Serous Tubal Intraepithelial Carcinoma Research Articles

Abstract B44: Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer, accounting for over 70% of all cases. HGSOC is frequently complicated by the inevitable development of therapeutic resistance, and thus remains an incurable disease. Recent insights supporting the fallopian tube epithelium (FTE) as a point of origin for HGSOC and the serous tubal intraepithelial carcinoma (STIC) as the precursor lesion for a majority of HGSOCs provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Understanding these key molecular processes is essential to inform the development of next-generation therapies. In this study we investigated the role of the ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis. H2Bub1, catalyzed largely by RNF20, is an epigenetic mark with tumor-suppressor properties. The loss of RNF20/H2Bub1 has been linked with cancer progression. We used immunohistochemistry to characterize the expression of H2Bub1 in HGSOC and FTE precursors. We found that H2Bub1 is lost or downregulated in a large proportion of STICs and HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in serous tumorigenesis. Consistent with our findings, analysis of TCGA data shows that the majority of HGSOCs exhibit heterozygous loss of RNF20. Functionally, we demonstrated that shRNA-mediated knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to increase cell migration and clonogenic growth of immortalized FTE cells. To understand the mechanisms underlying these effects, we performed RNA-seq and proteomics profiling (RPPA) in RNF20 knockdown cells. Major changes were observed in a number of structural, metabolic (e.g., glutamine pathway), and cytokines and inflammatory signaling pathways, providing early mechanistic insights for the observed oncogenic phenotypes. In summary, our study identifies that loss of H2Bub1 is an early epigenetic event in HGSOC that rewires glutamine metabolism and certain inflammatory pathways, which may represent unique therapeutic opportunities. Citation Format: Jagmohan Hooda, Marian Novak, Emily MacDuffie, Melissa Song, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, Ronny Drapkin. Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B44.

Abstract B76: Oncogenic Kras and Pik3ca can cooperate with inactivation of various tumor suppressor genes to generate high-grade serous carcinomas in the mouse oviduct

Abstract Recent studies suggest that most “ovarian” high-grade serous carcinomas (HGSCs) actually originate from precursors in the fallopian tubal epithelium (FTE) known as serous tubal intraepithelial carcinomas (STICs). We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen-regulated Cre recombinase in the oviductal epithelium—equivalent to human FTE. We recently employed Ovgp1-iCreERT2 mice to show that FTE-specific inactivation of several different combinations of tumor suppressor genes (TSGs) that are recurrently mutated in human HGSCs—namely Brca1, Trp53, Rb1, and Nf1---results in STICs that progress to HGSC or Müllerian carcinosarcoma over several months, and to widely metastatic disease in a subset of mice. The histopathologic features of the mouse tumors closely resemble those of their human tumor counterparts. The PI3K and RAS signaling pathways are frequently dysregulated in human HGSCs, often via amplification (and much less frequently mutation) of PIK3CA and KRAS, respectively. We wished to determine if mutant Kras or Pik3ca can cooperate with inactivation of various combinations of the aforementioned TSGs to generate oviductal HGSCs in the mouse, and were particularly interested in generating tumors in the context of intact Brca1/2. We found that conditional mutation of Kras (G12D) can cooperate with Brca1, Trp53, Rb1, and/or Nf1 inactivation in the generation of HGSCs in the mouse. Only two TSGs alterations (Trp53 and Rb1) were required for tumor development in the context of mutant Kras. HGSCs and/or carcinosarcomas developed rapidly in the context of mutant Kras and bi-allelic inactivation of Trp53 and Rb1, even when Brca1 and Brca2 were intact. HGSC and/or carcinosarcoma also developed in the oviducts following conditional mutation of Pik3ca (E545K) and various combinations of inactivated Brca1, Trp53, Rb1, and/or Nf1 alleles. When compared to our prior study of mouse tumors arising in the context of TSG inactivation alone, our data show that that 1) oncogenic Kras or Pik3ca accelerates tumor development and progression in mice carrying floxed Brca1, Trp53, Rb1, and/or Nf1 alleles compared to mice with the same TSG defects but without mutant Kras or Pik3ca; 2) oviductal tumorigenesis in the mouse requires fewer TSGs defects when mutant Kras or Pik3ca is also present; and 3) oviductal HGSCs can arise in the context of wild-type Brca1/2. Collectively, these models recapitulate the heterogeneity of human HGSC and should prove useful for testing new approaches for prevention, early detection, and treatment. Citation Format: Yali Zhai, Stephanie Schulman, Neil Khandwala, Eric R. Fearon, Kathleen R. Cho. Oncogenic Kras and Pik3ca can cooperate with inactivation of various tumor suppressor genes to generate high-grade serous carcinomas in the mouse oviduct. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B76.

Abstract IA16: PapGene, PapSEEK, and PapDREAming for early detection of ovarian cancer

Abstract Advances in genomic technologies are revolutionizing how we understand pathogenesis in ovarian cancer. These technologies are critical in developing innovative strategies to diagnose cancer earlier by detecting rare mutant alleles or aberrant methylation marks among a pool of normal DNA. Studies integrating these technologies provide the fundamental scientific underpinning for designing future standards of care to reduce the burden of ovarian cancer through early detection and prevention. This presentation will focus on two related topics. One is to summarize the recent research findings from the Johns Hopkins Ovarian Cancer Early Detection (JHOCD) group in deciphering the major molecular alterations involving in ovarian cancer in situ lesions (serous tubal intraepithelial carcinoma, STIC) and its precursors (including serous tubal intraepithelial lesion, STIL and so-called “p53” signatures) in fallopian tubes. The clinicopathologic and molecular studies we have done have helped define the precursor lesions in many high-grade serous carcinomas (HGSC) of the ovary, the most common and aggressive type of ovarian epithelial cancer. The other focus is to discuss the promise and challenges in applying genetic and epigenetic methods to detect ovarian HGSC. In an effort to replicate the success of cervical cancer screening, several approaches for the early detection of ovarian cancers have been proposed. JHOCD team has first reported the feasibility of using cervical cytology samples to detect ovarian carcinomas. We have extended this original study by determining whether different sample collection methods including cervical cytology specimens, uterine lavage/brush, and blood, alone or in combination with each other or serum CA-125 levels, can achieve a better sensitivity and specificity. The objective of JHOCD is to facilitate the proposed clinical studies to assess the clinical benefit in applying the aforementioned molecular diagnostics for early ovarian cancer diagnosis in high-risk women (including those carrying BRCA mutations). Citation Format: Ie-Ming Shih. PapGene, PapSEEK, and PapDREAming for early detection of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA16.

Abstract B58: Progesterone receptor (PR) isoforms drive distinct cell-cell interactions and gene expression programs in human fallopian tube models of early HGSOC

Abstract High-grade serous ovarian carcinoma (HGSOC), the most prevalent and aggressive form of ovarian cancer (OC), contains abundant receptors for the ovarian steroid hormones, estrogen (ER; 76%) and progesterone (PR; 35%). These receptors contribute to the development of breast and reproductive tract cancers via complex mechanisms. Estrogen, acting through ERalpha, is well accepted as a stimulatory hormone while progesterone is thought to be a protective factor that reduces OC risk. Our understanding, however, of the molecular and cell-type specific mechanisms of PR isoform action in the initiation and progression of OC is limited. Therefore, to investigate altered PR isoform signaling in early-stage HGSOC, we utilized p53-dominant negative mutant fallopian tube epithelial (FTE) cells to generate stable cell lines expressing either PR-A or PR-B. Progestin (R5020) treatment of 2D adherent cultures revealed functional PR signaling through MAPK-dependent PR S294 phosphorylation as well as isoform specific expression of PR target genes encoding adhesion molecules (e.g., HEF1), cell cycle regulators (e.g., FOXO1), and glucocorticoid signaling proteins (e.g., CRISPLD2, NDRG1). In order to mimic early dissemination of FTE cells from serous tubal intraepithelial carcinoma (STIC) lesions, a precursor for the majority of HGSOCs, we established a 3D spheroid culture model. Interestingly, we observed that PR expression greatly increased the formation, size, and number of total spheroids compared to PR-negative controls. Progestin treatment resulted in additional enhancement of spheroid size with distinct morphologic differences observed between PR-A and PR-B expressing lines. Furthermore, progestin-treated cells grown as 3D spheroids exhibited increased basal PR protein and PR S294 phosphorylation levels relative to cells maintained in 2D adherent cultures, suggesting that hyperactivation of PRs occurs via cell-cell interactions, in part conferred by 3D architecture. Both PR-A and PR-B spheroids secreted matrix proteins such as fibronectin and other EMT biomarkers (e.g., integrin alpha 5) and progestin treatment modulated the PR isoform-specific expression of these markers. Preliminary RNA-seq analyses, comparing PR-A and PR-B spheroids, revealed differential expression of genes encoding pathways that regulate cell adhesion and cell movement as well as cytokine signaling and cell metabolism. Our results highlight the importance of cell context in understanding PR action and suggest that activation of PR signaling promotes and enhances the formation of nonadherent 3D structures in an isoform-specific manner. Such effects of progesterone are predicted to influence the shedding, aggregation, and dissemination of early FTE lesions. These preliminary findings demonstrate the importance of understanding the impact of steroid hormone receptors, including PR isoforms, on early OC development. Citation Format: Megan I. Seibel, Angela Spartz, Nuri Temiz, Laura J. Mauro, Carol A. Lange. Progesterone receptor (PR) isoforms drive distinct cell-cell interactions and gene expression programs in human fallopian tube models of early HGSOC. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B58.

Abstract A63: Estrogen receptor signaling in fallopian tube epithelia of BRCA mutation carriers

Abstract Background: The most common and aggressive type of epithelial ovarian cancers (EOC) is high-grade serous carcinoma (HGSC), which accounts for 90% of ovarian cancer deaths. HGSC is the predominant histotype associated with BRCA1 and BRCA2 mutations. Prophylactic surgery in BRCA mutation carriers has implicated the fallopian tube epithelium (FTE), a hormonal responsive tissue, as the etiologic site of origin for HGSC. Estrogen and its receptors are major regulators of growth and differentiation in normal ovaries and fallopian tubes, and its mutagenic properties have been linked to ovarian carcinogenesis. Estrogen receptors (ER) are rarely mutated, amplified, or deleted in HGSC, yet only 10% of patients respond to antiestrogen treatment. TP53 mutations in the form of the p53 signature have been found in serous tubal intraepithelial carcinomas (STIC) and are ubiquitously present in patients with HGSC. We hypothesized that in the presence of dysfunctional p53, subsequent promiscuous binding of ER will yield aberrant signaling, contributing to cellular transformation. Methods: We used our previously published gene expression profiles to generate a candidate gene list, which was chosen based on the presence of known estrogen-responsive elements. We analyzed expression of 6 ER responsive genes using data collected from laser capture microdissection in normal FTE tissues. Tissue microarray analysis (TMA) was also performed on a subset of HGSC tumor samples from this cohort, staining for PR, ER, and p53, and expression was analyzed alongside their respective outcome and overall survival Finally, to mimic the in vivo environment of early carcinogenesis, FTE-normal and FTE-p53 mutant cell lines were established and treated with 100nM estradiol, an estrogen analog, to observe changes in response. Results: Preliminary data showed that FTE-BRCA and FTE-nonBRCA seemingly look and express ER and PR proteins similarly. Underlying these morphologic similarities is a potential haploinsufficiency predisposing FTE-BRCA to cytotoxic stresses. Microarray gene expression of laser captured FTE-BRCA and FTE-nonBRCA showed varied levels of ER mRNA expression across samples (n=25) while PR transcript levels change dynamically. The data generated have facilitated the development of gene signatures and biomarkers that will predict response to antiestrogen therapy and identify patients who will benefit from hormonal therapies. Citation Format: Leah V. Dodds, Omar Nelson, Patricia Shaw, Anca Milea, Ramlogan Sowamber, Sophia HL George. Estrogen receptor signaling in fallopian tube epithelia of BRCA mutation carriers. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A63.

Abstract 5142: Elevated glycolysis in pre-malignant ovarian cancer

Abstract Ovarian cancer is the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy. High-grade serous ovarian carcinoma (HGSC) originates mainly from the fallopian tube epithelium, and is characterized by TP53 mutation identified in all HGSCs as well as the fallopian tubal precursor of serous tubal intraepithelial carcinomas (STICs). The loss of a functional TP53 is an early event in the malignant transformation of fallopian tube epithelium. We have established 4 primary cell cultures of normal fallopian tube epithelial (FTE) cells, and further generated immortalized FTE cells using SV40 large plus small T antigens (FTE-TAg) to disrupt TP53 function. This model mimics the primary lesions of ovarian cancer and is suitable to identify biomarkers and molecular targets of ovarian cancer. Therefore, we compared the secretomes of primary FTE cells with that of their parental isogenic pairs FTE-TAg cells using mass spectrometry analysis. We identified 813 proteins, 228 of which were differentially expressed. Ingenuity Pathway Analysis (IPA) core analysis revealed glycolysis as a major canonical pathway. Overexpression of key enzymes of glycolytic pathway was confirmed by IHC in human STIC lesions. Molecular mechanisms of glycolysis regulation in premalignant lesion of ovarian cancer were determined. Role of glycolysis in the establishment of premalignant ovarian cancer microenvironment (PME) was characterized. Prevention approaches targeting glycolysis were tested in transgenic animal model of ovarian cancer. Citation Format: Anna E. Lokshin, Mounia Alaoui El Azher, Liudmila Velikokhatnaya, Denise Prosser. Elevated glycolysis in pre-malignant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5142.

Non-Neoplastic Lesions that may Mimic Serous Tubal Intra-Epithelial and Invasive Carcinoma of the Fallopian Tube: Morphological and Immunohistochemical Analysis

Non-Neoplastic Lesions that may Mimic Serous Tubal Intra-Epithelial and Invasive Carcinoma of the Fallopian Tube: Morphological and Immunohistochemical Analysis

Non-Neoplastic Lesions that may Mimic Serous Tubal Intra-Epithelial and Invasive Carcinoma of the Fallopian Tube: Morphological and Immunohistochemical Analysis

Non-Neoplastic Lesions that may Mimic Serous Tubal Intra-Epithelial and Invasive Carcinoma of the Fallopian Tube: Morphological and Immunohistochemical Analysis

Management of STIC lesions in risk-reducing bilateral salpingo-oophorectomy (RRBSO)

Objective: Serous tubal intraepithelial carcinoma (STIC) is considered the precursor of many ovarian and primary peritoneal serous carcinomas in BRCA mutation-positive women. STIC are discovered incidentally in the fallopian tubes via risk-reducing salpingo-oophorectomy in approximately 5%–7% of women. Unfortunately, the biological and clinical relevance of these lesions in BRCA mutation-positive women is unknown. The purpose of this study was to review the incidence of STIC lesions in women undergoing risk-reducing salpingo-oophorectomy with a BRCA mutation compared to those without a mutation and their outcomes in follow-up.

Neurotensin signaling pathway as a potential therapeutic target in high-grade serous ovarian cancer

Objective: The presence of serous tubal intraepithelial carcinoma (STIC) in the fallopian tube (FT) is used to designate FT rather than ovary as the site of tumor origin in high-grade serous ovarian carcinomas (HGSOC). Based on gene profiling, we have identified neurotensin (NTS) as significantly over-expressed in HGSOC associated with STIC, but the role of NTS in HGSOC remains unclear. The objective of this study was to investigate the expression of NTS and its receptors in HGSOC and to test whether the neurotensin (NTS)-signaling pathway could be used as a therapeutic target.

Opportunistic Salpingectomy at the Time of Benign Laparoscopic Hysterectomy: Assessment of Possible Complications and Histopathological p53-Signatures.

Introduction The aim of this study is to assess the prevalence of tubal histopathological abnormalities (serous tubal intraepithelial carcinoma STIC and p53 signatures) and the prevalence of perioperative and postoperative complications related to opportunistic laparoscopic salpingectomy in a low risk population. Materials and Methods In this observational prospective cohort, prophylactic bilateral salpingectomy during benign laparoscopic hysterectomy was systematically performed in 100 consecutive women. Peri- and postoperative complications were registered. Duration of salpingectomy and post-salpingectomy blood loss were also measured. Histopathological and immunohistochemical analysis with anti-p53 antibody were performed on the whole fallopian tubes according to a specific and validated protocol. Results Laparoscopic salpingectomy was always possible without any peri- or postoperative complication attributable to the salpingectomy itself. The mean duration was 428 seconds (354 – 596) and the blood loss was 9 cm 3 (2 – 15). Using histopathological and immunohistochemical assessment with anti-p53 antibody on 199 fallopian tubes (99 bilateral salpingectomies and one unilateral salpingectomy because of previous salpingectomy for ectopic pregnancy), there was a prevalence of 5.52% (11/199) of p53 signatures. No STIC were observed and no associated cancer. Conclusions Laparoscopic salpingectomy is both feasible and innocuous during benign hysterectomy. Meticulous histopathologic examination of the tubes may reveal specific abnormalities.

Bilateral salpingectomy with delayed oophorectomy for ovarian cancer risk reduction: A pilot study in women with BRCA1/2 mutations

ObjectiveRisk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA1/2 mutation carriers, but the adverse effects of the associated early-onset surgical menopause are problematic. Despite suggestive evidence, no data demonstrate whether bilateral salpingectomy alone lowers the risk of developing ovarian cancer in BRCA mutation carriers. We conducted a pilot study of bilateral salpingectomy with delayed oophorectomy (BS/DO) in BRCA mutation carriers to determine the safety and acceptability of the procedure. MethodsIn this prospective, multicenter, non-randomized pilot study, pre-menopausal BRCA1/2 mutation carriers aged 30 to 47 years chose screening, RRSO, or BS/DO. For those undergoing BS/DO, the delayed oophorectomy was recommended at age 40 years for BRCA1 and age 45 years for BRCA2 patients. We compared surgical and psychosocial outcomes between time points and between arms. ResultsOf the 43 patients enrolled, 19 (44%) chose BS/DO, 12 (28%) chose RRSO, and 12 (28%) chose screening. The cohort was 37% BRCA1 carriers and 63% BRCA2 carriers. One serous tubal intraepithelial carcinoma (STIC) was found in an RRSO patient, and no cases of occult ovarian cancers were found. There were no surgical complications. Twelve months after surgery, responses on the Cancer Worry Scale indicated decreased worry in the BS/DO (P < 0.0001) and RRSO (P = 0.01) arms, while responses on the State Anxiety Inventory indicated decreased anxiety in the BS/DO arm (P = 0.02) compared with preoperative responses. ConclusionsIn this pilot study, BRCA mutation carriers who underwent bilateral salpingectomy had no intraoperative complications, were satisfied with their procedure choice, and had decreased cancer worry and anxiety after the procedure.

Evaluation of Screening and Risk Reducing Surgery for Women Followed in a High Risk Breast/Ovarian Cancer Clinic [25A

INTRODUCTION: Up to 20% of ovarian cancers are attributed to inherited predispositions, however current screening methods (Ca-125 and pelvic ultrasound) do not improve outcomes compared to risk-reducing (RR) surgery. The study objective was to evaluate surgical outcomes of women followed in an academic center’s High-Risk Breast/Ovarian Cancer (HBOC) clinic following RR surgery. METHODS: Retrospective chart review of women from the past decade who underwent RR surgery in a HBOC clinic. Surgical outcomes, pathology, pre-operative screening results, and pre-/post-operative cancer diagnoses were evaluated. RESULTS: One hundred and eighty-six high risk women were identified with a mean age of 50.2 years and a mean BMI of 28.9 kg/m2 at the time of surgery. The majority (106; 57%) had strong family history of ovarian cancer without an identified mutation but the rest had deleterious mutations (BRCA2-17.7%, BRCA1-15.1%, Lynch 3.2%, or p53 0.5%). The most common procedure was a risk-reducing bilateral salpingo-oophorectomy with or without hysterectomy (RRBSO, 88.7%). All women underwent the SEE-FIM protocol with extensive pathologic analysis which found 2 (0.8%) invasive ovarian cancers (1 ovary/tube carcinosarcoma, 1 granulosa cell), 3 (1.6%) serous tubal intraepithelial carcinomas (STIC), and 1 fallopian tube cancer (0.8%). All tubal pathology was diagnosed in women with documented BRCA mutations. No cancers were found on screening. CONCLUSION: Among all high-risk women undergoing RR surgery, about 3% are ultimately diagnosed with a STIC or an ovarian cancer of which none were identified on screening. All STIC and tubal cancers were diagnosed in women with BRCA mutations (6.6% rate).

Risk of Ovarian Malignancy in Patients Undergoing Surgery for an Adnexal Mass at a High-Volume Cancer Center [36A

INTRODUCTION: To characterize a cohort of patients presenting to a high-volume cancer center with an adnexal mass (AM), reporting pathologic outcomes and risk of malignancy. METHODS: All new visits to the gynecology service were prospectively screened from July 1, 2015-5/31/2017. Patients with ovarian complaints were categorized prospectively and followed through treatment. AM was defined as a pelvic mass suspected to originate from the adnexa without apparent metastatic disease based on available clinical and radiographic studies. Clinicopathologic data were collected and analyzed. RESULTS: 7690 new visits were screened and 2964 patients with an ovarian complaint were categorized: AM 35%, suspected advanced ovarian cancer (ovca) 28%, recurrent ovca 13%, hereditary ovca syndrome 14%, endocrine ablation 8%, other 2%. Of the 1046 with AM, 2% had evidence of metastatic disease on preoperative imaging, 40% were recommended observation, and 58% were managed surgically. For the 607 managed surgically, final pathology showed: benign 74%, non-ovarian malignancy 12%, ovca 8%, borderline tumor 5%, serous tubal intraepithelial carcinoma &gt;1%, no pathology available &gt;1%. Of the 51 patients diagnosed with ovca, median age was 57(27-79 years), median CA125 67 U/ml(9-353 U/ml), and median preoperative AM size was 9.8cm(2.6-21.4cm). Final histologic diagnosis was: epithelial ovca 40(78%), sex cord stromal tumor 5(9.8%), germ cell tumor 1(1.9%), other 5(9.8%). The most common epithelial histology was high grade serous 18(45%). CONCLUSION: In patients who underwent surgery for AM with no radiologic evidence of metastatic disease at a high-volume cancer center, risk of ovca was 8% with the majority of patients having benign disease.

Outcome and Prognostic Impact of Surgical Staging in Serous Tubal Intraepithelial Carcinoma: A Cohort Study and Systematic Review

The optimal management of breast cancer susceptibility gene (BRCA)1/2 carriers with isolated serous tubal intraepithelial carcinoma (STIC) found at risk-reducing salpingo-oophorectomy (RRSO) is unclear. The prevalence of occult carcinoma and STIC in a consecutive series of BRCA1/2 carriers undergoing RRSO is reported. The outcome of staging procedures in BRCA1/2 carriers with isolated STIC at RRSO as well as the relationship between staging, chemotherapy treatment and risk of recurrence was assessed via a systematic review of the literature. Our series included 235 BRCA1/2 carriers who underwent RRSO. Federation of Gynaecology and Obstetrics stage IA carcinoma or STIC was found at RRSO in three (1.3%) and two (0.9%) patients, respectively. A systematic review of the literature included 82 BRCA1/2 carriers with isolated STIC found at RRSO. In 13/82 (16%) cases with STIC, staging was reported. In none of these cases staging revealed more advanced disease. Recurrent disease was found in four of 36 patients with reported follow-up. The estimated risk of recurrence in patients with isolated STIC at RRSO was about 11% (95% confidence interval 3–26%) after a median follow-up of 42 months (range 7–138). No recurrences were reported in those patients with STIC at RRSO who underwent staging or received chemotherapy. We found 1.3% occult carcinoma and 0.9% STIC at RRSO in our cohort of BRCA1/2 carriers. A systematic review of the literature suggests that additional treatment after RRSO, i.e. staging and/or chemotherapy, is associated with a lower risk of recurrence. However, data on staging and follow-up are limited.

Pathology findings and clinical outcomes after risk reduction salpingo-oophorectomy in BRCA mutation carriers: a multicenter Spanish study.

To determine the incidence of serous tubal intraepithelial carcinoma (STIC) after risk reduction salpingo-oophorectomy(RRSO), and to describe oncological outcomes after RRSO. BRCA pathogenic mutation carriers who had undergone an RRSO were evaluated in this retrospective multicenter observational study. Patients were only included when fallopian tubes were analyzed following the protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Surgeries were performed between June 2010 and April 2017 at eight Spanish hospitals. A total of 359 patients met the inclusion criteria. STIC was diagnosed in 3 (0.8%) patients; one of them underwent surgical staging due to positive peritoneal washing, with absence of disease at the final pathology report. None of the three patients received adjuvant chemotherapy and were free of disease at last follow-up. Fallopian tube and ovarian carcinoma were diagnosed in 5 (1.4%) and 1 (0.3%), respectively. At a median (range) follow-up time of 29 (3-92) months, five patients had a newly diagnosed breast cancer. Other types of cancer, which were diagnosed during the follow-up time, included: serous primary peritoneal carcinoma (n = 1), serous endometrial carcinoma (n = 1), colon (n = 1), pancreas (n = 1), jaw (n = 1), and lymphoma (n = 1). Seven patients died due to different types of cancer: breast (n = 4), pancreas (n = 1), jaw (n = 1), and colon (n = 1). The incidence of STIC after RRSO in BRCA mutation carriers is low (0.8%) and it presents an excellent oncological outcome. Patients after RRSO, however, run the risk to develop other types of cancer during follow-up and should be properly advised before the prophylactic surgery.

STAT3/PIAS3 Levels Serve as "Early Signature" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube.

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states.Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739-50. ©2018 AACR.

Processing of fallopian tube, ovary, and endometrial surgical pathology specimens: A survey of U.S. laboratory practices

ObjectiveMany high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications. MethodsWe distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (χ2) tests for categorical variables. Free text comments were qualitatively reviewed. ResultsSurvey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p < 0.05). In specimens from surgery for benign indications in which initial microscopic sections showed an unanticipated suspicious finding, 75.9% of laboratories reported using SEE-Fim to process the remainder of the specimen (94.8% academic versus 76.4% non-academic, p < 0.01), and 84.6% submitted the entire fimbriae. ConclusionsChanges in the theories of pathogenesis of high-grade serous carcinoma have led to implementation of pathology specimen processing protocols that include detailed analysis of the fallopian tubes. These results have implications for interpreting trends in cancer incidence data and considering the feasibility of developing a bank of gynecologic tissues containing STIC or early cancer precursors.

Peritoneal carcinomatosis after risk-reducing surgery in BRCA1/2 mutation carriers.

Risk-reducing salpingo-oophorectomy (RRSO) is recommended for BRCA1/2 mutation carriers because of their increased risk of ovarian carcinoma. Despite RRSO, metachronous peritoneal carcinomatosis occasionally is diagnosed. The literature was searched for BRCA1/2 mutation carriers with peritoneal carcinomatosis after risk-reducing surgery. The authors were asked for additional data. Clinical and histopathological data were descriptively analyzed. Cases were compared with a single-institution control cohort. Of 36 cases, 86.1% concerned BRCA1 mutation carriers. The median age of the patients was 52 years (range, 30-71 years) at the time of risk-reducing surgery and 60 years (range, 37-75 years) at the time of diagnosis of peritoneal carcinomatosis. The median interval between the 2 events was 54.5 months (range, 11-292 months). Peritoneal carcinomatosis was mostly high-grade serous carcinoma. Histopathological details of the RRSO specimens were retrieved in 8 cases; 5 (62.5%) were found to have serous tubal intraepithelial carcinoma and 1 had epithelial atypia. Cases were older (P = .025) at the time of risk-reducing surgery and harbored more serous tubal intraepithelial carcinomas (P<.001) compared with women from the control cohort. Metachronous peritoneal carcinomatosis after risk-reducing surgery occurs predominantly in BRCA1 mutation carriers, usually within 5 years. Data have suggested that surgery at a younger age lowers the rates of peritoneal carcinomatosis. These data can be used in the gynecologic counseling of BRCA1/2 mutation carriers. RRSO should include complete salpingectomy. Detailed histopathological examination of specimens removed during RRSO is essential. Cancer 2018;124:952-9. © 2018 American Cancer Society.

Risk reduction surgery (RRS) for tubo-ovarian cancer in an Irish gynaecological practice: an analysis of indications and outcomes.

High-grade serous carcinoma (HGSC) is the most common tubo-ovarian cancer. The fallopian tube harbours the precursor lesion: serous tubal intraepithelial carcinoma (STIC). Bilateral salpingo-oophorectomy is an effective risk-reducing surgical (RRS) strategy for breast cancer susceptibility gene mutation carriers (BRCAm). The value of RRS in those without defined genetic risk is unknown but these women represent a substantial cohort in prophylactic surgical practice. This is a retrospective review of RRS at an Irish university teaching hospital. One hundred and thirty women underwent RRS; group 1 = 46 BRCAm; group 2 = 19 BRCAm negative/65 genetic status unknown. Group 1 had one occult HGSC. Group 2 had no STIC or cancers and were older and more likely to have hysterectomy and benign pathology. Other pathologies included serous tubal intraepithelial lesions (STIL) (2), p53 signatures (2), endometriosis (6), fibroids/adenomyosis (4) and atypical endometrial hyperplasia (1). More than 60% of women undergoing RRS were BRCAm negative or untested. Counselling of high-risk women without defined germline mutations remains a challenge for gynaecologists because the likelihood of removing STIC lesions or occult invasive cancer is low. Removal of coincidental pathology may give added value to RRS in these women.