Serous Tubal Intraepithelial Carcinoma Research Articles

Risk-reducing salpingo-oophorectomy among Chinese women at increased risk of breast and ovarian cancer

BackgroundRisk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of breast and ovarian cancer. We launched a prospective study of women receiving RRSO, including those with mutations in genes beyond BRCA1/2.Patients and methods80 women were enrolled for RRSO with sectioning and extensively examining the fimbriae (SEE-FIM) protocol between October 2016 and June 2022. The majority of participants had inherited susceptibility gene mutations or a family history suggesting ovarian cancer risk, while patients with isolated metastatic high-grade serous cancer of unknown origin were also included.ResultsOverall, two patients had isolated metastatic high-grade serous cancer with unknown origin, and four patients had family histories but refused to take genetic tests. The rest 74 patients harbored deleterious susceptible gene, including 43 (58.1%) with BRCA1 mutation, and 26 (35.1%) with BRCA2 mutation, respectively. Other mutated genes included ATM (1), BRIP1(1), PALB2(1), MLH1(1) and TP53 (1) in each patient. Among the 74 mutation carriers, three (4.1%) cancers were recognized, one (1.4%) was found to have serous tubal intraepithelial carcinoma (STIC), and five patients (6.8%) was diagnosed with serous tubal intraepithelial lesions (STILs). P53 signature was recognized in 24 patients (32.4%). For other genes, MLH1 mutation carrier had endometrial atypical hyperplasia and p53 signature in fallopian tubes. The germline TP53 mutation carrier had STIC in the surgical specimens. Evidence for precursor escape was also recognized in our cohort.ConclusionOur study demonstrated clinic-pathological findings of patients at increased risk of breast and ovarian cancer, and expand the clinical application of SEE-FIM protocol.

MMDAE-HGSOC: A novel method for high-grade serous ovarian cancer molecular subtypes classification based on multi-modal deep autoencoder

High-grade serous ovarian cancer (HGSOC) is a type of ovarian cancer developed from serous tubal intraepithelial carcinoma. The intrinsic differences among molecular subtypes are closely associated with prognosis and pathological characteristics. At present, multi-omics data integration methods include early integration and late integration. Most existing HGSOC molecular subtypes classification methods are based on the early integration of multi-omics data. The mutual interference among multi-omics data is ignored, which affects the effectiveness of feature learning. High-dimensional multi-omics data contains genes unassociated with HGSOC molecular subtypes, resulting in redundant information, which is not conducive to model training. In this paper, we propose a multi-modal deep autoencoder learning method, MMDAE-HGSOC. MiRNA expression, DNA methylation, and copy number variation (CNV) are integrated with mRNA expression data to construct a multi-omics feature space. The multi-modal deep autoencoder network is used to learn the high-level feature representation of multi-omics data. The superposition LASSO (S-LASSO) regression algorithm is proposed to fully obtain the associated genes of HGSOC molecular subtypes. The experimental results show that MMDAE-HGSOC is superior to the existing classification methods. Finally, we analyze the enrichment gene ontology (GO) terms and biological pathways of these significant genes, which are discovered during the gene selection process.

Insulin-like growth factor (IGF) and hepatocyte growth factor (HGF) in follicular fluid cooperatively promote the oncogenesis of high-grade serous carcinoma from fallopian tube epithelial cells: Dissection of the molecular effects.

Incessant ovulation is believed to be a potential cause of epithelial ovarian cancer (EOC). Our previous investigations have shown that insulin-like growth factor(IGF2) and hepatocyte growth factor(HGF) in the ovulatory follicular fluid (FF) contributed to the malignant transformation initiated by p53 mutations. Here we examined the individual and synergistic impacts of IGF2 and HGF on enhancing the malignant properties of high-grade serous carcinoma (HGSC), the most aggressive type of EOC, and its precursor lesion, serous tubal intraepithelial carcinoma (STIC). In a mouse xenograft co-injection model, we observed that FF co-injection induced tumorigenesis of STIC-mimicking cells, FE25. Co-injection with IGF2 or HGF partially recapitulated the tumorigenic effects of FF, but co-injection with both resulted in a higher tumorigenic rate than FF. We analyzed the different transformation phenotypes influenced by these FF growth signals through receptor inhibition. The IGF signal was necessary for clonogenicity, while the HGF signal played a crucial role in the migration and invasion of STIC and HGSC cells. Both signals were necessary for the malignant phenotype of anchoring-independent growth but had little impact on cell proliferation. The downstream signals responsible for these HGF activities were identified as the tyrosine-protein kinase Met (cMET)/mitogen-activated protein kinase and cMET/AKT pathways. Together with the previous finding that the FF-IGF2 could mediate clonogenicity and stemness activities via the IGF-1R/AKT/mammalian target of rapamycin and IGF-1R/AKT/NANOG pathways, respectively, this study demonstrated the cooperation of the FF-sourced IGF and HGF growth signals in the malignant transformation and progression of HGSC through both common and distinct signaling pathways. These findings help develop targeted prevention of HGSC.

Apendektomi sonrası tesadüfen teşhis edilen tubal yüksek dereceli seröz karsinom olgu sunumu

Primary tubal carcinoma is a uncommon tumor of female ganitale system. The clinical approach of primary tubal cancers is similar to primary ovarian cancers. Fallopian tube carcinoma is hard to diagnosed preoperatively because of its uncertain symptoms. Providing optimal cytoreductive surgery is the most important treatment step in ovarian, tubal and peritoneal carcinomas.
 We report a case of serous tubal intraepithelial carcinoma and appendix metastasis. A 65 years old post-menopausal woman (gravida 4, para 3) submitted to an external hospital with lower abdominal pain and acute abdominal symptoms. Appendectomy was performed on the patient with preliminary diagnosis of appenditis. The pathology result was reported as high grade serous carcinoma infiltration. Staging surgery was performed with the diagnosis of carcinoma. Until the final pathology result, the diagnosis was considered as appendiceal metastasis of serous tubal cancer. Our clinical and surgical approach to the case, which was diagnosed incidentally with an appendectomy specimen and reported as high grade tubal serous carcinoma, is presented as a case study.

SPON1 is an independent prognostic biomarker for ovarian cancer

BackgroundOvarian cancer has the worst outcome among gynecological malignancies; therefore, biomarkers that could contribute to the early diagnosis and/or prognosis prediction are urgently required. In the present study, we focused on the secreted protein spondin-1 (SPON1) and clarified the prognostic relevance in ovarian cancer.MethodsWe developed a monoclonal antibody (mAb) that selectively recognizes SPON1. Using this specific mAb, we determined the expression of SPON1 protein in the normal ovary, serous tubal intraepithelial carcinoma (STIC), and ovarian cancer tissues, as well as in various normal adult tissues by immunohistochemistry, and verified its clinicopathological significance in ovarian cancer.ResultsThe normal ovarian tissue was barely positive for SPON1, and no immunoreactive signals were detected in other healthy tissues examined, which was in good agreement with data obtained from gene expression databases. By contrast, upon semi-quantification, 22 of 242 ovarian cancer cases (9.1%) exhibited high SPON1 expression, whereas 64 (26.4%), 87 (36.0%), and 69 (28.5%) cases, which were designated as SPON1-low, possessed the moderate, weak, and negative SPON1 expression, respectively. The STIC tissues also possessed SPON1-positive signals. The 5-year recurrence-free survival (RFS) rate in the SPON1-high group (13.6%) was significantly lower than that in the SPON1-low group (51.2%). In addition, high SPON1 expression was significantly associated with several clinicopathological variables. Multivariable analysis revealed that high SPON1 was an independent prognostic factor for RFS of ovarian cancer.ConclusionsSPON1 represents a prognostic biomarker for ovarian cancer, and the anti-SPON1 mAb could be valuable as an outcome predictor.

Risk-Reducing Salpingectomy And Other Strategies For Prevention Of Ovarian And Tubal Carcinoma

Objective: To provide a review of most current evidence and data for risk-reducing strategies used in prevention of ovarian cancer. Methods of study selection: PubMed was used as a search tool for articles with key words focusing on current strategies on prevention of ovarian cancer such as “risk-reducing salpingectomy, “risk-reducing salpingo-oophorectomy, “salpingectomy with delayed oophorectomy”. General consensus and society guidelines from leading organizations such as Society of Gynecologic Oncology, American Cancer Society, and American College of Obstetricians and Gynecologists were reviewed and summarized in this review article with supporting evidence and research studies on most current riskreduction strategies for prevention of ovarian and tubal carcinoma. Result: There is growing evidence that high-grade serous ovarian carcinoma arises in the fallopian tube in the form of serous tubal intraepithelial carcinoma (STIC). Therefore, opportunistic salpingectomy has been increasingly offered at the time of routine benign gynecologic surgery. Risk-reducing bilateral salpingo-oophorectomy has been shown to reduce risk of ovarian cancer up to 90% and offered to women with high hereditary predisposition for ovarian cancer. Riskreducing salpingectomy with delayed oophorectomy (SDO) has been suggested in younger women to balance the effects of infertility and surgically induced menopause resulting from oophorectomy. Conclusion: Combined oral Contraceptive COCs confer long-term protection against ovarian cancer with reported 20% reduction for every 5 years of use, which have been cited as a confounding factor in most of the published studies. Women who used HRT (estrogen alone or combined estrogen and progesterone) carry 20% higher risk of ovarian cancer compared to never-users. The associated increased risk of cervical and breast cancer with COCs/HTR use, have recently let women prefer the RRSO over COCs for prevention of ovarian cancer. Bilateral risk reducing Salpingo-oophorectomy (RRSO) at the age of 40–45 in BRCA1 and 45–50 in BRCA2 mutation carriers is recommended to be the primary approach for risk reduction of ovarian cancer. There is well-supported evidence of lowering the risk of ovarian cancer in high-risk population by 90%. The American college of obstetrics and gynecology committee opinion, recommended opportunistic salpingectomy for the primary prevention of ovarian cancer in a woman already undergoing pelvic surgery for another indication. Bilateral salpingectomy at the time of cesarean delivery is recommended to replace the tubal ligation as the method of choice for sterilization performed with cesarean delivery. The novel alternative procedure of Risk-reducing Salpingectomy with delayed risk-reducing oophorectomy (RRSO-RRO) have growing attention as a better alternative to improve the menopause-related morbidity and quality of life.

Abstract 6782: Spatial transcriptomics of serous tubal intraepithelial carcinoma and its putative precursor lesions

Abstract Background: Increasing evidence over the past two decades has implicated serous tubal intraepithelial carcinoma (STIC) of the fallopian tube (FT) epithelium as the putative precursor lesion for high-grade serous ovarian cancer (HGSC). Additional atypical lesions of the FT known as p53 signature lesions and serous tubal intraepithelial lesions (STIL) have been proposed as early precursors in the carcinogenic sequence based on morphology, histochemical and genetic studies. Little however is known about the molecular events that drive FT epithelial cells to transform into HGSC. Methods: To elucidate the molecular changes that underlie the progression from p53 signature to STIL to STIC, we performed spatial transcriptomics on formalin-fixed paraffin embedded (FFPE) tissue sections using the Nanostring GeoMx Whole Transcriptome Atlas panel (18,000 protein-encoding gene panel). Our study cohort consisted of 16 representative cases (3 p53 signature cases, 3 STIL cases, 3 STIC lesions, and 7 STIC cases with matched HGSC). Results: We characterized gene expression to a depth of over 9400 genes in these rare precursor cell populations. Our analysis demonstrated that by gene expression profiles, p53 signatures and STIL lesions bear close resemblance to normal FT secretory cells compared to FT ciliated cells or even STIC and invasive HGSC. We identify for the first time, several pathways altered in expression between normal fallopian tube epithelium and early p53 signature lesions including those related to signaling pathways (Trop-2), Wnt pathway (LGR5), identifying new pathways observed in the progression from normal FT cells to precursor intraepithelial lesion. Our data show that STIC lesions bear significant similarities to invasive HGSC by gene expression, especially compared to the earlier precursor lesions (p53 signature and STIL). We observed several alterations in cell-adhesion(EGR1) and signaling pathways, transcription factors (Trop-2) and metabolism that mark the transition from STIC to HGSC, representing possible mechanisms by which these intraepithelial lesions transform into disseminated invasive disease. Conclusion: Our data profile HGSC precursor lesions in high-depth with characterization of over 9400 genes providing new insight into the molecular alterations that characterize these intraepithelial lesions. Our future direction is to pair transcriptomics data with our established spatial proteomics platform (Deep Visual Proteomics) to measure matched spatial protein expression in our cohort. Citation Format: Rahul Krishnan, Lisa Schweizer, Agnes Bilecz, Aasa Shimizu, Rachelle Mendoza, Diane Yamada, Ricardo Lastra, Matthias Mann, Ernst Lengyel. Spatial transcriptomics of serous tubal intraepithelial carcinoma and its putative precursor lesions [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 6782.

Extracellular matrix in high-grade serous ovarian cancer: Advances in understanding of carcinogenesis and cancer biology.

High-grade serous ovarian cancer (HGSOC) is notoriously known as the "silent killer" of post-menopausal women as it has an insidious progression and is the deadliest gynaecological cancer. Although a dual origin of HGSOC is now widely accepted, there is growing evidence that most cases of HGSOC originate from the fallopian tube epithelium. In this review, we will address the fallopian tube origin and involvement of the extracellular matrix (ECM) in HGSOC development. There is limited research on the role of ECM at the earliest stages of HGSOC carcinogenesis. Here we aim to synthesise current understanding of the contribution of ECM to each stage of HGSOC development and progression, beginning at serous tubal intraepithelial carcinoma (STIC) precursor lesions and proceeding across key events including dissemination of tumourigenic fallopian tube epithelial cells to the ovary, survival of these cells in peritoneal fluid as multicellular aggregates, and colonisation of the ovary. Likewise, as part of the metastatic series of events, serous ovarian cancer cells survive travel in peritoneal fluid, attach to, migrate across the mesothelium and invade into the sub-mesothelial matrix of secondary sites in the peritoneal cavity. Halting cancer at the pre-metastatic stage and finding ways to stop the dissemination of ovarian cancer cells from the primary site is critical for improving patient survival. The development of drug resistance also contributes to poor survival statistics in HGSOC. In this review, we provide an update on the involvement of the ECM in metastasis and drug resistance in HGSOC. Interplay between different cell-types, growth factor gradients as well as evolving ECM composition and organisation, creates microenvironment conditions that promote metastatic progression and drug resistance of ovarian cancer cells. By understanding ECM involvement in the carcinogenesis and chemoresistance of HGSOC, this may prompt ideas for further research for developing new early diagnostic tests and therapeutic strategies for HGSOC with the end goal of improving patient health outcomes.

Serous tubal intraepithelial carcinoma detected during benign gynecologic surgery: a case report

High-grade serous carcinoma (HGSC) is the most common type of pelvic cancer among women. Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion of HGSC. Herein, we report a rare occurrence of STIC in patients undergoing surgery for benign indications without a family history of ovarian cancer. A 77-year-old woman underwent total laparoscopic hysterectomy and bilateral salpingo-oophorectomy for uterine prolapse. Pathological examination revealed bilateral STIC without ovarian abnormalities, and no other abnormal findings were noted. Another patient, a 49-year-old woman, underwent laparoscopic total hysterectomy and bilateral salpingectomy for uterine fibroids. STIC lesions were observed in both fallopian tubes. Subsequently, a staging was performed. No additional lesions were found, and the patient was followedup through imaging and blood tests. As reports of STIC lesions are rare, data on their clinical outcomes and management strategies are limited. In this report, we present cases of incidental STIC in benign surgery and discuss its proper interpretation and management. Through the early detection of STIC lesions, patients with risk factors can be identified in advance, which will allow prevention and early detection of ovarian cancer. Opportunistic salpingectomy was also actively discussed in this regard.

Risk-reducing salpingo-oophorectomy for Japanese women with hereditary breast and ovarian cancer: a single-institution 10-year experience.

For women diagnosed with hereditary breast and ovarian cancer, the clinical guidelines recommend risk-reducing salpingo-oophorectomy at age 35-40years or after completion of childbearing. However, there is limited information regarding the current status of risk-reducing salpingo-oophorectomy in Japan. To clarify factors influencing decision-making for risk-reducing salpingo-oophorectomy among Japanese women diagnosed with hereditary breast and ovarian cancer and their clinical outcomes, we analyzed the medical records of 157 Japanese women with germline BRCA pathogenic variants (BRCA1 n=85, BRCA2 n=71 and both n=1) at our institution during 2011-21. Specimens obtained from risk-reducing salpingo-oophorectomy were histologically examined according to the sectioning and extensively examining the fimbriated end protocol. The risk-reducing salpingo-oophorectomy uptake rate was 42.7% (67/157). The median age at risk-reducing salpingo-oophorectomy was 47years. Older age, married state and parity were significantly associated with risk-reducing salpingo-oophorectomy (P<0.001, P=0.002 and P=0.04, respectively). History of breast cancer or family history of ovarian cancer did not reach statistical significance (P=0.18 and P=0.14, respectively). Multivariate analyses revealed that older age (≥45years) and married state may be independent factors associated with risk-reducing salpingo-oophorectomy. Interestingly, the annual number of risk-reducing salpingo-oophorectomy peaked in 2016-17 and has increased again since 2020. The rate of occult cancers at risk-reducing salpingo-oophorectomy was 4.5% (3/67): ovarian cancer (n=2) and serous tubal intraepithelial carcinoma (n=1). Age and marital status significantly affected decision-making for risk-reducing salpingo-oophorectomy. This is the first study to suggest possible effects of Angelina Jolie's risk-reducing salpingo-oophorectomy in 2015 and the National Health Insurance introduced for risk-reducing salpingo-oophorectomy in 2020. The presence of occult cancers at risk-reducing salpingo-oophorectomy supports clinical guidelines recommending risk-reducing salpingo-oophorectomy at younger ages.

Consensus based recommendations for the diagnosis of serous tubal intraepithelial carcinoma: an international Delphi study.

Reliably diagnosing or safely excluding serous tubal intraepithelial carcinoma (STIC), a precursor lesion of tubo-ovarian high-grade serous carcinoma (HGSC), is crucial for individual patient care, for better understanding the oncogenesis of HGSC, and for safely investigating novel strategies to prevent tubo-ovarian carcinoma. To optimize STIC diagnosis and increase its reproducibility, we set up a three-round Delphi study. In round 1, an international expert panel of 34 gynecologic pathologists, from 11 countries, was assembled to provide input regarding STIC diagnosis, which was used to develop a set of statements. In round 2, the panel rated their level of agreement with those statements on a 9-point Likert scale. In round 3, statements without previous consensus were rated again by the panel while anonymously disclosing the responses of the other panel members. Finally, each expert was asked to approve or disapprove the complete set of consensus statements. The panel indicated their level of agreement with 64 statements. A total of 27 statements (42%) reached consensus after three rounds. These statements reflect the entire diagnostic work-up for pathologists, regarding processing and macroscopy (three statements); microscopy (eight statements); immunohistochemistry (nine statements); interpretation and reporting (four statements); and miscellaneous (three statements). The final set of consensus statements was approved by 85%. This study provides an overview of current clinical practice regarding STIC diagnosis amongst expert gynecopathologists. The experts' consensus statements form the basis for a set of recommendations, which may help towards more consistent STIC diagnosis.

A questionnaire-based survey on the diagnostic and therapeutic approaches for patients with STIC in Germany

PurposeDespite the growing understanding of the carcinogenesis of pelvic high-grade serous carcinoma (HGSC) of the ovary and peritoneum and its precursor lesion serous tubal intraepithelial carcinoma (STIC), evidence-based proven recommendations on the clinical management of patients with STIC are lacking so far.MethodsA questionnaire containing 21 questions was developed to explore the clinical experience with patients with the diagnosis of STICs and the diagnostic, surgical and histopathological approaches in Germany. Overall, 540 clinical heads of department in all German gynaecological centres were asked to participate.Results131 questionnaires (response rate 24.3%) were included in this survey. 45.8% of the respondents had treated one to three STIC patients during their career. 75.6% of the respondents performed opportunistic bilateral salpingectomies during other gynaecological surgeries. Most of the participants (31.3%) started with the SEE-FIM (Sectioning and Extensively Examining the FIMbria) protocol in 2014. It was requested by 39.7% centres for prophylactic salpingectomies, by 13.7% for both prophylactic and opportunistic salpingectomies and by 22.1% for neither of both. 38.2%, 1.5% and 24.4% of the participants would use the laparoscopic, transverse and midline laparotomic approach for a surgical staging procedure, respectively. 25.6% (54.7%) of the respondents recommended a hysterectomy in premenopausal (versus postmenopausal) patients with a STIC, 24.4% (88.4%) a bilateral oophorectomy and 50.0% (4.7%) an affected side oophorectomy (all p values < 0.001). Omentectomy, pelvic and para-aortic lymphadenectomy would be performed by 60.5% (64.0%), 9.3% (11.6%) and 9.3% (11.6%) of respondents in premenopausal (versus postmenopausal) patients (all p values > 0.05).ConclusionOur survey highlights significant inconsistency in the management of patients with STIC. Prospective data are urgently needed to elucidate the clinical impact of a STIC lesion and its clinical management.

Frequency of serous tubal intraepithelial carcinoma (STIC) in patients with high grade serous ovarian cancer

ObjectiveSerous tubal intraepithelial carcinoma (STIC) is a known precursor of high-grade serous ovarian cancer (HGSOC). This study aimed to evaluate the proportion of STIC in patients with HGSOC and analyze the STIC-related prognosis in patients with HGSOC. Materials and methodsAll pathology reports at our institution that included bilateral salpingectomies of patients with HGSOC from January 2013 to December 2018 were reviewed by two experienced pathologists. The specimens from the ovaries and the salpinx including fimbria were examined. We analyzed the correlation between STIC and HGSOC and compared the clinical characteristics and STIC-related prognostic outcomes in patients with HGSOC. ResultsEleven of the 76 cases were STIC. BRCA mutations were found in 16.9% of patients with HGSOC. STIC was observed in 30.0% of patients with BRCA mutations and in 14.3% of patients without BRCA mutations. The incidence of STIC in patients with BRCA mutations was approximately twice that in patients without BRCA mutations; however, the difference was not statistically significant (P = 0.231). Further, the 5-year survival rate of patients without STIC appeared to be high; nevertheless, the difference was not statistically significant (59.7% vs. 47.4%, P = 0.633). Moreover, there was no significant difference in disease-free survival rate according to STIC (36.4% vs. 33.1%, P = 0.956). ConclusionSTIC was identified in patients with HGSOC, and STIC incidence was prominent in HGSOC related to BRCA mutation. Although low frequency, STIC was detected in patients without BRCA mutation. Therefore, prophylactic salpingectomy may be useful for prevention of HGSOC.

Abstract P017: Early detection of ovarian cancer in high-risk individuals using circulating miRNAs: The MiDe study

Abstract Background: Epithelial ovarian cancers generally carry a poor prognosis due to late-stage presentation and a high rate of disease recurrence. In contrast, diagnosis of early-stage disease is associated with a high rate of durable remission. Prior studies using archival samples have suggested that a neural network analysis of circulating miRNA expression levels may be an informative biomarker for early-stage ovarian cancer diagnosis. Methods: The miRNA Detection Study (MiDe Study) is a prospective, observational clinical trial open to individuals in all 50 U.S. states. Persons with at least one ovary classified as being at high-risk for ovarian cancer, either due to known genetic predisposition or family history suggestive of possible hereditary breast and ovarian cancer syndrome or Lynch syndrome, are eligible to enroll. Study subjects will submit a blood sample every 6 months for up to 5 years. Neural network analysis of serum miRNA profiles will be correlated with the subsequent diagnosis of ovarian cancer or serous tubal intraepithelial carcinoma, either clinically or at the time of risk-reducing salpingectomy or salpingo-oophorectomy. The primary outcomes are the sensitivity and specificity of the neural network for anticipating a diagnosis of epithelial ovarian cancer or a cancer precursor within 2 years of the index blood sample. The goal recruitment is 1000 study subjects. Based on a presumed cancer incidence of 0.5-1% per year among this population, approximately 25 incident cancers or precursors are expected to be diagnosed over the timespan of the study. Results: Enrollment began in September 2019. As of August 1, 2022, 372 subjects had consented to the study. Among study subjects, 270/372 (72.5%) carry a known mutation in BRCA1/2, 63/372 (16.9%) carry a known mutation in a different high-risk gene (e.g., PALB2, BRIP1), and 39/372 (10.5%) are considered high-risk due to a mutation in a gene potentially related to ovarian cancer (e.g., ATM, CHEK2) or based on family history alone. To date, 215 (57.8%) participants have contributed at least one sample, among whom 90/215 (41.9%) of subjects have contributed multiple blood samples. Among the study subjects who have given a sample, 2/215 (0.9%) have been later diagnosed with ovarian cancer. Conclusions: The MiDe Study seeks to establish the feasibility of a circulating miRNA-based test for early diagnosis of epithelial ovarian cancer among high-risk individuals. The results of this study will clarify the performance of the neural network test among a high-risk population and inform subsequent interventional trials. Citation Format: Kevin M. Elias, Dipanjan Chowdhury, Judy Garber, Ryan C. Buehler. Early detection of ovarian cancer in high-risk individuals using circulating miRNAs: The MiDe study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P017.

L1CAM is required for early dissemination of fallopian tube carcinoma precursors to the ovary

Most ovarian high-grade serous carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). Formation of STIC lesions from FT secretory cells leads to seeding of the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical cells of STIC lesions and contributed to ovarian colonization by upregulating integrins and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study dissemination to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in a L1CAM-dependent manner.

Pathologic Findings at Risk Reducing Surgery in BRCA and Non-BRCA Mutation Carriers: A Single-Center Experience.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.

Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.

High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.

Aetiology, Epidemiology, Histopathology, Classification, Detailed Evaluation, and Treatment of Ovarian Cancer.

There are a minimum of five distinct sub-types of ovarian cancer based on histology, each of which has distinct factors of risk, types of cells, molecular makeups, clinical characteristics, and therapeutic approaches. Ovarian cancer is detected usually at later stages, and there is no reliable screening method. Cytoreductive surgery and chemotherapy which use platinum-containing drugs are the standard treatments used for freshly detected cancer. Chemotherapy, drugs that are anti-angiogenic, poly ADP-ribose polymerase inhibitors, and immunological treatments are all used to treat recurrent cancer. The most frequent type of ovarian cancer to be diagnosed is high-grade serous carcinoma (HGSC), which often responds well to platinum-based chemotherapy when discovered. However, HGSCs commonly relapse and develop increased treatment resistance in addition to the other histologies. As a result, ovarian cancer research is actively focused on understanding the processes causing platinum resistance and developing strategies to combat it. Serous tubal intraepithelial carcinoma is an HGSC precursor lesion. It is one of the early complications seen in ovarian carcinoma. It has been very useful in identifying the people who have a greater chance of developing ovarian cancer and development of strategies to prevent it. This has led to a significant progress for identification of the genes which are found in people with greater chances of development of ovarian carcinoma (for example, the BRCA1 and BRCA2).

Prevalence of Serous Tubal Intraepithelial Carcinoma (STIC) at the Time of Postpartum Contraceptive Procedures during Caesarean Delivery

Background: To assess the prevalence of serous tubal intraepithelial carcinoma (STIC) in women underwent opportunistic salpingectomy at the time of caesarean delivery (CD). Methods: We conducted a retrospective cohort study (2014–2017) of women who received either bilateral total or partial salpingectomy as postpartum permanent contraception procedure during CD. We collected the characteristics of the patients, the type of CD (elective versus unscheduled), the type of surgical procedure and the related complications. We analysed surgical outcomes and calculated the point prevalence of STIC. Results: We enrolled 280 patients. Of these, 107 (38.2%) and 173 (61.8%) underwent respectively total and partial bilateral salpingectomy. Majority of CDs were elective (81.8%); we did not find differences for intra- and post-operative surgical procedure-related complications. Bilateral fimbriated-part of the tube was available for analysis in 245 patients and STIC was identified in only one patient (prevalence of 0.4%). Conclusions: The frequency of STIC in patients undergoing partial or total bilateral salpingectomy during CD is extremely low, less than 1%. Total bilateral salpingectomy can be proposed as post-partum permanent contraception procedure without increasing surgical related complications. Further randomised studies are needed to confirm the benefits and safety of this procedure.

Serous tubal intra-epithelial carcinoma: what do we really know at this point?

Serous tubal intra-epithelial carcinoma (STIC) is the earliest morphologically recognisable step in the development of invasive high-grade serous carcinoma of the fallopian tube. Lesions occurring prior to STIC within the carcinogenic sequence for the pathogenesis of invasive high-grade serous carcinoma include the p53 signature and secretory cell outgrowth (SCOUT). Variable histological criteria have been used for diagnosing STIC, but a combination of morphology and immunohistochemistry for p53/Ki-67 improves interobserver agreement. Half of all carcinomas identified in risk-reducing salpingo-oophorectomy specimens are in the form of STIC; however, STIC also may be incidentally found on occasion in specimens from women at low or average risk of ovarian/tubal/peritoneal carcinoma. TP53 mutation is the earliest known DNA sequence alteration in STIC and almost all invasive high-grade serous carcinomas of the ovary and peritoneum. Data on the clinical behaviour of STIC are limited. While the short-term follow-up in the prior literature suggests a low risk of malignant progression, a more recent meta-analysis indicates a 10-year risk of 28%. STIC probably should be best regarded as a lesion with uncertain malignant potential at present, and future molecular analysis will help to classify those with higher risk of dissemination. This review provides an update on the current knowledge of STIC and related issues.