INTRODUCTION:The prognostic value of FIGO grading in endometrial cancer (EC) varies across molecular subgroups: it is no longer considered relevant in POLEmut and p53abn tumours, but remains prognostic in NSMP tumours. Its relevance is unclear in mismatch repair deficient (MMRd) EC. Using a large collection of molecularly classified EC, this study evaluated the prognostic role of FIGO grading in MMRd EC. METHODS:Data from three randomised trials (PORTEC-1 (n = 714); PORTEC-2 (n = 427); PORTEC-3 (n = 660)) and five clinical cohorts (n = 1357) were pooled, yielding patients with stage I-III endometrioid and non-endometrioid EC. Tumours were molecularly classified according to the 2020 WHO diagnostic algorithm, with central pathology review by an expert gynaecopathologist. Cause-specific cumulative incidence was estimated using the Aalen-Johansen method and compared using Gray's test. The independent prognostic value of FIGO grading was assessed using multivariable cause-specific Cox regression models. RESULTS:In total, 2621 (83.0%) of the 3158 EC cases were molecularly classified, including 730 (27.9%) MMRd tumours: 405 (55.5%) were low-grade and 325 (44.5%) were high-grade. Median follow-up was 7.2 years. Five-year cumulative incidence of overall recurrence (18.0% vs. 18.8%, p = 0.67) and cancer-specific death (12.3% vs. 14.2%; p = 0.44) did not differ between low- and high-grade MMRd EC. In multivariable analyses, corrected for age, stage, histotype, LVSI and adjuvant treatment, FIGO grading was not independently associated with overall recurrence (HR 0.83 [95%CI 0.56-1.24]; p = 0.37) or cancer-specific death (HR 0.97 [0.62-1.51]; p = 0.89). CONCLUSION:In conclusion, FIGO grading has no prognostic role in MMRd EC and may be omitted in risk stratification and adjuvant treatment decisions.

Computational pathology leverages deep learning to extract clinically relevant information from digitized tumor slides, predicting histopathological subtypes, molecular alterations, and patient outcomes. Recent pipelines increasingly rely on foundation models trained on large pan-cancer datasets to generate generalizable features. In endometrial cancer (EC), their comparative performance for clinical diagnostic tasks remains unexplored. This study evaluates the performance of seven state-of-the-art foundation models across morphological, molecular, and prognostic tasks using a large EC dataset of 3,293 patients from randomized trials and clinical cohorts. In addition, their performance was compared to two versions of an EC-specific feature extractor (EsVIT) exclusively trained on EC. The foundation models H-OPTIMUS-0, CONCH, and VIRCHOW2 achieved the highest mean performance, but the best-performing foundation model varied by task. The top-performing foundation model outperformed EsVIT across all tasks, which highlights the superiority of foundation models over the domain-specific feature extractor EsVIT in EC. Selecting the optimal foundation model for novel tasks remains challenging due to performance plateaus and limited information on the training datasets, requiring rigorous benchmarking and domain insight to reach maximum potential.

This study represents a omprehensive characterization of high-grade endometrial carcinoma (EC) of no specific molecular profile (NSMP) to improve our understanding of their poor clinical outcome. A previously molecularly classified cohort of 412 high-grade EC from the Danish Cancer Registry was extensively reviewed by 2 expert pathologists blinded for associated clinical and molecular data. Immunohistochemistry (IHC) was performed to determine ER, PR, and L1CAM status and a 10% cut-off value was applied for positivity. Shallow whole-genomic sequencing (sWGS) and next-generation sequencing (NGS) was performed to describe the molecular landscape. Survival analysis was performed using the Kaplan-Meier method, and survival difference was tested using the log-rank test. Of the 57 high-grade NSMP tumors, ER negativity was found in 30 (53%). All clear cell NSMP EC (n=12, 21%) were ER negative. L1CAM overexpression was found in 29 high-grade NSMP EC (53%) and showed overlap (n=20, 69%) with ER negativity. A high frequency of copy number (CN) events and fraction genome altered (FGA) was observed, with the median number of CN events clustering by ER status (28 vs. 43, P <0.05). Overall, the cohort showed a 52% (CI: 31.6%, 72.4%) 5-yr overall survival (OS) and 61% (CI: 42.6%, 79.4%) 5-yr disease-specific survival (DSS). No significant additional prognostic refinement was found when stratifying for ER status (5-yr OS: 46% vs. 65%, P =0.068). High-grade NSMP ECs are a heterogenous group of tumors with high prevalence of loss of ER, L1CAM overexpression, and substantial copy number alterations. Within this group, no prognostic effect of ER was identified, providing support for grouping these tumors into one risk group. This work adds to the growing body of evidence that both high-grade and/or loss of ER expression can be used to identify NSMP EC patients with a poor clinical outcome.

OBJECTIVES:To evaluate a scoring system using transvaginal ultrasound (TVS) to predict high-risk endometrial cancer. METHODS:Consecutive patients with endometrial cancer/atypical hyperplasia (n = 266) were preoperatively examined by residents using TVS. Clinical parameters, endometrial morphology and Doppler scores were recorded using a gray scale and Doppler TVS and related to final histopathology at hysterectomy. Multivariate logistic regression was used to correlate imaging and clinical parameters to the presence of high-risk endometrial cancer (defined as FIGO stage Ib-IV or high-grade tumors [grade 3/non-endometroid]) to develop the High-Risk Endometrial Cancer (HIREC) score. RESULTS:High-risk endometrial cancer (n = 128) and lympho-vascular space invasion (LVSI) (n = 43) were predicted by increased endometrial thickness (ET), age, and Doppler score. The HIREC scoring system, based on age, Doppler score, and ET performed well with an AUC of 78.5% (CI 95%: 73-84) to predict high-risk cancer. By using a 2-step strategy of (1) Preoperative identification of high-grade tumors by biopsy, (2) Assessing the HIREC score, high-risk endometrial cancer could be predicted at a HIREC score of ≥7 with sensitivity, specificity, and accuracy of 72.7, 88.4, and 80.8%. Low-risk endometrial cancer was predicted at HIREC scores of <5 with sensitivity, specificity, and accuracy values of 91.4, 46.4 and 68.1%, respectively. CONCLUSIONS:Low and high HIREC scores effectively predicted low- and high-risk endometrial cancer. The score is a simple point system suitable for the first ultrasound assessment. It may be used in preoperative work-up to select treatment and additional imaging, but it needs to be validated in further studies.

OBJECTIVE:Patterns of recurrence may impact the possibilities for salvage treatment and prognosis of patients with endometrial carcinoma (EC). We evaluated the recurrence rate and distribution pattern of the molecular EC subgroups in patients with stage I high-grade disease without adjuvant treatment and those staged by lymphadenectomy. METHOD:412 high-grade EC from the Danish Gynecological Cancer Database were molecularly profiled and classified into POLE mutant (POLEmut), mismatch repair deficient (MMRd), p53-abnormal (p53abn) or no specific molecular profile (NSMP) EC. Patients with stage II-IV (FIGO 2009) or residual disease after surgery were excluded. Crude and actuarial recurrence rates were calculated. RESULTS:Stage I high-grade POLEmut and MMRd EC rarely recurred (5-year overall recurrence rate 7 % (95 % CI 3-16) and 6 % (95 % CI 2-22), respectively), also when not receiving adjuvant treatment. Stage I high-grade NSMP and p53abn EC had high recurrence rates (5-year overall recurrence rate 29 % (95 % CI 16-48) and 35 % (95 % CI 27-45), respectively), mostly presenting with abdominal (NSMP EC n = 1 (3.0 %); p53abn EC n = 28 (22.4 %)) or distant recurrences (NSMP EC n = 8 (24.2 %); p53abn EC n = 21 (16.8 %)). CONCLUSION:Stage I high-grade EC present more frequently with abdominal and distant recurrences rather than isolated loco-regional recurrences, independently of molecular subgroup. Stage I high-grade POLEmut EC and MMRd EC have a favorable prognosis with few recurrences, even with no adjuvant treatment. Stage I high-grade NSMP and p53abn EC have a high recurrence rate, frequently with abdominal or distant recurrences, underscoring the need to investigate more effective adjuvant systemic treatments for these patients.

OBJECTIVE:In Denmark, adjuvant radiotherapy has gradually been omitted after surgery in endometrial cancer. This study analyses the impact of this strategy on patterns of recurrence and outcome after salvage radiotherapy. Moreover, the potential effect of adjuvant radiotherapy is estimated in the non-low-risk cohort. METHODS:The cohort included 3723 consecutive Danish patients with endometrial cancer who had radical surgery without adjuvant treatment (2005-2012). The patients were divided into low-risk (stage 1A, endometrioid, grades 1, 2 and no lymph-vascular space invasion) and non-low-risk. Crude/actuarial recurrence rates evaluated the number of patients who might have benefited from additional adjuvant radiotherapy. RESULTS:Within 9 years' observation time using crude recurrence rates, 13.4% recurred.The rate of isolated vaginal recurrences was 2.9% in low-risk compared with 6.7% in non-low-risk patients. Isolated pelvic recurrences were 0.8% in low-risk compared with 2.1% in non-low-risk patients. In all, 15.8% of non-low-risk patients died from endometrial cancer, mainly due to primary or secondary non-local recurrences (a later non-local recurrence after a primary isolated local recurrence). Only 0.6% and 1.1% of all non-low-risk patients died from an isolated vaginal or pelvic recurrence, respectively. In all, 86% of all patients with an isolated vaginal recurrence were treated with curative intent. Of these, 72% were given radiotherapy with a local control rate of 91% (crude rate). However, even though only 5.8% died of an unsuccessfully treated isolated vaginal recurrence after curative intended radiotherapy, 23.1% died from a secondary non-local recurrence, while 22.3% died from other causes. CONCLUSION:The Danish strategy of omitting adjuvant radiotherapy is safe. Adjuvant external beam radiotherapy may have prevented isolated local recurrences in 8.7% of the Danish non-low-risk patients, but a majority of these patients were salvaged by curative radiotherapy with 91% and 70% crude local control rates for isolated vaginal and isolated pelvic recurrences, respectively.

Predicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. Here we developed HECTOR (histopathology-based endometrial cancer tailored outcome risk), a multimodal deep learning prognostic model using hematoxylin and eosin-stained, whole-slide images and tumor stage as input, on 2,072 patients from eight EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal (n = 353) and two external (n = 160 and n = 151) test sets of 0.789, 0.828 and 0.815, respectively, outperforming the current gold standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low-, intermediate- and high-risk groups, respectively, by Kaplan-Meier analysis). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold standard and may help delivery of personalized treatment in EC.

Abstract Copy-number (CN)-high endometrial carcinoma (EC) is characterized by abundant CN-alterations, thought to be driven by TP53 aberrations, and is the subgroup with the poorest prognosis. CN-high EC exhibit substantial heterogeneity in histotypes, molecular markers, and mutational profiles. Here, we aimed to refine this subgroup by assessing the evolution and identifying CN-signatures (Drews et al. Nature) to establish CN-clusters. We used whole-genome sequencing (WGS;100X) data from 146 CN-high cases from Genomics England (GeL) as discovery cohort. We then performed shallow WGS (sWGS;0.1X) of FFPE tumor DNA of n=307 CN-high EC from (non-)trial cohorts. Timing of canonical driver mutations by MutationTimer in CN-high GeL revealed that TP53 mutations were: (i) not ubiquitous and (ii) not consistently identified as early clonal events (Table), challenging conventional belief that TP53 inactivation is necessary for initiation of CN-high EC. Evolutionary analyses (Plackett-Luce) are ongoing to identify carcinogenesis trajectories and assess how driver mutations other than TP53 influence CN-phenotypes. Unsupervised clustering of 307 EC by CN-signatures identified five clusters (E1: 19%; E2: 2%; E3; 20%; E4: 19%; E5: 40%), characterized by CN-signatures linked to biological phenomena. Clusters E1/E4 reflect homologous recombination deficiency (CX3), while cluster E5 seems driven by chromosomal missegregation (CX1). Notably, there was no one-to-one relationship between CN-clusters and histotypes, suggesting CN-evolution is independent of morphology. In conclusion, we have identified TP53-dependent and -independent pathways in CN-high EC evolution. Potentially clinically relevant CN-clusters were identified using cost-effective sWGS. sWGS of additional n=475 CN-high EC are ongoing. Furthermore, we will analyze in-depth clinicopathological relationships of clusters, including prognosis/prediction, using PORTEC trials prior to the meeting. Table. Timing of canonical driver mutations in CN-high EC Clonal - early Clonal - late Subclonal Clonal - NA Total 1. TP53 87 (67%) 4 (3%) 3 (2%) 36 (28%) 130 (100%) 2. PIK3CA 42 (76%) 1 (2%) 1 (2%) 11 (20%) 55 (100%) 3. PPP2R1A 18 (47%) 1 (3%) 2 (5%) 17 (45%) 38 (100%) 4. PTEN 17 (59%) 1 (3%) 2 (7%) 9 (31%) 29 (100%) 5. PIK3R1 11 (46%) 0 (0%) 3 (13%) 10 (42%) 24 (100%) 6. FBXW7 14 (61%) 0 (0%) 0 (0%) 9 (39%) 23 (100%) 7. KRAS 9 (64%) 0 (0%) 2 (14%) 3 (21%) 14 (100%) Abbreviation: NA, timing not applicable. Citation Format: Claire J. Kramer, Dina Ruano, Aliah Hawari, Felix Blanc-Durand, Cor D. de Kroon, Judith R. Kroep, Gitte Ortoft, Estrid Hogdall, Alexandra Leary, Carien L. Creutzberg, Maaike P. Vreeswijk, Nanda Horeweg, David N. Church, David C. Wedge, Tjalling Bosse. Evolutionary characterization and refinement of copy-number high endometrial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5051.

Predicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. We developed HECTOR ( H istopathology-based E ndometrial C ancer T ailored O utcome R isk), a multimodal deep learning prognostic model using hematoxylin-and-eosin-stained whole-slide-images and tumor stage as input, on 1,912 patients from seven EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal ( n = 353) and external ( n = 151) test sets of 0.788 and 0.816 respectively, outperforming the current gold-standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low, intermediate and high risk groups). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold-standard and may help delivery of personalized treatment in EC.

Abstract Accurate risk prediction of distant recurrence (DR) is crucial for personalized adjuvant systemic therapy of endometrial cancer (EC) stage I-III patients, as DR is associated with a 5-year overall survival of 10-20%. Risk stratification and treatment recommendation are currently based on histopathological and molecular markers, which is challenging due to high inter-observer variability and testing costs respectively. Deep Learning (DL) models can predict prognosis by identifying relevant visual features from H&E whole slide images (WSIs) at different resolutions without prior assumptions. Here, we developed and tested the first interpretable state-of-the-art DL model for WSI-based risk prediction of DR of stage I-III EC (DeREC) from the randomized PORTEC-1/-2/-3 trials and three clinical cohorts with long-term follow-up data. We used one representative H&E WSI each from 1761 EC patients, excluding those who received adjuvant chemotherapy as it lowers the risk of DR. We randomly sampled 20% as a held-out internal test set (N=353 with 62 events; 8.45 year median follow-up) and performed a 5-fold cross-validation on the training set (N=1408). WSIs were partitioned into 360 micron patches at 40x magnification. DeREC combined self-supervised representation learning of patches using a multi-resolution vision transformer and a WSI-level graph attention-based time-to-event prediction model. The model performance of correctly ranking patients by predicted risk scores and true time to DR was measured with the concordance-index and compared with a Cox’ Proportional Hazards (CPH) model fitted on histopathological variables (histotype, grade, lymphovascular space invasion, stage). Discriminative quality of the predicted risk groups was investigated with Kaplan-Meier analysis and the log-rank test. Most predictive patches by predicted risk groups were reviewed by an expert gynecopathologist for identification of prognostic morphological features. DeREC achieved a concordance-index of 0.764 [95%CI 0.754-0.773] on 5-fold cross validation and 0.757 on the test set, as compared to 0.704 [95%CI 0.662-0.746] with CPH. Predicted risk groups around quartiles 1 and 3 accurately stratified patients between low (N=89), intermediate (N=175), high (N=89) risk of DR (p<0.0001). Among the predicted low-risk group only 3 (3.37%) patients relapsed whereas intermediate and high-risk groups counted 27 (15.43%) and 32 (35.96%) events respectively. DeREC is the first DL model accurately distinguishing EC patients at high risk of DR from those at low risk using one H&E WSI, which would aid decisions on adjuvant treatment. DeREC outperformed standard statistical prediction methods using histopathological variables, indicating that it identified prognostic visual features which can be further investigated. Future development includes the integration of clinicopathological and molecular information. Citation Format: Sarah Fremond, Sonali Andani, Jurriaan Barkey Wolf, Gitte Ørtoft, Estrid Høgdall, Jouke Dijkstra, Jan J. Jobsen, Ina M. Jürgenliemk-Schulz, Ludy CHW Lutgens, Melanie E. Powell, Naveena Singh, Linda R. Mileshkin, Helen J. Mackay, Alexandra Leary, Dionyssios Katsaros, Hans W. Nijman, Stephanie M. de Boer, Remi A. Nout, Vincent T.H.B.M Smit, Carien L. Creutzberg, Nanda Horeweg, Viktor H. Koelzer, Tjalling Bosse. Deep learning risk prediction model of distant recurrence from H&E endometrial cancer slides. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5695.

PURPOSEDetection of 11 pathogenic variants in the POLE gene in endometrial cancer (EC) is critically important to identify women with a good prognosis and reduce overtreatment. Currently, POLE status is determined by DNA sequencing, which can be expensive, relatively time-consuming, and unavailable in hospitals without specialized equipment and personnel. This may hamper the implementation of POLE-testing in clinical practice. To overcome this, we developed and validated a rapid, low-cost POLE hotspot test by a quantitative polymerase chain reaction (qPCR) assay, QPOLE.MATERIALS AND METHODSPrimer and fluorescence-labeled 5 '-nuclease probe sequences of the 11 established pathogenic POLE mutations were designed. Three assays, QPOLE-frequent for the most common mutations and QPOLE-rare-1 and QPOLE-rare-2 for the rare variants, were developed and optimized using DNA extracted from formalin-fixed paraffin-embedded tumor tissues. The simplicity of the design enables POLE status assessment within 4-6 hours after DNA isolation. An interlaboratory external validation study was performed to determine the practical feasibility of this assay.RESULTSCutoffs for POLE wild-type, POLE-mutant, equivocal, and failed results were predefined on the basis of a subset of POLE mutants and POLE wild-types for the internal and external validation. For equivocal cases, additional DNA sequencing is recommended. Performance in 282 EC cases, of which 99 were POLE-mutated, demonstrated an overall accuracy of 98.6% (95% CI, 97.2 to 99.9), a sensitivity of 95.2% (95% CI, 90.7 to 99.8), and a specificity of 100%. After DNA sequencing of 8.8% equivocal cases, the final sensitivity and specificity were 96.0% (95% CI, 92.1 to 99.8) and 100%. External validation confirmed feasibility and accuracy.CONCLUSIONQPOLE is a qPCR assay that is a quick, simple, and reliable alternative for DNA sequencing. QPOLE detects all pathogenic variants in the exonuclease domain of the POLE gene. QPOLE will make low-cost POLE-testing available for all women with EC around the globe.

Approximately 15% of patients with endometrial cancer present with high-risk disease (HREC). Moreover, assessing the extent of lymphovascular space invasion (LVSI) may provide prognostic insight among patients with HREC. The aim of this study was to determine whether the extent of LVSI can serve as a prognostic factor in HREC. All cases of ESMO-ESGO-ESTRO 2016 classified HREC in the Danish Gynecological Cancer Database (DGCD) diagnosed from 2005 to 2012 were reviewed for the presence and extent of LVSI (categorized using a 3-tiered definition). We used the Kaplan-Meier analysis to calculate actuarial survival rates, both adjusted and unadjusted Cox regression analyses were used to calculate the proportional hazard ratio (HR). A total of 376 patients were included in our analysis. Among 305 patients with stage I/II HREC, 8.2% and 6.2% had focal or substantial LVSI, respectively, compared with 12.7% and 38.0% of 71 patients with stage III/IV HREC, respectively. Moreover, the estimated 5-yr recurrence-free survival rate was significantly lower among patients with substantial LVSI compared with patients with no LVSI for both stage I/II (HR: 2.8; P=0.011) and stage III/IV (HR: 2.9; P=0.003) patients. Similarly, overall survival was significantly lower among patients with substantial LVSI for both stage I/II (HR: 3.1; P<0.001) and stage III/IV (HR: 3.2; P=0.020) patients. In patients with HREC, substantial LVSI is an independent adverse prognostic factor for lymph node and distant metastases, leading to reduced survival. Thus, the extent of LVSI should be incorporated into routine pathology reports in order to guide the appropriate choice of adjuvant treatment.

Introduction. The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment. Methods. DNA-sequencing for the detection of pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005-2012) to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis. Results. Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLEmut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLEmut EC (n = 26) had a recurrence. Conclusion. The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLEmut EC is independent of adjuvant treatment. (C) 2022 The Authors. Published by Elsevier Inc.

Background. A combination of tumour size, differentiation grade and location may identify a group of vulvar squamous cell cancer (VSCC) patients with a very low risk of inguinal lymph node metastasis. We aim to examine these findings in a large national cohort of VSCC patients. Materials and methods. Population based prospective data on VSCC patients treated with vulvectomy and primary groin surgery was obtained from the Danish Gynaecological Cancer Database. Univariate chi-square and multivariate logistic regression analysis were used. Statistical tests were 2-sided. P-values of <0.05 were considered statistically significant. Results. In all, 388 VSCC patients were identified. Of these 264 (63.3%) were node negative and 121 (36.7%) node positive. Increasing tumour size (diameter <= 2 cm vs.> 2 to 4 cm), grade (1 vs. 2-3) and location of tumour to clitoris were all associated with a significantly increased risk of inguinal lymph node metastasis OR 2.81(95%CI 1.52-520), OR 3.19 (95% CI 1.77-5.74) and OR 2.74 (95% CI 1.56-520), respectively. Previous vulvar disease was not associated with lymph node metastasis. No lymph node metastasis was demonstrated in patients with grade 1 tumours, tumour size less than 2 cm and located outside the clitoris area (n = 51). Conclusions. VSCC patients with grade 1 tumours, <= 2 cm and without clitoral involvement have a very low risk of inguinal lymph node metastasis. These patients may be spared inguinal lymph node staging to decrease operating time and perk and postoperative morbidity in the future. However, studies validating our findings are needed. (C) 2022 The Authors. Published by Elsevier Inc.

The aim of this study was to investigate the outcome of histological subtype review of high-grade endometrial carcinoma (EC) and its prognostic impact in a large well-documented Danish nationwide cohort. From the Danish Gynecological Cancer Database (DGCD) 2005–2012 cohort, we included 425 patients with an original diagnosis of high-grade EC, independent of histologic subtype. Of these, at least one hematoxylin and eosin (H&E)–stained slide from 396 cases (93.2%) was available for review. The histologic subtype was reviewed by specialized gynecopathologists blinded to the original diagnosis and clinical outcome. Interobserver variability between original and revised histologic subtypes was analyzed using simple Kappa statistics. Hazard ratios (HR), recurrence-free survival (RFS), and overall survival were calculated for original and revised subtypes, respectively. Overall histologic subtype agreement was moderate (kappa = 0.42) with the highest agreement for endometrioid-type EC (EEC; 75.5%) and serous-type EC (SEC; 63.8%). For clear cell carcinoma and un-/dedifferentiated EC, agreement was significantly lower: 30.1% and 33.3% respectively. Of the 396 reviewed cases, only two (0.5%) were re-classified as low-grade EEC upon revision. Interestingly, GR3 EEC had better RFS than SEC with stronger significance after revision (HR 2.36 (95% CI 1.43–3.89), p = 0.001), compared to original diagnosis (HR 1.74 (95% CI 1.07–2.81), p = 0.024). In conclusion, this study confirmed that pathology review results in substantial shift in histological subtype in high-grade EC. After review, a stronger prognostic benefit for GR3 EEC as compared to other histological subtypes was observed. This work supports maintaining a low threshold for pathology revision of high-grade EC in clinical practice.

ObjectiveTo identify women with high-risk endometrial cancers using expert and non-expert transvaginal ultrasonography (TVS) and MRI.Study designMyometrial involvement was prospectively evaluated in patients with atypical hyperplasia or endometrial cancer on ultrasound by non-experts at first visit (non-expert-TVS: n = 266) and experts (expert-TVS: n = 188) at second visit. MRI (n = 175) was performed when high-risk cancer was suspected on non-expert-TVS. Preoperatively, high-risk cancer was defined as myometrial involvement ≥50 %, or preoperative unfavorable tumor histology (grade 3 endometrioid, non-endometrioid tumors, or tumor in cervical biopsies) obtained by endometrial sampling or hysteroscopic biopsies. Preoperative evaluations were compared with final histopathology obtained at surgery, high-risk cancer being defined as unfavorable tumor histology or patients with FIGO stage ≥1b.ResultsPreoperative unfavorable tumor histology was seen in 64 women and correctly identified 63 of 128 high-risk cancers. Preoperative diagnosis of unfavorable tumor histology or myometrial involvement ≥50 %, i.e. judged high-risk, had an area under the curve (AUC), sensitivity, and specificity of 79.5 %, 93.8 %, 65.2 % on non-expert-TVS; 85.5 %, 84.4 %, 86.5 % on expert-TVS, and 85.4 %, 89.6 %, 81.2 % on MRI. AUC values were not significantly different between MRI and expert-TVS, but lower on non-expert-TVS (p < 0.02). However, sensitivity was highest on non-expert-TVS, where a low cutpoint for myometrial involvement was used (included potentially deep and difficult evaluations) in contrast to an exact cutpoint of myometrial involvement ≥50 % used on expert-TVS and MRI.The highest AUC, 88.6 %, was seen when MRI was performed in patients with myometrial involvement ≥50 %, determined on non-expert TVS. Sensitivity was reduced to 85.9 %, while specificity increased to 91.3 %. Thus, MRI was needed for risk classification in only 104 (39 %) patients.ConclusionDiagnostically, expert-TVS and MRI were comparable and superior to non-expert-TVS. However, non-expert-TVS classified all patients with unclear myometrial involvement ≥50 %, and thereby only misdiagnosed 6.2 % of high-risk cases. Non-expert-TVS combined with MRI when myometrial involvement was ≥50 % on non-expert-TVS was a simple and effective method comparable with expert imaging to identify low- and high-risk cancer and select patients for SLND. Addition of MRI to the diagnostic regimen was needed in only 39 % of our patients.

Introduction/Background* The molecular endometrial cancer (EC) classification has proven prognostic impact. However, patients included in previous studies were not always staged by lymphadenectomy (LND) and often received adjuvant treatment (AT). This may have moderated the prognostic effect of the molecular classification. We evaluated the prognostic significance of the molecular classification in high-grade EC patients staged by LND and those without AT. Methodology Targeted DNA-sequencing for pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynecological Cancer Database 2005-2012 to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Analyses were performed on patients staged by LND and on patients without AT. Time to recurrence analyses were performed using the Kaplan-Meier method, log-rank test and Cox proportional hazard's models. Pre-specified multivariate regression analyses were performed including age, ASA class, stage, lymphovascular space invasion and in the LND subgroup a propensity score to correct for confounding by indication. Result(s)* Molecular analysis was successful in 367 EC; 251 patients had undergone LND, see table 1. Median follow-up was 11 years (range 7.5-15.4). Multivariable analysis showed that molecular subgroup was a strong independent prognostic factor for recurrence: p53abn HR 3.88 (95%CI 1.89-7.94, p<0.001) and NSMP HR 4.80 (95%CI 2.14-10.78, p<0.001) compared to MMRd. Figure 1A shows time to recurrence among those patients staged by LND as IA-IB by molecular subgroup. Among 264 patients without AT, 247 (94%) had stage I-II disease and 17 (6%) stage III. None of the patients with POLEmut EC (n=26, 10%) had a recurrence (figure 1B). Multivariable analysis showed that the significant prognostic impact of molecular subgroup was independent of clinicopathological factors. Conclusion* The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among patients staged by LND and those without AT. This implies that the unfavourable prognosis of p53abn EC is not caused by undetected lymph node metastasis. POLEmut EC is inherently associated with an excellent prognosis even in the absence of adjuvant treatment.

The aim of this study was to explore the relationship between the amygdala and human sex drive. We compared amygdalar volume in groups of patients with or without sexual changes after temporal lobe resection and in age-matched neurologically normal subjects. Forty-five patients with intractable temporal lobe epilepsy who underwent surgical resection in the Comprehensive Epilepsy Program at the Austin and Repatriation Medical Centre completed a semistructured interview and questionnaire relating to sexual outcome after surgery. Volumetric analyses of both amygdalae were conducted on the patients' preoperative T-1-weighted magnetic resonance imaging scans and those of 46 neurologically normal controls. Patients who reported a postoperative. sexual increase had a significantly larger amygdalar volume contralateral to the site of their resective surgery than patients with a sexual decrease or no change than control subjects. There was a significant positive relationship between contralateral amygdalar volume and the maximum degree of sexual change. We have demonstrated a relationship between contralateral amygdalar volume and sexual outcome in patients undergoing temporal lobe resection. This finding provides evidence for an important role of the amygdala in regulating human sexual behavior. A larger contralateral amygdala may contribute to the expression of increased or improved sexuality after temporal lobe resection.