OBJECTIVES:Multiple studies have proven the prognostic value of molecular classification for stage I-III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients are lacking. Hypothetically, poor prognostic molecular subtypes are more common in higher stages of endometrial cancer. Considering the poor prognosis of stage IV endometrial cancer patients, it is questionable whether molecular classification has additional prognostic value. Therefore, we determined which molecular subclasses are found in stage IV endometrial cancer and if there is a correlation with progression-free and overall survival. METHODS:A retrospective multicenter cohort study was conducted using data from five Dutch hospitals. Patients with stage IV endometrial cancer at diagnosis who were treated with primary cytoreductive surgery or cytoreductive surgery after induction chemotherapy between January 2000 and December 2018 were included. Exclusion criteria were age <18 years or recurrent disease. The molecular classification was performed centrally on all tumor samples according to the World Health Organization 2020 classification (including POLE and estrogen receptor status). The Kaplan-Meier method was used to calculate progression free and overall survival in the molecular subclasses, for the different histological subtypes and for estrogen receptor positive versus estrogen receptor negative tumors. Groups were compared using the log-rank test. RESULTS:164 stage IV endometrial cancer patients were molecularly classified. Median age of the patients was 67 years (range 33-86). Most patients presented with a non-endometrioid histological subtype (58%). Intra-abdominal complete cytoreductive surgery was achieved in 60.4% of the patients. 101 tumors (61.6%) were classified as p53 abnormal, 35 (21.3%) as no specific molecular profile, 21 (12.8%) as mismatch repair deficient, and 6 (3%) as POLE mutated. Molecular classification had no significant impact on progression free (p=0.056) or overall survival (p=0.12) after cytoreductive surgery. Overall survival was affected by histologic subtype (p<0.0001) and estrogen receptor status (p=0.013). CONCLUSION:The distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I-III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.

Introduction/Background The molecular classification of endometrial cancer (EC) has been shown to surpass histological subtyping and grading and more efficiently predict prognosis. However, molecular classification has not affected our surgical approach and only a few studies investigated the relationship between the four molecular subgroups and the tumor spread beyond the uterus. We aim to improve the current risk classification system by integrating the disease stage into the molecular classification. Methodology EUGENIE is a prospective multicentre study aiming to include 1000 EC patients. Besides the standard surgical procedures, sentinel/lymphadenectomy, peritoneal biopsies, and omentectomy/omental biopsies will be performed in all the enrolled patients. EUGENIE is currently recruiting patients in UZ Leuven Belgium; Fondazione Policlinico Gemelli IRCCS, Italy, and University Medical Centre, Maribor, Slovenia Results At the data cut-off of 31/07/23, 170 patients have been enrolled but the histological and molecular data are available for 90 patients (table 1). Among them, 19 (21%) were advanced stages (2009 FIGO stage III or IV), where 11 EC cases were known as such before surgery. Instead, as a result of the EUGENIE procedures, 8 out of 79 (10%) apparent early stage cases were upstaged because of previously undetected metastases. Regarding the advanced cases, lymph nodes metastases were detected in all 4 molecular subgroups (mismatch repair deficiency, MMRd; Non specified molecular profile, NSMP; POLE mutated; p53 aberrant, p53abn), while transperitoneal spread was observed only in MMRd, p53abn and NSMP EC. Remarkably, 22,5% of NSMP EC showed positive pelvic lymph nodes. Conclusion Our preliminary results show that EUGENIE is feasible and reveal possible different spread patterns for the 4 different molecular groups of EC. The final results are expected in 2028 and may guide surgical staging and adjuvant treatment for each molecular type Disclosures The authors declare no disclosures.

ABSTRACT Endometrial cancer is the sixth most common cancer in women globally and has a rising incidence, accounting for 417,000 new diagnoses and more than 97,000 deaths in 2020. Early detection is critical because of a poor advanced-stage prognosis and high relapse risk. Postmenopausal bleeding precedes endometrial cancer in 90% of cases, yet only 5% to 10% of patients with this symptom have an underlying malignancy. Recent cytology research has demonstrated endometrial cancer cells in vaginal samples, suggesting urine and cervicovaginal self-samples may allow convenient and minimally invasive screening. In addition, screening samples for DNA methylation in tumor suppressor genes can increase testing efficacy of triaging patients with postmenopausal bleeding as it does not require intact tumor cells. This study aimed to evaluate the diagnostic performance of endometrial cancer detection using DNA methylation analysis in paired urine, cervicovaginal self-samples, and clinician-taken cervical scrapes. Paired samples from participants of the SOLUTION1 study with endometrial cancer were collected between October 2016 and August 2020. A complete urine void and cervicovaginal self-sample was collected at home, whereas the cervical scrape was taken by a clinician in the operating room before surgery. Each patient had a paired urine, cervicovaginal self-sample, and clinician-taken cervical scrape available for methylation analysis. Controls were collected from the Urine Controls (URIC) biobank and Dutch national cervical cancer screening program. Promoter hypermethylation of the ADCYAP1, BHLHE22, CDH13, CDO1, GALR1, GHSR, HAND2, SST, and ZIC1 genes was tested using quantitative methylation-specific polymerase chain reaction. Optimal 3-marker combinations were determined for each sample type using multivariable logistic regression analysis, and diagnostic performances of each marker and 3-marker panels were assessed by leave-one-out cross validation. A total of 103 endometrial cancer patients were included in this study, with 317 unpaired samples of control women. Methylation levels of all markers were significantly higher in all 3 sample types of endometrial cancer patients compared with healthy control women. In urine, the non–cross-validated area under the curve of the DNA methylation markers ranged between 0.61 and 0.93, in cervicovaginal self-samples between 0.62 and 0.91, and in clinician-taken cervical scrapes between 0.61 and 0.95. Most markers (7/9) showed the highest performance in urine, with the remaining 2 showing best performance in clinician-taken cervical scrapes. The optimal 3-marker combination panels showed area under the curve values of 0.95 (05% confidence interval [CI], 0.92–0.98) for urine, 0.94 (95% CI, 0.90–0.97) for cervicovaginal self-samples, and 0.97 (95% CI, 0.96–0.99) for clinician-taken cervical scrapes. The sensitivity and specificity of the optimal urine testing panel were both 90%, were 89% sensitivity and 92% specificity for cervicovaginal self-samples, and were 93% sensitivity and 90% specificity for clinician-taken cervical scrapes. The leave-one-out cross-validation analysis revealed virtually equal performances in marker panels for each of the 3 testing modalities. The results of this study demonstrate high diagnostic potential of DNA methylation testing in minimally and noninvasive samples for endometrial cancer detection, emphasizing the potential for patient-friendly home-based sample collection.

Primary cutaneous neuroendocrine tumors (CNET) are extremely rare. Only a few cases have been reported so far. CNET have an indolent clinical course and usually present as a single flesh-colored nodule with a predilection for the scalp and trunk in elderly patients. While primary CNET have characteristic histological and immunohistochemical features akin to other low-grade neuroendocrine tumors elsewhere in the body, diagnosing these tumors on skin biopsies can be challenging as they are particularly mistaken for other, more commonly diagnosed, entities. In the current report we present a unique case of primary CNET of the vulva. The clinical presentation will be discussed as well as the histopathologic and immunohistochemical features and most importantly the possible pitfalls in microscopic examination.

Background The molecular classification of endometrial cancer revolutionized our knowledge of its biology but so far has not affected our surgical approach. The exact risk of extra-uterine metastasis and hence the type of surgical staging for each of the four molecular subgroups are currently unknown. Primary Objective To determine the association between molecular classification and disease stage. Study Hypothesis Each endometrial cancer molecular subgroup has a specific pattern of spread and this pattern of spread could guide the extent of surgical staging. Trial Design Prospective, multicenter study Major Inclusion/Exclusion Criteria Participants eligible for inclusion in this study must meet all the following criteria: women ≥18 years with primary endometrial cancer, any histology and stage. Primary Endpoint Number and site of metastasis in each endometrial cancer molecular subgroup. Sample Size 1000 patients will be enrolled. Estimated Dates for Completing Accrual and Presenting Results The trial will last 6 years: 4 years of accrual, and 2 years of follow-up of all patients. Results on staging and oncological outcomes are expected in 2027 and 2029, respectively. Trial Registration The study has been accepted by UZ Leuven Ethical Committee. Belg. Reg. nr: B3222022000997

The aim was to investigate the incidence of sentinel lymph node (SLN) metastases and the contribution of SLN mapping in presumed low- and intermediate-risk endometrial cancer (EC). A multicenter, prospective cohort study in presumed low- and intermediate-risk EC patients was performed. Patients underwent SLN mapping using cervical injections of indocyanine green and a minimally invasive hysterectomy with bilateral salpingo-oophorectomy. The primary outcome was the incidence of SLN metastases, leading to adjusted adjuvant treatment. Secondary outcomes were the SLN detection rate and the occurrence of complications. Descriptive statistics and univariate general linear model analyses were used. A total of 152 patients were enrolled, with overall and bilateral SLN detection rates of 91% and 61%, respectively. At final histology, 78.9% of patients (n = 120) had truly low- and intermediate-risk EC. Macro- and micro-metastases were present in 11.2% (n = 17/152), and three patients had isolated tumor cells (2.0%). Nine patients (5.9%) had addition of adjuvant radiotherapy based on SLN metastases only. In 2.0% of patients with high-risk disease, adjuvant therapy was more limited due to negative SLNs. This study emphasizes the importance of SLN mapping in presumed early-stage, grade 1 and 2 EC, leading to individualized adjuvant management, resulting in less undertreatment and overtreatment.

Endometrial cancer incidence is rising and current diagnostics often require invasive biopsy procedures. DNA methylation marker analysis of minimally- and non-invasive sample types could provide an easy-to-apply and patient-friendly alternative to determine cancer risk. Here, we compared the performance of DNA methylation markers to detect endometrial cancer in urine, cervicovaginal self-samples and clinician-taken cervical scrapes. Paired samples were collected from 103 patients diagnosed with stage I to IV endometrial cancer. Urine and self-samples were collected at home. All samples were tested for nine DNA methylation markers using quantitative methylation-specific PCR. Methylation levels measured in endometrial cancer patients were compared to unpaired samples of 317 healthy controls. Diagnostic performances were evaluated by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Each methylation marker showed significantly higher methylation levels in all sample types of endometrial cancer patients compared to healthy controls (P < .01). Optimal three-marker combinations demonstrated excellent diagnostic performances with area under the receiver operating curve values of 0.95 (95% CI: 0.92-0.98), 0.94 (0.90-0.97) and 0.97 (0.96-0.99), for endometrial cancer detection in urine, self-samples and scrapes, respectively. Sensitivities ranged from 89% to 93% at specificities of 90% to 92%. Virtually equal performances were obtained after cross-validation and excellent diagnostic performances were maintained for stage I endometrial cancer detection. Our study shows the value of methylation analysis in patient-friendly sample types for endometrial cancer detection of all stages. This approach has great potential to screen patient populations at risk for endometrial cancer.

ImportancePatients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear.ObjectiveTo determine the association of molecular profiling with outcomes among patients with low-grade EC.Design, Setting, and ParticipantsThis retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon (POLE)-altered, microsatellite instable (MSI), tumor protein p53 (TP53)-altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022.ExposuresMolecular testing of the 4 molecular subgroups.Main Outcomes and MeasuresThe main outcome was disease-specific survival (DSS) within the molecular subgroups.ResultsA total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE-altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53-altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% (P < .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P < .001), TP53-altered (HR, 1.76; 95% CI, 1.04-2.95; P = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P < .001) disease were independently associated with reduced DSS.Conclusions and RelevanceThis cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness.

Introduction/Background Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries. Currently, the extent of the surgical staging depends on a pre-operative risk assessment, but it is relatively inaccurate. This leads to an incorrect risk estimation of metastases at the diagnosis. Furthermore, the relation between the four molecular subgroups and the risk of tumour spread beyond the uterus has insufficiently been investigated so far. Despite that, the new classification is being quickly incorporated, and the use of staging surgery to assess the presence of metastases dissuaded. Indeed, the disease stage has until now been the most important predictor of prognosis. We aim to improve the current risk classification system by integrating disease stage and molecular classification allowing an accurate estimation of the risk and type of metastases and the risk of recurrence in EC patients. Methodology EUGENIE is a prospective multicentre study including 1,000 EC patients. Patients will be included during the first four years and the follow-up will be at least two years. Patients with all histotypes EC, FIGO stage I-IV, will be enrolled. A surgical staging procedure will be performed in all patients, including assessment of lymph nodes (sentinel or lymphadenectomy), peritoneal biopsies, and omentectomy/omental biopsies. Results The protocol is submitted to the Ethical Committee at the UZ Leuven, Belgium. The study will start in UZ Leuven Gasthuisberg Campus and Fondazione Policlinico Gemelli IRCCS in Rome and it will last 6 years. Other centres are invited to participate and join EUGENIE. Conclusion EUGENIE will generate the largest dataset about the presence of metastatic disease in each molecular subtype of EC. The results will help to determine the primary surgical approach and the need for adjuvant treatment. This will lead to a reduction of over and undertreatment and more efficient management of EC in the molecular era.

The current review provides a literature overview of studies assessing the oncological and fertility outcomes of treatment with neo-adjuvant chemotherapy followed by fertility-sparing surgery in patients with cervical cancer >2 cm. Six cohort studies were included showing severe heterogeneity regarding patient selection, chemotherapy regimen, and surgical approach. In total, 111 patients were studied, with overall favorable characteristics. Patients were on average 29 years old, had a tumor of 36 mm, no lymph node metastasis, and response to chemotherapy. In approximately 5-year follow-up, the recurrence rate was 13% (0%-21%) and overall death rate 2.7% (0%-10%). Three patients were alive with recurrent disease (2.7% and 0%-11%). Of the 111 patients, 90 underwent successful fertility-sparing treatment (83%). Roughly one-third conceived and one-fourth had a healthy live-born child. More research is essential to determine proper selection criteria for fertility-sparing treatment of cervical cancer >2 cm and the optimal treatment management.

Molecular profiling of endometrial carcinoma according to The Cancer Genome Atlas (TCGA) points toward a paradigm shift from morphological to molecular classification.[1][1] TCGA and many subsequent studies confirm the existence of four specific types of endometrial carcinoma: POLE ultramutated (±7

Endometrial cancer (EC) is the most common gynaecologic malignancy in developed countries. The main challenge in EC management is to correctly estimate the risk of metastases at diagnosis and the risk to develop recurrences in the future. Risk stratification determines the need for surgical staging and adjuvant treatment. Detection of occult, microscopic metastases upstages patients, provides important prognostic information and guides adjuvant treatment. The molecular classification subdivides EC into four prognostic subgroups: POLE ultramutated; mismatch repair deficient (MMRd); nonspecific molecular profile (NSMP); and TP53 mutated (p53abn). How surgical staging should be adjusted based on preoperative molecular profiling is currently unknown. Moreover, little is known whether and how other known prognostic biomarkers affect prognosis prediction independent of or in addition to these molecular subgroups. This review summarizes the factors incorporated in surgical staging (i.e., peritoneal washing, lymph node dissection, omentectomy and peritoneal biopsies), and its impact on prognosis and adjuvant treatment decisions in an era of molecular classification of EC. Moreover, the relation between FIGO stage and molecular classification is evaluated including the current gaps in knowledge and future perspectives.

Objective Sentinel lymph node (SLN) mapping in endometrial cancer is gaining ground. However, patient views on this new technique are unknown. The aim of this study was to determine factors important to patients and gynecologists when considering SLN mapping in low- and intermediate-risk endometrial cancer. Methods We performed a vignette study. Patients who underwent a total hysterectomy for low- or intermediate-risk endometrial cancer between 2012 and 2015 were invited. Dutch gynecologists specializing in gynecologic oncology were also invited. We based the selection for attributes in the vignettes on literature and interviews: risk of complications of SLN mapping; chance of finding a metastasis; survival gain; risk of complications after radiotherapy; operation time; and hospital of surgery (travel time). We developed a questionnaire with 18 hypothetical scenarios. Each attribute level varied and for each scenario, participants were asked how strongly they would prefer SLN on a scale from 1 to 7. The strength of preference for each scenario was analyzed using linear mixed effects models. Results A total of 38% of patients (41/108) and 33% of gynecologists (42/126) participated in the study. Overall, they had a preference for SLN. The mean preference for patients was 4.29 (95% CI 3.72 to 4.85) and 4.39 (95% CI 3.99 to 4.78) for gynecologists. Patients' preferences increased from 3.4 in the case of no survival gain to 4.9 in the case of 3-year survival gain (P<0.05) and it decreased when travel time increased to >60 min (-0.4, P=0.024), or with an increased risk of complications after adjuvant radiotherapy (-0.6, P=0.002). For gynecologists all attributes except travel time were important. Conclusions Overall, patients and gynecologists were in favor of SLN mapping in low- and intermediate-risk endometrial cancer. Most important to patients were survival gain, travel time, and complication risk after adjuvant radiotherapy. These preferences should be taken into account when counseling about SLN mapping.

The incidence of endometrial cancer is rising, and current diagnostics often require invasive biopsy procedures. Urine may offer an alternative sample type, which is easily accessible and allows repetitive self-sampling at home. Here, we set out to investigate the feasibility of endometrial cancer detection in urine using DNA methylation analysis. Urine samples of endometrial cancer patients (n = 42) and healthy controls (n = 46) were separated into three fractions (full void urine, urine sediment, and urine supernatant) and tested for three DNA methylation markers (GHSR, SST, ZIC1). Strong to very strong correlations (r = 0.77–0.92) were found amongst the different urine fractions. All DNA methylation markers showed increased methylation levels in patients as compared to controls, in all urine fractions. The highest diagnostic potential for endometrial cancer detection in urine was found in full void urine, with area under the receiver operating characteristic curve values ranging from 0.86 to 0.95. This feasibility study demonstrates, for the first time, that DNA methylation analysis in urine could provide a non-invasive alternative for the detection of endometrial cancer. Further investigation is warranted to validate its clinical usefulness. Potential applications of this diagnostic approach include the screening of asymptomatic women, triaging women with postmenopausal bleeding symptoms, and monitoring women with increased endometrial cancer risk.

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.

BACKGROUND:We have assessed the impact of introducing robotics for a stage 1b cervical cancer service on laparotomy rates, complications, and costs.METHODS:Data were collected prospectively from 90 consecutive patients who had a radical hysterectomy between 1 April 2010 and 31 December 2017.RESULTS:There were 37 women before the first robotic procedure and 53 after. The laparotomy rate reduced from 75% (9/12) in 2010 to 0% (0/18) in 2017. The length of stay reduced from 6 days (range 3-39) to 3 days (range 1-15) (P < 0.0001). The complication rate before robotics was 68% (25/37) compared with 45% (24/53) afterwards (P = 0.0493). The blood transfusion rate reduced from 43% (16/37) to 11% (6/53) (P = 0.0007). There were no differences between the total costs before and after the introduction of robotics or between each route.CONCLUSIONS:In this series, introducing robotics for cervical carcinoma reduced hospital stay and complications. No cost differences were demonstrated.

Objective It is difficult to critically outline the optimal treatment for women with early-stage cervical cancer (eCC) wishing fertility preservation. Neoadjuvant chemotherapy (NAC) to downstage bulky eCC could potentially lead to fertility-sparing surgery (FSS) in a wider patient population. The rationale is to provide oncological safety balanced with maximal fertility effort. We aimed to obtain the most accurate fertility outcomes for eCC women treated with NAC followed by FSS and identify potential factors favoring fertility. Methods A systematic search of MEDLINE, EMBASE, Web of Science, and Cochrane Database was performed. Studies that reported obstetric outcomes of eCC women treated with NAC followed by FSS were located. For the meta-analysis, we calculated the proportions of women who had the outcomes per total number of women who were considered for FSS. For the meta-regression, we extracted the relative risk of the outcome variables to enable comparison of the results across the studies. Results Seven studies enrolling 86 patients were included in the meta-analysis. Pooling of results from seven studies rendered summary proportions of 0.49 (95% confidence interval [CI], 0.32-0.66) and 0.42 (95% CI, 0.32-0.53) for the outcomes of pregnancies and live births, respectively. The outcome of first- and second-trimester losses by pooling seven studies rendered a summary proportion of 0.16 (95% CI, 0.09-0.27). For the outcome of premature deliveries, pooling of results from five studies rendered a summary proportion of 0.06 (95% CI, 0.02-0.16). This reached 0.29 (95% CI, 0.15-0.48) in women who achieved live births. In multivariate meta-regression, the more radical surgical approach resulted in a less favorable pregnancy rate compared with the less radical surgical approach (P = 0.015). Conclusions This strategy achieves live births in four of 10 eCC women who desire fertility, whereas their risk of miscarriage is low. Three of 10 live births will be premature.