Search Results (36)

Folate receptor alpha (FRα) is a high-affinity folate transporter overexpressed in various epithelial malignancies, particularly high-grade serous ovarian carcinoma. Given its restricted expression in normal tissues and accessibility in tumors, FRα is an emerging therapeutic target. Immunohistochemistry (IHC) is the standard method for FRα assessment; however, interpretation is semi-quantitative and prone to interobserver variability. This study aimed to evaluate interobserver agreement among 12 pathologists in the IHC assessment of FRα in ovarian cancer, focusing on internal control adequacy, staining intensity, and the percentage of FRα-positive tumor cells. Thirty-seven high-grade serous ovarian carcinoma cases were stained using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay. A reference panel of four expert pathologists established consensus diagnoses. Twelve pathologists independently assessed the slides, recording internal control adequacy, staining intensity (positive vs. negative), and percentage of FRα-positive tumor cells. Interobserver agreement was measured using Fleiss’ kappa and intraclass correlation coefficient (ICC). Agreement on internal control adequacy was almost perfect (κ = 0.84). Substantial agreement was observed for staining intensity (κ = 0.76), while percentage estimation showed almost perfect concordance (ICC = 0.89). Discrepancies were primarily confined to borderline cases (65–85% positivity) and tumors with intermediate staining, reflecting interpretive challenges near clinical decision thresholds. Pathologists demonstrated high reproducibility in FRα IHC assessment, particularly in estimating percentage positivity and control adequacy. These findings support the clinical utility of FRα IHC but underscore the need for standardized scoring criteria and potential integration of digital tools to enhance consistency, especially in borderline cases. Full article

Background/Objectives: According to recent reports, the BRAF^V600E mutation in serous borderline tumors (SBTs) plays a protective role against progression to low-grade serous carcinoma through oncogene-induced senescence. One consequence of this is the appearance of eosinophilic cells (ECs). The aim of the current study was to determine the interobserver reproducibility of ECs and their predictive significance for the detection of the BRAF^V600E mutation in SBTs. Methods: The study was conducted using 63 cases of ovarian SBTs. Three gynecological pathologists, blinded to each tumor’s mutation status, assessed the presence of ECs. Immunohistochemical staining with p16 and Ki-67 was performed to validate ECs. Mutational analysis was carried out using targeted NGS. Results: Genetic analysis revealed 30 BRAF-mutated, 1 NRAS-mutated, and 9 KRAS-mutated SBTs. ECs were identified by the majority of pathologists (two or three) in 78% of the BRAF^V600E-mutated and 11% of the wild-type tumors with other mutations (p < 0.0001). The interobserver reproducibility of the presence of ECs was substantial (κ = 0.66). ECs validated with p16/Ki-67 were identified in 92.6% of the BRAF^V600E-mutated and in 13.8% of the wild-type tumors with other mutations (p < 0.0001). For the ECs identified by the majority of pathologists, the sensitivity and specificity when predicting the BRAF^V600E mutation were 77.8% and 88.9%, respectively. For the ECs validated with p16/Ki-67, the sensitivity and specificity when predicting the BRAF^V600E mutation were 95.3% and 90.5%, respectively. Conclusions: Overall, these results suggest that ECs in SBTs have potential association with the BRAF^V600E mutation. Full article

Background: Tumor recurrence significantly impacts the quality of life and fertility of patients with serous borderline ovarian tumors (SBOT) and early-stage low-grade serous ovarian carcinoma (LGSOC). This study aims to characterize recurrence patterns, identify independent risk factors for recurrence, and develop a nomogram to predict recurrence-free survival (RFS). Methods: We conducted a retrospective case-control study to investigate recurrence in patients undergoing fertility-sparing surgery (FSS) and radical surgery (RS). Logistic regression and Cox regression were used to identify risk factors. Kaplan–Meier analysis was applied to evaluate RFS. A nomogram was developed based on identified variables to predict RFS. Results: Tumor capsule disruption and micropapillary were associated with higher recurrence risk in the FSS group. Non-invasive implants were associated with higher recurrence risk in the RS group. The nomogram prediction model was developed based on identified risk factors. The area under the curve (AUC) for RFS predictions was 0.74 (95% CI: 0.62–0.85) at 3 years and 0.78 (95% CI: 0.67–0.89) at 5 years for the FSS group and 0.87 (95% CI: 0.76–0.98) at 3 years and 0.81 (95% CI: 0.65–0.97) at 5 years for the RS group. Conclusions: We identified the risk factors for recurrence of SBOT and early-stage LGSOC following FSS and RS procedures and developed a predictive model for forecasting RFS. This model provides valuable guidance for patients and clinicians in predicting recurrence risk for patients. Full article

Background: Ovarian cysts (OCs) are a common gynecological issue, with approximately 20% of women developing at least one pelvic mass during their lifetime. The incidence of large ovarian cysts has decreased substantially due to regular gynecological screenings. However, giant ovarian tumors still continue to pose significant diagnostic and therapeutic challenges. Methods: We report two cases of giant ovarian tumors (GOTs). Case 1 involves a 17-year-old woman who presented with a 2-year history of gradual abdominal enlargement, accompanied by repeated attempts at weight reduction. A computed tomography (CT) scan revealed a large tumor. It was excised by laparotomy. Histopathologic examination revealed ovarian cystadenofibroma. Case 2 presents a 25-year-old female who had a 3-month history of progressive, severe abdominal distension and weight gain, accompanied by nausea and diarrhea. CT imaging revealed a giant cystic neoplasm. The cyst was removed by laparotomy. The histopathological study revealed the intestinal–endocervical mucinous borderline tumor. In this context, we performed a narrative literature review, including cases of giant ovarian tumors in young women over the past five years. We centered on diagnoses and management in these cases. Results: The surgical management of both cases was successful, with complete tumor excision and favorable postoperative outcomes. hese cases underscore the importance of including giant ovarian tumors in the differential diagnosis of young women presenting with progressive abdominal distension. The narrative review analyzed 39 relevant publications on the management of giant ovarian tumors in young women. Conclusions: It is important to highlight a possible risk of malignancy, and risk of fatal complications during the surgical removal of giant ovarian cysts (GOCs). To ensure safer and more successful outcomes, multidisciplinary care should be provided. The early detection and diagnosis of OCs are challenging, as patients may not seek medical attention until the tumor has become large enough to cause symptoms. It is crucial to raise awareness among family doctors and other primary care providers (PCPs) regarding OCs to ensure optimal diagnostic and therapeutic management and improve the outcomes for patients with OCs. Full article

Background and Clinical Significance: Borderline ovarian tumors (BOTs) are a rare diagnosis, especially in the adolescent population. This can make initial management and surveillance strategies difficult, given the limited guidelines and experience in this young age group. Case Presentation: We present two cases of recurrent serous BOTs diagnosed in adolescent patients. Both patients were initially treated with fertility-sparing surgery and followed with transabdominal pelvic ultrasounds. Secondary surgical debulking of recurrent disease with uterine preservation was successful in both patients with a long-term disease-free status. Conclusions: Although rare, BOTs can occur in adolescent patients and should be on the differential for ovarian masses in this age group. Fertility-sparing surgical techniques, reproductive endocrinology consultation, surveillance strategies, and hormone replacement therapy should all be taken into consideration when treating adolescent patients with BOTs. Full article

Background/Objectives: Advances in treatment options have barely improved the prognosis of ovarian carcinoma (OC) in recent decades. The inherent heterogeneity of OC underlies challenges in treatment (development) and patient stratification. One hurdle for effective drug development is the lack of patient-representative disease models available for preclinical drug research. Based on quantitative measurement of signal transduction pathway (STP) activity in cell lines, we aimed to identify cell line models that better mirror the different clinical subtypes of OC. Methods: The activity of seven oncogenic STPs (signal transduction pathways) was determined by previously described STP technology using transcriptome data from untreated OC cell lines available in the GEO database. Hierarchal clustering of cell lines was performed based on STP profiles. Associations between cell line histology (original tumor), cluster, and STP profiles were analyzed. Subsequently, STP profiles of clinical OC tissue samples were matched with OC cell lines. Results: Cell line search resulted in 80 cell line transcriptome data from 23 GEO datasets, with 51 unique cell lines. These cell lines were derived from eight different histological OC subtypes (as determined for the primary tumor). Clustering revealed seven clusters with unique STP profiles. When borderline tumors (n = 6), high-grade serous (n = 51) and low-grade (n = 31) OC were matched with cell lines, twelve different cell lines were identified as potentially patient-representative OC cell line models. Conclusions: Based on STP activity, we identified twelve different cell lines that were the most representative of the common subtypes of OC. These findings are important to improve drug development for OC. Full article

Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa. Full article

Ovarian cancer is classified as type 1 or 2, representing low- and high-grade serous carcinoma (LGSC and HGSC), respectively. LGSC arises from serous borderline tumor (SBT) in a stepwise manner, while HGSC develops from serous tubal intraepithelial carcinoma (STIC). Rarely, HGSC develops from SBT and LGSC. Herein, we describe the case of a patient with HGSC who presented with SBT and LGSC, and in whom we analyzed the molecular mechanisms of carcinogenesis. We performed primary debulking surgery, resulting in a suboptimal simple total hysterectomy and bilateral salpingo-oophorectomy due to strong adhesions. The diagnosis was stage IIIC HGSC, pT3bcN0cM0, but the tumor contained SBT and LGSC lesions. After surgery, TC (Paclitaxel + Carbopratin) + bevacizumab therapy was administered as adjuvant chemotherapy followed by bevacizumab as maintenance therapy. The tumor was chemo-resistant and caused ileus, and bevacizumab therapy was conducted only twice. Next-Generation Sequencing revealed KRAS (p.G12V) and NF2 (p.W184*) mutations in all lesions. Interestingly, the TP53 mutation was not detected in every lesion, and immunohistochemistry showed those lesions with wild-type p53. MDM2 was amplified in the HGSC lesions. DNA methylation analysis did not show differentially methylated regions. This case suggests that SBT and LGSC may transform into HGSC via p53 dysfunction due to MDM2 amplification. Full article

According to recent reports, ovarian serous borderline tumor (SBT) harboring the BRAF V600E mutation is associated with a lower risk of progression to low-grade serous carcinoma. Preliminary observations suggest that there may be an association between eosinophilic cells (ECs) and the above-mentioned mutation, so this study aimed to evaluate interobserver reproducibility for assessing ECs. Forty-two samples of SBTs were analyzed for ECs with abundant eosinophilic cytoplasm. Immunohistochemical staining and genetic pro-filing were performed in all cases to verify the BRAF V600E mutation. A BRAF V600E mutation was found in 19 of 42 (45%) cases. Inter-observer reproducibility in the assessment of ECs was substantial (κ = 0.7). The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively. Patients with BRAF-mutated SBTs were significantly younger than those without mutation (p = 0.005). SBTs with BRAF mutation were less likely to be accompanied by non-invasive implants than wild-type SBT: 12% (2/17) versus 33% (6/18). Seven cases were excluded due to incomplete cytoreductive surgery. Nevertheless, Fisher’s exact test showed no significant differences between the two groups (p = 0.228). Overall, this study strengthens the idea that ECs in ovarian SBTs may represent a mutation with prognostic significance, which can serve as a primary screening test for BRAF V600E mutation in this pathologic entity. Full article

Background. Advances in the treatment of gynecological cancer have led to improvements in survival but also an increase in menopausal symptoms, especially in young women with premature iatrogenic menopause. Methods. A narrative review was performed to clarify the possibility of prescribing hormone replacement therapy (HRT) after hormone-dependent gynecological cancers (ovarian cancer [OC], cervical adenocarcinoma [AC], and endometrial cancer [EC]). Results. HRT can be prescribed to patients with early-stage, grade I–II OC who experience bothersome menopausal symptoms non-responsive to alternative non-hormone therapy after optimal surgery. Caution should be exercised in administering HRT after serous borderline tumors and endometrioid OC, and HRT is not recommended in low-grade serous OC. HRT is not contraindicated in AC survivors. After surgery for EC, HRT can be prescribed in women with early-stage low-grade EC. There is not enough data to give indications to patients with advanced EC. Conclusions. HRT can be discussed with patients, evaluating the risks and benefits of hormone-dependent gynecological cancer. Counseling should be performed by gynecologic oncologists experienced in the management of these patients. Full article

This paper aims to elucidate the differentially coexpressed genes, their potential mechanisms, and possible drug targets in low-grade invasive serous ovarian carcinoma (LGSC) in terms of the biologic continuity of normal, borderline, and malignant LGSC. We performed a bioinformatics analysis, integrating datasets generated using the GPL570 platform from different studies from the GEO database to identify changes in this transition, gene expression, drug targets, and their relationships with tumor microenvironmental characteristics. In the transition from ovarian epithelial cells to the serous borderline, the FGFR3 gene in the “Estrogen Response Late” pathway, the ITGB2 gene in the “Cell Adhesion Molecule”, the CD74 gene in the “Regulation of Cell Migration”, and the IGF1 gene in the “Xenobiotic Metabolism” pathway were upregulated in the transition from borderline to LGSC. The ERBB4 gene in “Proteoglycan in Cancer”, the AR gene in “Pathways in Cancer” and “Estrogen Response Early” pathways, were upregulated in the transition from ovarian epithelial cells to LGSC. In addition, SPP1 and ITGB2 genes were correlated with macrophage infiltration in the LGSC group. This research provides a valuable framework for the development of personalized therapeutic approaches in the context of LGSC, with the aim of improving patient outcomes and quality of life. Furthermore, the main goal of the current study is a preliminary study designed to generate in silico inferences, and it is also important to note that subsequent in vitro and in vivo studies will be necessary to confirm the results before considering these results as fully reliable. Full article

The genotyping of long non-coding RNA (lncRNA)-related single-nucleotide polymorphisms (SNPs) could be associated with cancer risk and/or progression. This study aimed to analyze the angiogenesis-related lncRNAs MALAT1 (rs3200401) and MIAT (rs1061540) variants in patients with ovarian cancer (OC) using “Real-Time allelic discrimination polymerase chain reaction” in 182 formalin-fixed paraffin-embedded (FFPE) samples of benign, borderline, and primary malignant ovarian tissues. Differences in the genotype frequencies between low-grade ovarian epithelial tumors (benign/borderline) and malignant tumors and between high-grade malignant epithelial tumors and malignant epithelial tumors other than high-grade serous carcinomas were compared. Odds ratios (ORs)/95% confidence intervals were calculated as measures of the association strength. Additionally, associations of the genotypes with the available pathological data were analyzed. The heterozygosity of MALAT1 rs3200401 was the most common genotype (47.8%), followed by C/C (36.3%). Comparing the study groups, no significant differences were observed regarding this variant. In contrast, the malignant epithelial tumors had a higher frequency of the MIAT rs1061540 C/C genotype compared to the low-grade epithelial tumor cohorts (56.7% vs. 37.6, p = 0.031). The same genotype was significantly higher in high-grade serous carcinoma than its counterparts (69.4% vs. 43.8%, p = 0.038). Multivariate Cox regression analysis showed that the age at diagnosis was significantly associated with the risk of OC development. In contrast, the MIAT T/T genotype was associated with a low risk of malignant epithelial tumors under the homozygote comparison model (OR = 0.37 (0.16–0.83), p = 0.017). Also, MIAT T allele carriers were less likely to develop high-grade serous carcinoma under heterozygote (CT vs. CC; OR = 0.33 (0.12–0.88), p = 0.027) and homozygote (TT vs. CC; OR = 0.26 (0.07–0.90), p = 0.034) comparison models. In conclusion, our data provide novel evidence for a potential association between the lncRNA MIAT rs1061540 and the malignant condition of ovarian cancer, suggesting the involvement of such lncRNAs in OC development. Full article

Our study aimed to analyze the prognosis and reproductive outcomes of patients with advanced-stage serous borderline ovarian tumors (SBOTs) who underwent fertility-sparing surgery (FSS). This study included patients aged ≤ 45 years diagnosed with advanced-stage (International Federation of Gynecology and Obstetrics II and III) SBOTs who were treated with FSS. Conservative surgeries were performed in 65 patients with advanced-stage SBOT with a median age of 28 years (range, 16–44 years). Nine patients had invasive implants. The median follow-up was 81.7 months. Forty-six patients (70.8%) had a relapse (median time to first recurrence, 22.8 months). Thirteen patients subsequently developed recurrence as an invasive disease, and two died due to disease progression. After multivariate analysis, age < 30 years and incomplete cytoreduction were independent risk factors for recurrence. Invasive implants and postoperative residual tumors were significantly associated with shorter disease-free survival. Of 35 patients attempting to conceive, 12 underwent assisted reproductive technology. Additionally, 19 pregnancies, including 15 full-term births, were documented. FSS provides a good chance of reproductive success in women with advanced-stage SBOT who desire fertility preservation, but it has a high recurrence rate and risk of malignancy transformation. Patients with invasive implants should be strictly selected for FSS. Full article

Background: Ultrasound features help to differentiate benign from malignant masses, and some of them are included in the ultrasound (US) scores. The main aim of this work is to describe the ultrasound features of certain adnexal masses of difficult classification and to analyse them according to the most frequently used US scores. Methods: Retrospective studies of adnexal lesions are difficult to classify by US scores in women undergoing surgery. Ultrasound characteristics were analysed, and masses were classified according to the Subjective Assessment of the ultrasonographer (SA) and other US scores (IOTA Simple Rules Risk Assessment-SRRA, ADNEX model with and without CA125 and O-RADS). Results: A total of 133 adnexal masses were studied (benign: 66.2%, n:88; malignant: 33.8%, n:45) in a sample of women with mean age 56.5 ± 7.8 years. Malignant lesions were identified by SA in all cases. Borderline ovarian tumors (n:13) were not always detected by some US scores (SRRA: 76.9%, ADNEX model without and with CA125: 76.9% and 84.6%) nor were serous carcinoma (n:19) (SRRA: 89.5%), clear cell carcinoma (n:9) (SRRA: 66.7%) or endometrioid carcinoma (n:4) (ADNEX model without CA125: 75.0%). While most teratomas and serous cystadenomas have been correctly differentiated, other benign lesions were misclassified because of the presence of solid areas or papillae. Fibromas (n:13) were better identified by SA (23.1% malignancy), but worse with the other US scores (SRRA: 69.2%, ADNEX model without and with CA125: 84.6% and 69.2%, O-RADS: 53.8%). Cystoadenofibromas (n:10) were difficult to distinguish from malignant masses via all scores except SRRA (SA: 70.0%, SRRA: 20.0%, ADNEX model without and with CA125: 60.0% and 50.0%, O-RADS: 90.0%). Mucinous cystadenomas (n:12) were misdiagnosed as malignant in more than 15% of the cases in all US scores (SA: 33.3%, SRRA: 16.7%, ADNEX model without and with CA125: 16.7% and 16.7%, O-RADS:41.7%). Brenner tumors are also difficult to classify using all scores. Conclusion: Some malignant masses (borderline ovarian tumors, serous carcinoma, clear cell carcinoma, endometrioid carcinomas) are not always detected by US scores. Fibromas, cystoadenofibromas, some mucinous cystadenomas and Brenner tumors may present solid components/papillae that may induce confusion with malignant lesions. Most teratomas and serous cystadenomas are usually correctly classified. Full article

The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of MMP7 and MUC16, along with downregulation of PGR, in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target MUC16, MMP7, and MMP9, as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial–mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, and hsa_piR_019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa_piR_020813, miR-16-5p, and hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa_piR_022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment’s effectiveness and the patient’s longevity. Full article