancies between preoperative and postoperative diagnosis in EC. Preoperative endometrial tissue of 378 included patients with EC was stained with 15 different antibodies. Clinically relevant discrepancies in grade or histological subtype between original preoperative and reviewed postoperative diagnosis were observed in 75 (20%) patients. Highest clinically relevant discrepancy was found in grade 2 ECs (20%), compared to 5% and 14% in respectively grade 1 and 3 endometrioid endometrial carcinomas (EECs). A practical two-biomarker panel with PR and p53 improved diagnostic accuracy (AUC = 0.92; 95%CI = 0.88–0.95) compared to solely morphological evaluation (AUC = 0.86). In preoperative high-grade EC, the diagnostic accuracy of histological subtype was improved by a three–immunohistochemical biomarker panel (PR, IMP3, and L1CAM) (AUC = 0.93; 95%CI = 0.88–0.98) compared to solely morphological evaluation (AUC = 0.81). In conclusion to improve correct preoperative diagnosis in EC, we recommend use of a panel of at least two easily accessible immunohistochemical biomarkers (PR and p53), only in grade 2 ECs. Overall, this will reduce clinically relevant discrepancies in tumor grade and subtype with postoperative diagnosis with 6% (from 20% to 14%). Addition of PR, IMP3, and L1CAM for histological subtyping in high-grade EECs resulted in a further decrease in discrepancies with 8% (from 20% to 12%).

Objectives Investigate the importance of a set of easy accessible biomarkers besides lymphnode(LN) status within the ESMO risk stratification for optimizing adjuvant treatment in endometrial cancer. Methods Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), a retrospective multicenter cohort study was performed with a median follow-up of 5.5-years. Immunohistochemical analysis of tumor protein 53(p53), estrogen receptor(ER), progesterone receptor(PR) and L1 cell-adhesion molecule(L1CAM) expression were analyzed on pre-operative specimens. Biomarker expression was related to LN status, defined as positive(N1), negative(N0) or unknown(Nx). Correlations and Cox regression analysis were performed. Results A total of 763 EC patients were included. Lymphadenectomy was performed in 493(64.6%) patients of whom 53(6.9%) had N1. Adjuvant treatment was applied in 347(46.5%) patients. Abnormal p53(p53-abn) expression was observed in 14.7%, L1CAM expression in 10.4%, loss of ER in 10.0%, and loss of PR in 18.1%. Significant reduced disease specific survival(DSS) and/or recurrence free survival(RFS) was observed within patients with N1 and 53-abn, L1CAM positive expression, or loss of ER/PR. N1 and normal biomarkers show the same prognosis as patients with N0 or Nx, and abnormal biomarkers. In the multivariate Cox regression analysis loss of ER/PR and p53-abn were in addition to the ESMO classification ‘high-intermediate and high’ significantly associated with decreased DSS (HR 2.47[CI 1.20–5.07]p=0.013, HR 2.13[CI 1.02–4.41]p=0.043, HR 3.93[CI 1.98–7.81]p Conclusions We have shown that abnormal biomarker expression in addition to N1 or N0, is highly relevant in survival analysis and could potentially complement the ESMO risk stratification and therefore optimize adjuvant treatment.

Contains fulltext : 232535.pdf (Publisher’s version ) (Closed access) There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1-2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.

Background Bayesian networks (BNs) are machine-learning–based computational models that visualize causal relationships and provide insight into the processes underlying disease progression, closely resembling clinical decision-making. Preoperative identification of patients at risk for lymph node metastasis (LNM) is challenging in endometrial cancer, and although several biomarkers are related to LNM, none of them are incorporated in clinical practice. The aim of this study was to develop and externally validate a preoperative BN to predict LNM and outcome in endometrial cancer patients. Methods and findings Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), we performed a retrospective multicenter cohort study including 763 patients, median age 65 years (interquartile range [IQR] 58–71), surgically treated for endometrial cancer between February 1995 and August 2013 at one of the 10 participating European hospitals. A BN was developed using score-based machine learning in addition to expert knowledge. Our main outcome measures were LNM and 5-year disease-specific survival (DSS). Preoperative clinical, histopathological, and molecular biomarkers were included in the network. External validation was performed using 2 prospective study cohorts: the Molecular Markers in Treatment in Endometrial Cancer (MoMaTEC) study cohort, including 446 Norwegian patients, median age 64 years (IQR 59–74), treated between May 2001 and 2010; and the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study cohort, including 384 Dutch patients, median age 66 years (IQR 60–73), treated between September 2011 and December 2013. A BN called ENDORISK (preoperative risk stratification in endometrial cancer) was developed including the following predictors: preoperative tumor grade; immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), p53, and L1 cell adhesion molecule (L1CAM); cancer antigen 125 serum level; thrombocyte count; imaging results on lymphadenopathy; and cervical cytology. In the MoMaTEC cohort, the area under the curve (AUC) was 0.82 (95% confidence interval [CI] 0.76–0.88) for LNM and 0.82 (95% CI 0.77–0.87) for 5-year DSS. In the PIPENDO cohort, the AUC for 5-year DSS was 0.84 (95% CI 0.78–0.90). The network was well-calibrated. In the MoMaTEC cohort, 249 patients (55.8%) were classified with, Casper Reijnen and co-workers report on risk prediction in endometrial cancer., Author summary Why was this study done? Bayesian networks are graphical networks that are based on machine learning and can be used for prediction purposes without the need to have values for all predictor variables available for each patient. Approximately 10% of patients with endometrial cancer have lymph node metastasis. The risk of lymph node metastasis and poor outcome differs substantially between individuals. Preoperative identification of patients at risk for lymph node metastasis and poor outcome allows tailoring of individualized treatment. What did the researched do and find? A Bayesian network to predict the risk of lymph node metastasis and survival was constructed with data from a retrospective multicenter development cohort from 10 centers across Europe (n = 763). The predictive capability of the final network was tested in 2 external cohorts from the Netherlands (PIpelle Prospective ENDOmetrial carcinoma [PIPENDO], n = 384) and from Norway (Molecular Markers in Treatment in Endometrial Cancer [MoMaTEC], n = 446). What do these findings mean? The Bayesian network we propose allows refined risk stratification before surgery and is easily usable. Because of its graphical character, the interactions between the different variables included into the network are directly visualized. A prospective feasibility study will be needed prior to implementation in the clinic.

Summary Endometrioid endometrial carcinomas (EECs) are correlated with high serum levels of androgens and estrogen. We hypothesized that Leydig cells and ovarian stromal hyperplasia contribute to postmenopausal ovarian androgen production and are observed more frequently in EEC patients. Ovaries of postmenopausal women with EEC (n = 36) or non-endometrioid endometrial carcinoma (NEEC; n = 19) were examined for the presence of hilar Leydig cells and compared with ovaries resected for benign conditions (n = 22). Leydig cells were counted manually, and a Leydig cell density was calculated per millimeter squared hilar surface. Ovarian stromal hyperplasia was scored as atrophic, moderate hyperplastic, or marked hyperplastic. In all endometrial carcinomas, these findings were correlated with the serum levels of sex steroids and hormone receptor expression in their endometrial carcinomas. In EEC patients, mean number of Leydig cells was 282.8 cells compared with 76.3 cells in NEEC patients and 66.4 cells in controls. Leydig cells, marked stromal hyperplasia, and combined presence were observed more frequently in EEC patients compared with NEEC and controls. Combined presence was associated with higher serum sex steroid levels and increased tumor expression of estrogen and progesterone receptor. A cutoff value for Leydig cell hyperplasia could be proposed at a total of 300 Leydig cells bilaterally, examining a representative cross section of both hili. Concluding, we have quantified hilar Leydig cells and demonstrated that Leydig cells may contribute to the development of EEC by increased androgen production in postmenopausal women. The correlation between sex hormone levels and Leydig cell hyperplasia may support endometrial pathology screening in these women.

Contains fulltext : 219885.pdf (Publisher’s version ) (Closed access)

Objective Uterine serous carcinoma (USC) is presumed to arise from endometrial intra-epithelial carcinoma (EIC), whereas tubo-ovarian high-grade serous carcinomas have similar precursor lesions in the Fallopian tube, i.e. serous tubal intra-epithelial carcinoma (STIC). The presence of Fallopian tube abnormalities and their clonal relationship to the concurrent USC was investigated. Methods In this multicenter study, all patients treated for USC between 1992 and 2017 were retrospectively identified. Histopathological diagnosis of USC, EIC and STIC was revised by an expert pathologist. Additionally, all Fallopian tube sections were immunohistochemically stained (p53 and Ki-67). Fallopian tube abnormalities were classified as either p53 signature, serous tubal intra-epithelial lesion (STIL) or STIC. The USCs and Fallopian tube abnormalities were analyzed by targeted next-generation sequencing. Results In 168 included patients, Fallopian tube abnormalities were found in 27.4% (46/168): p53-signatures in 17.9% (30/168), STILs in 3.0% (5/168) and STICs in 6.5% (11/168). In subgroup analysis, STICs were found in 9.5% (11/115) of patients with at least one section of the fimbriated end embedded. Next-generation sequencing showed identical TP53-mutations in the STIC and corresponding USC. Conclusions In conclusion, the presence of Fallopian tube abnormalities was shown in a high percentage of patients with USC, representing either true precursor lesions or metastasized disease.

Synchronous primary endometrial and ovarian cancers (SEOs) represent 10% of all endometrial and ovarian cancers and are assumed to develop as independent entities. We investigated the clonal relationship between endometrial and ovarian carcinomas in a large cohort classified as SEOs or metastatic disease (MD). The molecular profiles were compared to The Cancer Genome Atlas (TCGA) data to explore primary origin. Subsequently, the molecular profiles were correlated with clinical outcome. To this extent, a retrospective multicenter study was performed comparing patients with SEOs (n = 50), endometrial cancer with synchronous ovarian metastasis (n = 19) and ovarian cancer with synchronous endometrial metastasis (n = 20). Targeted next‐generation sequencing was used, and a clonality index was calculated. Subsequently, cases were classified as POLE mutated, mismatch repair deficient (MMR‐D), TP53‐wild‐type or TP53‐mutated. In 92% of SEOs (46/50), the endometrial and concurrent ovarian carcinoma shared at least one somatic mutation, with a clonality index above 0.95, supporting a clonal origin. The SEO molecular profiles showed striking similarities with the TCGA endometrial carcinoma set. SEOs behaved distinctly different from metastatic disease, with a superior outcome compared to endometrial MD cases (p, What's new? When primary endometrial and ovarian tumors are found simultaneously in the same patient, it has been assumed that they are separate cancers that developed independently. However, in this study, the authors found that these tumors share a clonal origin 92% of the time. They also found that these “synchronous” cancers tend to have a favorable prognosis, with far better outcomes than metastatic disease. Some subgroups, including TP53 mutations and extra‐utero‐ovarian disease, were independent predictors for poor clinical outcome, which may impact adjuvant treatment planning.

Contains fulltext : 220457.pdf (Publisher’s version ) (Open Access) The incidence of endometrial cancer, the most common gynecological malignancy, is increasing as life expectancy and obesity both rise. Lymph node status is the most important predictor for outcome, yet routine lymphadenectomy does not confer a survival benefit and is associated with substantial surgical morbidity. In the last decade, sentinel lymph node (SLN) mapping has emerged as a feasible and accurate alternative to full lymphadenectomy. Yet, SLN has introduced a distinction between micro- and macrometastasis, and the entity of non-SLN involvement with their attendant impact on outcome. Included among the raised issues is the question of whether positive sentinel nodes should be followed by pelvic and/or para-aortic lymphadenectomy dependent on the presence of macrometastasis at frozen section or other criteria. Moreover, the proper adjuvant treatment for individual cases with micrometastasis and/or isolated tumor cells is unclear. Recently published data on this topic are summarized in order to optimize the current treatment algorithm as it relates to the results of SLN assessment in endometrial cancer.

Contains fulltext : 220441.pdf (Publisher’s version ) (Open Access) BACKGROUND: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage III endometrial cancer (EC) have a substantial risk of adverse outcomes. After surgery, adjuvant therapy is recommended with external beam radiotherapy (EBRT), chemotherapy (CT) or both EBRT and CT. Recent trials suggest that EBRT + CT is superior to EBRT or CT alone but also results in more toxicity. We have compared the outcome of different adjuvant treatments in a population-based cohort to identify subgroups that benefit most from EBRT + CT. METHODS: All patients diagnosed with FIGO stage III EC and treated with surgery in 2005-2016 were identified from the Netherlands Cancer Registry. The primary outcome was overall survival (OS); associations with adjuvant treatment were analysed using Cox regression analysis. RESULTS: Among 1241 eligible patients, EBRT + CT was associated with a better OS than CT (hazard ratio [HR] = 1.84, 95% confidence interval [CI] = 1.34-2.52) and EBRT alone (HR = 1.37, 95% CI = 1.05-1.79). In stage IIIC, there was a significant benefit of EBRT + CT compared with CT or EBRT alone. In stage IIIA-B, there was no difference between EBRT + CT or EBRT alone. In endometrioid EC (EEC) and carcinosarcomas, EBRT + CT was associated with a better OS than CT or EBRT alone. For uterine serous cancers, there was no survival benefit of EBRT + CT over CT. In all analysis by stage and histology, any adjuvant treatment was superior to no adjuvant therapy. CONCLUSIONS: In this population-based study, adjuvant EBRT + CT was associated with improved OS compared with CT or EBRT alone in FIGO stage IIIC EC, EEC and carcinosarcoma. This suggests that application of EBRT + CT in stage III should be further stratified according to these subgroups.

Introduction/Background Endometrial carcinoma (EC) is traditionally diagnosed by histopathological assessment of an endometrial biopsy, leaving up to 30% of patients undiagnosed due to technical failure of the biopsy procedure or an inadequate amount of tissue. The aim of the current study is to assess whether mutational analyses of cervical cytology including self-samples or pipelle endometrial biopsies can improve the diagnostic accuracy of traditional histopathological diagnosis of EC. Methodology A prospective multicentre cohort study was performed in three hospitals in the Netherlands. Patients surgically treated for EC or a benign gynecological condition (control group) were included. A Pap brush sample, a cervicovaginal self-sample, a pipelle endometrial biopsy and the surgical specimen of the endometrial carcinoma (endometrial carcinoma group) or normal endometrium (control group) were obtained. A targeted next-generation sequencing panel was used to analyze these samples for mutations in eight genes. Diagnostic accuracy was determined by calculating sensitivity, specificity and predictive values. Results Fifty-nine EC patients and 31 control patients were included. In these patients traditional histopathological diagnosis by pipelle had a sensitivity of 78.9% and a specificity of 100%. For EC patients, 96.6% of surgical specimens contained at least 1 mutation. Mutational analysis of Pap brush samples, self-samples, and pipelle endometrial biopsies yielded a sensitivity of 78.0%, 67.3% and 96.5% with a specificity of 96.8%, 96.8% and 93.5%, respectively. Combining these three methods individually with histopathological pipelle endometrial biopsy evaluations yielded a sensitivity of 95.8%, 93.0% and 96.5, respectively. Conclusion This study has shown that mutational analysis of either cervical cytology, self-samples or pipelle endometrial biopsies improves diagnosis of EC, and is feasible for detection of endometrial pathology. Prospective validation will support implementation in routine clinical practice. Disclosure M.L.: advisory board AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen pharmaceuticals, Roche; sponsored research by Astra Zeneca, Bristol-Myers Squibb, llumina; royalties by Nimagen. Furthermore, no completing interests were declared.

Introduction/Background Preoperative risk stratification in endometrial cancer (EC) is mainly based on the histological diagnosis of endometrial biopsies. Yet, easily accessible clinical biomarkers sampled prior to surgery, might contribute to improved risk stratification. Previous studies demonstrated the prognostic value of haematological parameters. Cancer antigen 125 (CA-125) has been widely accepted as tumour marker in EC, yet so far not studied in relation to pre-operative haematological parameters. Our aim is to investigate the prognostic value of preoperative haematological parameters in relation with CA-125. Methodology Data collection was performed out of available samples of the prospective multicentre PIPENDO cohort. A total of 285 patients (66%) had complete available serum analysis of at least one. Anaemia ( 390 × 109platelets/L), leucocytosis (>10 × 109/L) were related to CA-125 (>35 kU/L), patients, histopathological characteristics and outcome. Results Preoperative anaemia was present in 9.8% (n=28), leucocytosis in 10.9% (n=31) and thrombocytosis in 7.4% (n=21). Anaemia, thrombocytosis and leucocytosis were associated with BMI, comorbidity of diabetes and hypertension. Age was only associated with anaemia. Histopathological characteristics showed no association between anaemia, thrombocytosis and leucocytosis. In multivariate Cox regression analysis anaemia and increased CA-125 were associated as risk factor for recurrence with hazard ratio (HR) of 2.50 (95% CI, 1.20–5.24 p=0.016) and 2.02 (95% CI 1.10–3.71 p=0.024). Only increased CA-125 was associated as risk factor for overall survival with HR of 2.12 (95% CI 1.21–3.72 p=0.008). Conclusion Preoperative anaemia and increased CA-125 are associated with a two times increased risk of recurrence in women with EC. Disclosure Nothing to disclose.

Introduction/Background The diagnostic accuracy of endometrial biopsy has been related to the amount of tissue. In endometrial cancer (EC) there is only moderate agreement on tumor grade between preoperative endometrial sampling and final diagnosis with the lowest agreement for grade 2 carcinoma. Since the amount of preoperative endometrial tumor tissue has not yet been related to the degree of discordance, we aim to determine this relation with regard to final tumor type and grade. Methodology Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), 582 preoperative endometrial biopsy samples of EC patients were retrospectively collected and classified into low-grade (grade 1–2) and high-grade carcinoma (grade 3). The endometrial tissue surface was digitally calculated using ImageJ software and the correlation between the amount of tissue and concordance of diagnosis was calculated. Results Agreement on tumor grade between preoperative endometrial sampling and final diagnosis was 62.5%. Up- or downgrading was found in respectively 27.1% and 10.3%. Clinically relevant up- or downgrading was found in respectively 7.8% and 27% of the cases. Premalignant endometrial tissue contained less endometrium compared to malignant endometrium (4.4 vs. 19.3 mm2,p=0.03). Serous EC contained less endometrial tissue compared with grade 1–3 endometrioid EC (13.0 vs. 19.1 mm2,p=0.017). The median endometrial tissue surfaces of grade 1-3 did not significantly differ from each other (18.7 vs. 19.8 vs. 24.1 mm2). Samples with a discordant diagnosis consisted of significantly more endometrial tissue compared to the concordant group (p=0.018). Conclusion Based on postoperative diagnosis, there is no difference in the amount of endometrial tissue between the different endometrial grades. However, there is a tendency to underestimate a sample with less and overestimate a sample with more endometrial tissue. Awareness is especially needed, in serous EC with in general less tissue. Disclosure Nothing to disclose.

Introduction/Background Endometrial cancer (EC) is the most common gynecological cancer in the Western world. For those with advanced stage EC outcome is significantly worse despite adjuvant treatment. Different adjuvant treatment strategies for these patients have been compared in the GOG-258 and PORTEC-3 studies. Since EC patients are mainly elderly women with substantial comorbidity, these patients are often underrepresented in clinical trials. The aim of this study is to evaluate outcome in stage III EC patients, according different applied treatment strategies in a population based study. Methodology All patients treated for FIGO stage III EC in the period 2005–2015 were extracted from the Netherlands Cancer Registry (NCR). Patients without surgery, and those with residual tumor after surgery were excluded from analyses. The 5-year overall survival was compared for different adjuvant treatment strategies: observation, vaginal brachytherapy (VBT), external beam radiation (EBRT), chemotherapy (CT), and chemoradiation (CRT). Results A total of 997 EC patients were eligible for analysis. The mean age at diagnosis was 67, and most patients (68%) were diagnosed with endometrioid histology. Adjuvant treatment was applied in 83%, and consisted of EBRT/VBT (53%), CT (12%), and CRT (15%). Patients >70 years more often received no adjuvant treatment, 23% compared to 13% ( Conclusion This population based study demonstrates the benefit of chemoradiation in FIGO III EC, with a significant better 5-year overall survival compared to external beam radiation. Disclosure Nothing to disclose.

Introduction/Background Mismatch repair (MMR) deficiency is found in 20 to 40% of endometrial cancers (ECs) and was recently identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas. There is accumulating evidence that MMR proteins are involved in the DNA repair processes following radiotherapy. We investigated the predictive value of MMR status for response to adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). Methodology A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between adjuvant treatment and outcome. Results A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p=0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n=55], vaginal brachytherapy [n=27]). In multivariable analysis, adjuvant radiotherapy was associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05–0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37–2.31). Conclusion Adjuvant radiotherapy improved survival in patients with MMR-deficient EECs. MMR status could be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy. Disclosure Nothing to disclose.

Objectives Endometrial carcinoma (EC) is traditionally diagnosed by histopathological assessment of endometrial biopsies, leaving up to 22% of patients undiagnosed. This study explores the feasibility of the clinical implementation of detecting EC using mutational analysis of cervical cytology. Methods This prospective multicentre study included patients that underwent a hysterectomy for histopathologically proven EC or a benign gynecological condition (control group). A Pap brush sample, cervicovaginal self sample, pipelle and hysterectomy specimen were obtained from each patient. A targeted next-generation sequencing panel was used to screen these samples for mutations in eight genes. Diagnostic accuracy was calculated, including sensitivity, specificity and predictive values. Results Fifty-nine EC patients and 31 control patients were included. In these patients traditional histopathological diagnosis had a sensitivity of 78.9% and a specificity of 100%. For EC patients, 96.6% of surgical specimens contained at least 1 mutation. Blinded mutational analysis of Pap brush samples, self-samples, and pipelle endometrial biopsies yielded a sensitivity of 78.0%, 67.3% and 96.5% with a specificity of 96.8%, 96.8% and 93.5%, respectively. Combining these three methods with histopathological pipelle endometrial biopsies evaluations yielded a sensitivity of 95.8%, 93.0% and 96.5 respectively. Conclusions This study has shown the potential of mutational analysis of cervical cytology and pipelle endometrial biopsies to improve diagnosis of EC, whether or not in additional to traditional histopathological assessment. Prospective evaluation is required for validation and clinical implementation.

BACKGROUND: Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. METHODS: Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan-Meier curves and Cox regression analysis. RESULTS: Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). CONCLUSIONS: This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients. ispartof: BRITISH JOURNAL OF CANCER vol:120 issue:11 pages:1037-1044 ispartof: location:England status: published

Item does not contain fulltext BACKGROUND: Mismatch repair (MMR) deficiency is found in 20 to 40% of endometrial cancers (ECs) and was recently identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas. There is accumulating evidence that MMR proteins are involved in the DNA repair processes following radiotherapy. We investigated the predictive value of MMR status for response to adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). METHODS: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between adjuvant treatment and outcome. RESULTS: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p=0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n=55], vaginal brachytherapy [n=27]). In multivariable analysis, adjuvant radiotherapy was associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05-0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37-2.31). CONCLUSION: Adjuvant radiotherapy improved survival in patients with MMR-deficient EECs. MMR status could be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy.

Introduction/Background The presence of pelvic and/or para-aortic lymph node metastasis (LNM) is one of the most important prognostic factors for poor outcome in endometrial carcinoma (EC). Current risk stratification for lymphadenectomy is mainly based on preoperative tumor grade, results in over- and undertreated of approximately 25% and 15% of the patients. Use of preoperative prediction models allow a personalized risk estimation and contribute to shared decision making, balancing risks and clinical benefit in tailored treatment. The aim of this study is to develop a Bayesian network (BN), based on easily-accessible clinical, histopathological and molecular biomarkers, for the prediction of lymph node metastasis and outcome in endometrial carcinoma patients. Second, the calibration and discrimination this network will be tested by means of external validation. Methodology This network was constructed within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), using a cohort including 809 patients treated for EC. The network was based both on expert knowledge of EC progression and learned from data of the construction cohort. Variables used to construct to BN included: preoperative tumor grade; immunohistochemical profile including estrogen receptor-, progesterone receptor-, p53- and L1CAM-expression; cancer antigen 125 serum levels, thrombocyte count, imaging results and cervical cytology. Internal cross-validation and external validation was performed using two independent validation cohorts comprising 431 and 400 patients. Results A Bayesian network was constructed to predict the presence of lymph node metastasis and 1-, 3- and 5-year disease-specific survival (figure 1). Internal cross-validation showed good discrimination (area under the receiver operator characteristic curve 0.86) and was calibrated well with respect to the prediction of lymph node metastasis. External validation will be completed soon. Conclusion We have developed and externally validated a Bayesian network predicting lymph node metastasis in endometrial carcinoma using preoperative markers with high diagnostic accuracy. Disclosure Nothing to disclose.

Objectives: The global obesity epidemic has great impact on the prevalence of low-grade endometrial carcinoma. The preoperative tumor serum marker cancer antigen 125 (CA-125) might contribute to improved identification of high-risk patients within this group. The study aimed to investigate the prognostic value of CA-125 in relation to established preoperative prognosticators, with a focus on identifying patients with poor outcome in low-grade endometrial carcinoma (EC) patients. Methods: Prospective multicenter cohort study including all consecutive patients surgically treated for endometrial carcinoma in nine collaborating hospitals from September 2011 until December 2013. All preoperative histopathological diagnoses were reviewed in a blinded manner. Associations between CA-125 and clinicopathological features were determined. Univariable and multivariable analysis by Cox regression were used. Separate analyses were performed for preoperatively designated low-grade and high-grade endometrial carcinoma patients. Results: A total of 333 patients were analyzed. CA-125 was associated with poor prognostic features including advanced International Federation of Gynecology and Obstetrics (FIGO) stage. In multivariable analysis, age, preoperative tumor and CA-125 were significantly associated with disease-free survival (DFS); preoperative grade, tumor type, FIGO and CA-125 were significantly associated with disease-specific survival (DSS). Low-grade EC patients with elevated CA-125 revealed a DFS of 80.6% and DSS of 87.1%, compared to 92.1% and 97.2% in low-grade EC patients with normal CA-125. Conclusion: Preoperative elevated CA-125 was associated with poor prognostic features and independently associated with DFS and DSS. Particularly patients with low-grade EC and elevated CA-125 represent a group with poor outcome and should be considered as high-risk endometrial carcinoma.

Contains fulltext : 177877.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To assess the agreement between preoperative endometrial sampling and final diagnosis for tumor grade and subtype in patients with endometrial carcinoma. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane library were searched from inception to January 1, 2017, for studies that compared tumor grade and histologic subtype in preoperative endometrial samples and hysterectomy specimens. METHODS OF STUDY SELECTION: In eligible studies, the index test included office endometrial biopsy, hysteroscopic biopsy, or dilatation and curettage; the reference standard was hysterectomy. Outcome measures included tumor grade, histologic subtype, or both. TABULATION, INTEGRATION, AND RESULTS: Two independent reviewers assessed the eligibility of the studies. Risk of bias was assessed (Quality Assessment of Diagnostic Accuracy Studies). A total of 45 studies (12,459 patients) met the inclusion criteria. The pooled agreement rate on tumor grade was 0.67 (95% CI 0.60-0.75) and Cohen's kappa was 0.45 (95% CI 0.34-0.55). Agreement between hysteroscopic biopsy and final diagnosis was higher (0.89, 95% CI 0.80-0.98) than for dilatation and curettage (0.70, 95% CI 0.60-0.79; P=.02); however, it was not significantly higher than for office endometrial biopsy (0.73, 95% CI 0.60-0.86; P=.08). The lowest agreement rate was found for grade 2 carcinomas (0.61, 95% CI 0.53-0.69). Downgrading was found in 25% and upgrading was found in 21% of the endometrial samples. Agreement on histologic subtypes was 0.95 (95% CI 0.94-0.97) and 0.81 (95% CI 0.69-0.92) for preoperative endometrioid and nonendometrioid carcinomas, respectively. CONCLUSION: Overall there is only moderate agreement on tumor grade between preoperative endometrial sampling and final diagnosis with the lowest agreement for grade 2 carcinomas.

Optimal identification of endometrial carcinoma (EC) patients at high risk of recurrence is currently lacking. Hypoxia is an important feature of aggressive EC leading to activation of hypoxic and angiogenetic target genes. The present study investigates the prognostic role of hypoxia and angiogenesis in EC. Data and tissues were used from 11 collaborating European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centers. Tumor slides were stained for CAIX as a hypoxic marker and CD-34 for assessment of microvessel density (MVD) as a marker for angiogenesis. Complete slides were digitalized and analyzed using ImageJ software after exclusion of areas without tumor. A cutoff of 1% for the fraction of CAIX positive tumor cells was used. The MVD was assessed according to the Weidner method with the median as cutoff. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Cox regression analysis. Sixty-three (16.4%) of 385 ECs showed positive CAIX-expression with high vascular density. Multivariable analysis showed that ECs with combined positive CAIX-expression and high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002) and DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). Multivariable analyses with CAIX-expression and vascular density as separate markers, showed that both were independent prognostic markers as well. This study found an impaired DSS and DDFS in ECs with positive CAIX-expression and high vascular density. Differential adjuvant treatment might be indicated for these ECs. Citation Format: Casper Reijnen, Willem Jan van Weelden, Martijn SJP Arts, Johan P. Peters, Paul F. Rijken, Koen van de Vijver, Maria Santacana, Peter Bronsert, Johan Bulten, Marc Hirschfeld, Eva Colas, Antonio Gil-Moreno, Amando Reques, Gemma Mancebo, Fransesc Alameda, Camilla Krakstad, Jone Trovik, Ingfrid S. Haldorsen, Jutta Huvila, Stefanie Schrouwen, Martin Koskas, Francine Walker, Vit Weinberger, Lubos Minar, Eva Jandakova, Marc PLM Snijders, Saskia van den Berg-van Erp, Heidi VN Küsters-Vandevelde, Xavier Matias-Guiu, Frederic Amant, ENITEC-consortium, Leon FAG Massuger, Johan Bussink, Johanna MA Pijnenborg. Poor outcome in hypoxic endometrial carcinoma is related to vascular density [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4879.

5586 Background: Adjuvant radiotherapy improves progression-free survival in intermediate and high-risk endometrial cancer. However, so far there is no evidence of improved overall or disease-specific survival after adjuvant radiotherapy. There is accumulating evidence that MMR proteins are involved in DNA repair following radiotherapy. We investigated the predictive value of MMR status in terms of survival benefit after adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). Methods: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between patient characteristics, adjuvant treatment and outcome. Results: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p = 0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n = 55], vaginal brachytherapy [n = 27]). In multivariate analysis, adjuvant radiotherapy was independently associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05 - 0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37 - 2.31). Conclusions: Adjuvant radiotherapy improved disease-specific survival in patients with MMR-deficient EECs, but not in those with MMR-proficient EECs. This study demonstrates the predictive ability of MMR IHC to identify women who likely have increased benefit from radiotherapy.

AimsFor the diagnostic workup of postmenopausal bleeding, histological examination of the endometrium is frequently performed. Failure of endometrial sampling due to insufficient material is often reported but objective criteria for quality assessment of endometrial biopsies are lacking. The aim of the present study is to evaluate the association between the amount of tissue obtained by endometrial sampling and the diagnostic accuracy, and to establish a cut-off level for a minimal amount of tissue required for a conclusive diagnosis.MethodsFor this retrospective cohort study, clinicopathological data and Pipelle endometrial sampling slides of 139 patients who were treated with hysterectomy were collected. The surface of evaluable endometrial tissue was measured by means of structured digital assessment. The correlation between the predictive values in relation to the endometrial tissue surface was calculated for different cut-off values.ResultsThe median endometrial tissue surface was 4.7 mm2 (range 0.4–156.4) for benign endometrium, 27.8 mm2 (range 0.0–208.4) for premalignant endometrium and 43.8 mm2 (range 0.0–223.6) for malignant endometrium. There was a significant association between the endometrial tissue surface and the correctness of diagnosis. A minimal endometrial tissue surface of 35 mm2 could be defined, for positive and negative predictive values of 92.6% and 85.7%, respectively.ConclusionsThe diagnostic accuracy of Pipelle endometrial sampling is associated with the amount of endometrial tissue surface, with a minimal cut-off value of 35 mm2 required to classify an endometrial sample as conclusive. Quantification of endometrial tissue can contribute to standardisation of quality assessment of endometrial samplings.

Item does not contain fulltext BACKGROUND: There are limited cases in literature of patients with mucinous adenocarcinoma of the vulva with neuroendocrine differentiation have. With this new case, we aim to provide an overview of the existing literature and present a tool with relevant markers for the pathologist in the differential diagnosis. CASE DESCRIPTION: A 92-year-old multiparous, Caucasian woman presented with a 8cm spherical tumor of the left major labium. Since the initial punch biopsy was not conclusive, a local resection was performed. Histopathological examination showed mucus production, large pools of mucin with trabeculae and cribriform glandular structures with strongly atypical columnar epithelium. Additional immunohistochemical analysis demonstrated expression of: CEA, CK7, EMA, and the neuroendocrine markers synaptophysin and chromogranin supporting the diagnosis. CONCLUSION: In this report, we present a new case of a mucinous adenocarcinoma of the vulva with neuroendocrine differentiation based immunohistochemical analysis. Due to the indolent tumor behavior, partial vulvectomy is the therapy of choice.