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High‐grade serous carcinoma of the ovary, fallopian tube and peritoneum (HGSC), the most common type of ovarian cancer, ranks among the deadliest malignancies. Many HGSC patients have excess fluid in the peritoneum called ascites. Ascites is a tumour microenvironment (TME) containing various cells, proteins and extracellular vesicles (EVs). We isolated EVs from patients' ascites by orthogonal methods and analyzed them by mass spectrometry. We identified not only a set of 'core ascitic EV‐associated proteins' but also defined their subset unique to HGSC ascites. Using single‐cell RNA sequencing data, we mapped the origin of HGSC‐specific EVs to different types of cells present in ascites. Surprisingly, EVs did not come predominantly from tumour cells but from non‐malignant cell types such as macrophages and fibroblasts. Flow cytometry of ascitic cells in combination with analysis of EV protein composition in matched samples showed that analysis of cell type‐specific EV markers in HGSC has more substantial prognostic potential than analysis of ascitic cells. To conclude, we provide evidence that proteomic analysis of EVs can define the cellular composition of HGSC TME. This finding opens numerous avenues both for a better understanding of EV's role in tumour promotion/prevention and for improved HGSC diagnostics. [ABSTRACT FROM AUTHOR]

Introduction: Among industrialized countries, endometrial cancer is a common malignancy with generally an excellent outcome. To personalize medicine, we ideally compile as much information as possible concerning patient prognosis prior to effecting an appropriate treatment decision. Endometrial cancer preoperative risk stratification (ENDORISK) is a machine learning-based computational Bayesian networks model that predicts lymph node metastasis and 5-year disease-specific survival potential with percentual probability. Our objective included validating ENDORISK effectiveness in our patient cohort, assessing its application in the current use of sentinel node biopsy, and verifying its accuracy in advanced stages. Methods: The ENDORISK model was evaluated with a retrospective cohort of 425 patients from the University Hospital Brno, Czech Republic. Two hundred ninety-nine patients were involved in our disease-specific survival analysis; 226 cases with known lymph node status were available for lymph node metastasis analysis. Patients were included undergoing either pelvic lymph node dissection (N = 84) or sentinel node biopsy (N =70) to explore the accuracy of both staging procedures. Results: The area under the curve was 0.84 (95% confidence interval [CI], 0.77-0.9) for lymph node metastasis analysis and 0.86 (95% CI, 0.79-0.93) for 5-year disease-specific survival evaluation, indicating quite positive concordance between prediction and reality. Calibration plots to visualize results demonstrated an outstanding predictive value for low-risk cancers (grades 1-2), whereas outcomes were underestimated among high-risk patients (grade 3), especially in disease-specific survival. This phenomenon was even more obvious when patients were subclassified according to FIGO clinical stages. Conclusions: Our data confirmed ENDORISK model's laudable predictive ability, particularly among patients with a low risk of lymph node metastasis and expected favorable survival. For high-risk and/or advanced stages, the ENDORISK network needs to be additionally trained/improved. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is common malignancy with an excellent prognosis due to its early symptoms—abnormal bleeding. It is still common in some countries to provide a biopsy in asymptomatic patients based on ultrasound findings; even though, it is not supported by the European guidelines. The aim of our study was to find out if there is a prognostic difference among symptomatic and bleeding-free patients with similar clinical histological characteristics. Background: Endometrial cancer is the most common gynecological malignancy in developed countries with no screening available. There is still a tendency to provide invasive bioptic verification in asymptomatic women with abnormal ultrasound findings to diagnose carcinoma in a preclinical phase; even though, it is not supported by European guidelines. Our goal was to determine DFS (disease-free survival), OS (overall survival), and DSS (disease-specific survival) differences between symptom-free and symptomatic (bleeding, or spotting) endometrial cancer patients with similar stage and tumor/clinical characteristics. Methods: All of our patients with endometrial cancer following surgical treatment between 2006 and 2019 were assessed, evaluating risk factors for recurrence and death while focusing on bleeding using univariable and multivariable analysis. Results: 625 patients meeting the inclusion criteria were divided into asymptomatic (n = 144, 23%) and symptomatic (n = 481, 77%) groups. The median follow-up was 3.6 years. Using univariable analysis, symptomatic patients had a three times higher risk of recurrence (HR 3.1 (95% Cl 1.24–7.77), p = 0.016). OS (HR 1.35 (0.84–2.19), p = 0.219) and DSS (HR 1.66 (0.64–4.28), p = 0.3) were slightly worse without reaching statistical significance. In our multivariable analysis, symptomatology was deemed completely insignificant in all monitored parameters (DFS: HR 2.03 (0.79–5.24), p = 0.144; OS: HR 0.72 (0.43–1.21), p = 0.216). Conclusions: The symptomatic endometrial cancer patients risk factor of earlier recurrence and death is insignificantly higher when compared with the asymptomatic cohort. However, multivariable analysis verifies that prognosis worsens with other clinically relevant parameters, not by symptomatology itself. In terms of survival outcome in EC patients, we recognized symptomatology as a non-significant marker for the patient's prognosis. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most common gynecologic malignancy in Europe and usually diagnosed in its initial stage owing to early symptoms of abnormal bleeding. There is no population screening for this disease, although it can sometimes be accidentally diagnosed in asymptomatic patients. Our study aims to determine differences in clinical and tumor characteristics between an asymptomatic and symptomatic group of patients. This unicentric prospective observational study took place in University Hospital Brno between January 2016 and December 2019. A total of 264 patients met inclusion criteria (26% asymptomatic, 74% with reported symptoms). We did not find a statistically significant difference in clinical characteristics (menopausal status, parity, age, BMI, and serum level of CA 125) between groups. According to ultrasound examination, bleeding tumors were larger (19.5 vs. 12.7 mm, p ≤ 0.001). Definitive histology results indicated more frequent lymphovascular space invasion (p < 0.001), along with deep myometrial (p = 0.001) and cervical (p = 0.002) invasion. There was no difference in advanced stages of the tumor. We did not substantiate statistically significant difference in immunohistochemical profile (estrogen and progesterone receptors, L1 cell adhesion molecule, tumor protein p53), which is relevant for tumor recurrence risk and survival capacity. Our conclusions affirmed that bleeding occurs more often among patients with local tumor invasion into the myometrium and cervical stroma. Final International Federation of Gynecology and Obstetrics (FIGO) stage, histology, and immunohistochemical characteristics do not significantly affect symptom appearance. [ABSTRACT FROM AUTHOR]

Aims: To describe the ultrasound features of benign struma ovarii that often mimic ovarian cancer in the background of complex clinical and histopathological pictures.Material and Methods: We retrospectively identified patients with histologically confirmed benign struma ovarii, treated in our institution between 2003-2016 with complete imaging, clinical, nd histopathological data available. Ultrasound findings were drawn from images, and reports using terms and definitions of the International Ovarian Tumor Analysis group and pattern recognition description was applied.Results: In all, 19 patients were identified; 10 with pure and 9 with impure struma. Median age was 47 (range 24-69); 10 (53%) were premenopausal. Only four (21%) patients presented with pain, others were asymptomatic. Using pattern recognition, 74% strumas (14/19) were uni-/multilocular solid or solid tumors. The solid components were roundish with smooth contours. Six struma pearls were detected. The subjective color score was moderate or abundant in the majority of solid components. Only 5 (26%) tumors were purely cystic.Conclusions: The ultrasound characteristics differ widely from typical mature ovarian teratoma. Features such as, solid roundish components with smooth contours, struma pearls, acoustic shadowing and occasionally signs of dermoid are clues and may help preoperatively to differentiate benign struma from malignant adnexal lesions. [ABSTRACT FROM AUTHOR]

Expression of neuroendocrine (NE) markers in primary ovarian non-NE epithelial tumors has rarely been evaluated. The aim of our study was to evaluate the expression of the most widely used NE markers in these neoplasms and to determine any prognostic significance of NE marker expression. The cohort consisted of 551 primary ovarian tumors, including serous borderline tumors, low-grade serous carcinomas, high-grade serous carcinomas (HGSC), clear cell carcinomas, endometroid carcinomas, mucinous borderline tumors, and mucinous carcinomas. Immunohistochemical analysis was performed using antibodies against INSM1, synaptophysin, chromogranin, and CD56 on tissue microarray. Positivity for INSM1, synaptophysin, chromogranin, and CD56 was most frequently observed in mucinous tumors (48.7%, 26.0%, 41.5%, and 100%, respectively). The positivity for these NE markers was mostly restricted to nonmucinous elements distributed throughout the tumor. The mucinous borderline tumor and mucinous carcinomas groups had similar proportions of positivity (mucinous borderline tumor: 53%, mucinous carcinomas: 39%). In the other tumor types, except for HGSC, there was only focal expression (5%-10%) or negativity for NE markers. HGSC showed high CD56 expression (in 26% of cases). Survival analysis was only performed for CD56 in HGSC as this was the only group with sufficient positive cases, and it showed no prognostic significance. Except for mucinous tumors, expression of NE markers in non-NE ovarian epithelial tumors is low. CD56 expression in HGSC occurs frequently but is without diagnostic or prognostic value., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Background: Endometrial cancer is the most common gynecological malignancy in developed countries with no screening available. There is still a tendency to provide invasive bioptic verification in asymptomatic women with abnormal ultrasound findings to diagnose carcinoma in a preclinical phase; even though, it is not supported by European guidelines. Our goal was to determine DFS (disease-free survival), OS (overall survival), and DSS (disease-specific survival) differences between symptom-free and symptomatic (bleeding, or spotting) endometrial cancer patients with similar stage and tumor/clinical characteristics., Methods: All of our patients with endometrial cancer following surgical treatment between 2006 and 2019 were assessed, evaluating risk factors for recurrence and death while focusing on bleeding using univariable and multivariable analysis., Results: 625 patients meeting the inclusion criteria were divided into asymptomatic ( n = 144, 23%) and symptomatic ( n = 481, 77%) groups. The median follow-up was 3.6 years. Using univariable analysis, symptomatic patients had a three times higher risk of recurrence (HR 3.1 (95% Cl 1.24-7.77), p = 0.016). OS (HR 1.35 (0.84-2.19), p = 0.219) and DSS (HR 1.66 (0.64-4.28), p = 0.3) were slightly worse without reaching statistical significance. In our multivariable analysis, symptomatology was deemed completely insignificant in all monitored parameters (DFS: HR 2.03 (0.79-5.24), p = 0.144; OS: HR 0.72 (0.43-1.21), p = 0.216)., Conclusions: The symptomatic endometrial cancer patients risk factor of earlier recurrence and death is insignificantly higher when compared with the asymptomatic cohort. However, multivariable analysis verifies that prognosis worsens with other clinically relevant parameters, not by symptomatology itself. In terms of survival outcome in EC patients, we recognized symptomatology as a non-significant marker for the patient's prognosis.

High grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is the deadliest gynecological disease which results in a five-year survival rate of 30% or less. HGSC is characterized by the early and rapid development of metastases accompanied by a high frequency of ascites i.e. the pathological accumulation of fluid in peritoneum. Ascites constitute a complex tumor microenvironment and contribute to disease progression by largely unknown mechanisms. Methods: Malignant ascites obtained from HGSC patients who had undergone cytoreductive surgery were tested for their ability to induce WNT signaling in the Kuramochi cell line, a novel and clinically relevant in vitro model of HGSC. Next, cancer spheroids (the main form of metastatic cancer cells in ascites) were evaluated with respect to WNT signaling. Kuramochi cells were used to determine the role of individual WNT signaling branches in the adoption of metastatic stem cell-like behavior by HGSC cells. Furthermore, we analyzed genomic and transcriptomic data on WNT/Planar Cell Polarity (PCP) components retrieved from public cancer databases and corroborated with primary patient samples and validated antibodies on the protein level. Results: We have shown that ascites are capable of inducing WNT signaling in primary HGSC cells and HGSC cell line, Kuramochi. Importantly, patients whose ascites cannot activate WNT pathway present with less aggressive disease and a considerably better outcome including overall survival (OS). Functionally, the activation of non-canonical WNT/PCP signaling by WNT5A (and not canonical WNT/β-catenin signaling by WNT3A) promoted the metastatic stem-cell (metSC) like behavior ( i.e. self-renewal, migration, and invasion) of HGSC cells. The pharmacological inhibition of casein kinase 1 (CK1) as well as genetic ablation (dishevelled 3 knock out) of the pathway blocked the WNT5A-induced effect. Additionally, WNT/PCP pathway components were differentially expressed between healthy and tumor tissue as well as between the primary tumor and metastases. Additionally, ascites which activated WNT/PCP signaling contained the typical WNT/PCP ligand WNT5A and interestingly, patients with high levels of WNT5A protein in their ascites exhibited poor progression-free survival (PFS) and OS in comparison to patients with low or undetectable ascitic WNT5A. Together, our results suggest the existence of a positive feedback loop between tumor cells producing WNT ligands and ascites that distribute WNT activity to cancer cells in the peritoneum, in order to promote their pro-metastatic features and drive HGSC progression. Conclusions: Our results highlight the role of WNT/PCP signaling in ovarian cancerogenesis, indicate a possible therapeutic potential of CK1 inhibitors for HGSC, and strongly suggest that the detection of WNT pathway inducing activity ascites (or WNT5A levels in ascites as a surrogate marker) could be a novel prognostic tool for HGSC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: To describe the ultrasound features of benign Brenner tumor in the background of complex clinical and histopathological pictures., Material and Methods: We retrospectively identified patients with histologically confirmed benign Brenner tumor of the ovary who were treated in our institution in 2003-2016, and for whom complete imaging, clinical, perioperative and histopathological data were available in the database. Ultrasound findings were drawn from images and reports using terms and definitions of the International Ovarian Tumor Analysis group and pattern recognition description was applied., Results: Twenty-three patients were identified, most postmenopausal and asymptomatic. On ultrasound, 19/23 tumors were found unilaterally, 4/23 bilaterally, and 82% of tumors were detected in the left ovary. Most Brenner tumors (16/23) contained solid components and revealed no or minimal blood flow by subjective color score upon Doppler examination (19/23, 83%). Calcifications with shadowing were observed in 57% of all Brenner tumors and in 81% of tumors containing solid components. The complex appearance of the tumor misled the sonographers to describe the mass as malignant in 9 cases (39%), and frozen section was performed perioperatively. Surgery was performed via laparoscopy in 11 (48%) and via laparotomy in 12 (52%) cases., Conclusions: The complexity of the ultrasound picture, consisting of features like calcifications with acoustic shadowing, a poorly vascularized solid mass, and a left-sided localization could be signs of a benign Brenner tumor and could preop-eratively help to differentiate between benign and malignant tumor.