High-Grade Serous Carcinoma at Risk-Reducing Salpingo-Oophorectomy in Asymptomatic Carriers of BRCA1/2 Pathogenic Variants: Prevalence and Clinical Factors.

PURPOSE: To investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic variant (PV) carriers. PATIENTS AND METHODS: We included BRCA1/2-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO. RESULTS: Of the 2,557 included women, 1,624 had BRCA1, 930 had BRCA2, and three had both BRCA1/2-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for BRCA1-PV and 46.8 years (27.6-77.9) for BRCA2-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%) BRCA1-PV and 6 (0.6%) BRCA2-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among BRCA1/2-PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective. CONCLUSION: We detected HGSC in 1.5% (BRCA1-PV) and 0.6% (BRCA2-PV) of RRSO specimens from asymptomatic BRCA1/2-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP.

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis.

PURPOSE: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS: From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION: BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

Genomic catastrophe, the peritoneal cavity and ovarian cancer prevention.

The current theory of carcinogenesis for the deadliest of 'ovarian' cancers-high-grade serous carcinoma (HGSC)-holds that the malignancy develops first in the fallopian tube and spreads to the ovaries, peritoneum, and/or regional lymph nodes. This is based primarily on the observation of early forms of serous neoplasia (serous tubal intraepithelial lesions [STILs], and serous tubal intraepithelial carcinomas [STICS]) in the fimbria of women undergoing risk reduction surgery. However, these lesions are uncommon in the general population, confer a low risk (5%) of HGSC following their removal in at-risk women with germ-line BRCA1/2 mutations, and require 4 or more years to recur as intraperitoneal HGSC. These features suggest that isolated STILs and STICs behave as precursors, with uncertain cancer risk rather than carcinomas. Their evolution to HGSC within, or after, escape from the tube could proceed stepwise with multiple biologic events; however, it is unclear whether tubal or ovarian HGSCs encountered in the setting of advanced disease evolved in the same fashion. The latter scenario could also be explained by a 'catastrophic' model in which STICs suddenly develop with invasive and metastatic potential, overwhelming or obscuring the site of origin. Moreover, a similar model might explain the sudden emergence of HGSC in the peritoneal cavity following escape of precursor cells years before. Long-term follow-up data from opportunistic or prophylactic salpingectomy should shed light on where malignant transformation occurs, as well as the timeline from precursor to metastatic HGSC. © 2022 The Pathological Society of Great Britain and Ireland.

Progestin Significantly Inhibits Carcinogenesis in the Mogp-TAg Transgenic Mouse Model of Fallopian Tube Cancer.

Recent studies suggest that the fallopian tube epithelium (FTE) harbors the precursor for high-grade ovarian cancer, creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE is not well characterized. The murine oviduct-specific glycoprotein promotor-driven simian virus 40 large T-Antigen (mogp-TAg) transgenic mouse model develops neoplastic lesions in the fallopian tube in a manner similar to that described in human fallopian tube and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin depo-medroxyprogesterone acetate (DMPA) on fallopian tube carcinogenesis following treatment for 3 and 7 weeks in 5-week-old mogp-TAg mice. Overall, compared with vehicle-treated mice, the fallopian tube of DMPA-treated mice was significantly smaller (P < 0.0005), accumulated fewer p53-positive cells, had normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and had a significantly lower proliferative index (P = 0.001). Accumulation of p53 signatures and serous tubal intraepithelial carcinomas (STIC) in the fallopian tube was significantly reduced in the DMPA (P < 0.0005) treatment group. Moreover, the fallopian tube of the DMPA-treated mice developed significantly less adenocarcinoma compared with vehicle (P < 0.005) at both treatment time points. DMPA treatment significantly induced cleaved caspase-3 (P < 0.0005) in the FTE compared with vehicle suggesting that apoptosis is involved in DMPA-related clearance of abnormal cells from the fallopian tube. These data demonstrate that DMPA targets early events in fallopian tube carcinogenesis by clearing genetically damaged cells, leading to marked reduction in adenocarcinoma, supporting progestins as chemopreventive agents for fallopian tube and ovarian cancers. PREVENTION RELEVANCE: The fallopian tube is thought to harbor the cell of origin for most ovarian cancers. We show in a mouse model of fallopian tube cancer that progestin eradicates the earliest known precancerous lesions and markedly inhibits fallopian tube carcinogenesis, adding to growing preclinical evidence supporting progestins as potent ovarian cancer chemopreventive agents.

Efficacy of risk-reducing salpingo-oophorectomy in BRCA1-2 variants and clinical outcomes of follow-up in patients with isolated serous tubal intraepithelial carcinoma (STIC).

OBJECTIVE: Serous tubal intraepithelial carcinoma (STIC) is currently considered the precursor lesion of pelvic high-grade serous carcinoma. The management of STIC diagnosed after risk-reducing salpingo-oophorectomy (RRSO) in women with BRCA1-2 variants remains unclear. The aim of our study was to evaluate the incidence of STIC, serous tubal intraepithelial lesions (STIL) and occult invasive cancer (OC) and to determine the long-term outcomes of these patients. METHODS: We conducted a retrospective study of patients with BRCA 1-2 variants who underwent RRSO between January-2010 and Dicember-2020 at the Clinic of Gynaecology of University of Padova. INCLUSION CRITERIA: women with a negative pelvic examination at the last screening prior to RRSO, patients with fallopian tubes analysed using the SEE-FIM protocol. EXCLUSION CRITERIA: patients with a positive gynaecologic screening or with ovarian/tubal cancer prior to RRSO. RESULTS: We included 153 patients. STICs were diagnosed in 4 patients (2.6%) and STILs in 6 patients (3.9%). None of the patients with STIC underwent restaging surgery or adjuvant chemotherapy; all patients were followed closely every 6 months. None of the patients developed primary peritoneal carcinomas (PPCs) with a median FUP of 54.5 months (15-106). OC was diagnosed in 3 patients (2%). All patients with OC underwent staging surgery, and one patient developed a peritoneal carcinoma (PC) after 18 months by staging surgery. CONCLUSION(S): The incidence of STIC, STIL and OC after RRSO in BRCA1-2 variants was low. Our results demonstrated that long-term close surveillance in patients diagnosed with STIC should be considered a possible management strategy.

Clinical and pathological outcomes of risk-reducing salpingo-oophorectomy for Japanese women with hereditary breast and ovarian cancer.

BACKGROUND: To clarify the clinical as well as pathological outcomes in Japanese women with germline pathogenic BRCA1/2 variants who underwent risk-reducing salpingo-oophorectomy (RRSO). METHODS: This prospective study examined the rate of occult cancer and primary peritoneal cancer after RRSO at our institution in the period from 2011 to 2020. Clinical records of genetically confirmed patients with germline pathogenic BRCA1/2 variants who desired to undergo RRSO were reviewed. Specimens obtained during RRSO were pathologically diagnosed as per SEE-FIM protocol. All the participants underwent magnetic resonance imaging (MRI) about 1 month preoperatively. RESULTS: One hundred and seventeen women underwent RRSO during this period. Of these, the numbers of women with germline pathogenic BRCA1 and BRCA2 variants were 72 and 45, respectively. The mean observational time after RRSO was 35.8 months. Despite negative preoperative screening results, three (2.6%) serous tubal intraepithelial carcinoma and three (2.6%) invasive carcinomas were identified. Of the three invasive carcinomas cases, two were International Federation of Gynecology and Obstetrics (FIGO) stage I primary fallopian tube cancer, and the third case was double cancer (ovarian cancer and fallopian tube cancer) with FIGO stage IC3. CONCLUSIONS: The rate of occult neoplasms was similar to those reported by studies performed in other countries. Although women with occult cancer were diagnosed with FIGO stage I, the MRI performed 1 month preoperatively did not show any such malignant findings. Thus, RRSO is the only promising method that can improve the prognosis in women with germline pathogenic BRCA1/2 variants.

Pathologic findings and clinical outcomes in women undergoing risk-reducing surgery to prevent ovarian and fallopian tube carcinoma: A large prospective single institution experience.

OBJECTIVES: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of ovarian, fallopian tube (FT), and peritoneal carcinoma (collectively OC). We describe rates of occult neoplasia in the largest single-institution prospective cohort of women undergoing RRSO, including those with mutations in non-BRCA homologous repair (HRR) genes. METHODS: Participants undergoing RRSO enrolled in a prospective tissue bank between 1999 and 2017. Ovaries and FTs were serially sectioned in all cases. Participants had OC susceptibility gene mutations or a family history suggesting OC risk. Analyses were completed in Stata IC 15.1. RESULTS: Of 644 women, 194 (30.1%) had mutations in BRCA1, 177 (27.5%) BRCA2, 27 (4.2%) other HRR genes, and 15 (2.3%) Lynch Syndrome-associated genes. Seventeen (2.6%) had occult neoplasms at RRSO, 15/17 (88.2%) in the FT. Of BRCA1 carriers, 14/194 (7.2%) had occult neoplasia, 8/194 (4.1%) invasive. One PALB2 and two BRCA2 carriers had intraepithelial FT neoplasms. Occult neoplasm occurred more frequently in BRCA1/2 carriers ≥45 years of age (6.5% vs 2.2%, chi square, p = .04), and 211/371 (56.9%) BRCA1/2 carriers had surgery after guideline-recommended ages. Four in 8 (50%) invasive and 2/9 (22%) intraepithelial neoplasms had positive pelvic washings. None with intraepithelial neoplasms developed recurrence or peritoneal carcinoma. CONCLUSIONS: BRCA1 carriers have the highest risk of occult neoplasia at RRSO, and the frequency increased with age. Women with BRCA1/2 mutations often have RRSO beyond recommended ages. One PALB2 carrier had FT intraepithelial neoplasia, a novel finding. Serial sectioning is critical to identifying occult neoplasia and should be performed for all risk-reducing surgeries.

The incidence of occult ovarian neoplasia and cancer in BRCA1/2 mutation carriers after the bilateral prophylactic salpingo-oophorectomy (PBSO): A single-center prospective study.

BACKGROUND: Due to ineffective ovarian cancer (OC) screening programs, prophylactic bilateral salpingo-oophorectomy (PBSO) is suggested for BRCA1/2 genes mutation carriers. The reported incidence of clinically occult neoplasia and OC detected during PBSO varies widely (2-17 %), reflecting differences in studies design. OBJECTIVE: We aimed to prospectively evaluate the incidence of occult neoplasia in specimens collected during PBSO performed in a single tertiary center and to determine the effectiveness of this procedure in BRCA1/2 mutation carriers. STUDY DESIGN: Between January 2010 and October 2016 a total of 564 new germline BRCA1/2 mutation positive women were identified and 71 carriers underwent laparoscopic PBSO. Patients were prospectively followed-up after the surgery and data on operation, age, complications, histological reports and BRCA1/2 gene mutation types were collected and analyzed. RESULTS: Serous tubal intraepithelial carcinoma (STIC) was diagnosed in 7 (9.85 %) and OC in 4 (5.6 %) women (one advanced (FIGO IIIC) and 3 early (FIGO IA/C) stages); total incidence 15.5 %. Women's mean age at the time of surgery was 46.5 years. The mean age of women diagnosed with STIC and OC was 45.9 years (42-64). The mean follow up time for women being diagnosed with OC/STIC was 3.72 years; no recurrence was observed. The median time to perform laparoscopic PBSO was 43 min. (ranging from 25 to 65 min.), no surgical complications occurred during this operation. Interestingly, we found statistically significant (P = 0.0105) enrichment of STIC lesions in BRCA1 c.4035delA (an established Baltic founder mutation) carriers group. CONCLUSION: The incidence of pathological findings in BRCA1/2 mutation carries after PBSO is sufficiently high and our prospective study data supports PBSO as the most effective measure for reducing the risk of OC in BRCA1/2 mutation carriers. A novel finding of the enrichment of STIC lesions in BRCA1 c.4035delA carriers may show important biological differences in OC tumorigenesis between different BRCA1 mutations, which warrant further investigations.

The fallopian tube as origin of ovarian cancer: Change of diagnostic and preventive strategies.

Ovarian cancer is the leading cause of gynecologic cancer death in the world, and its prevention and early diagnosis remain the key to its treatment, especially for high-grade serous carcinoma (HGSC). Accumulating epidemiological and molecular evidence has shown that HGSC originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. Comprehensive molecular analyses and mouse studies have uncovered the key driver events for serous carcinogenesis, providing novel molecular targets. Risk-reducing bilateral salpingo-oophorectomy (RRSO) has been proposed to reduce the subsequent occurrence of serous carcinoma in high-risk patients with BRCA mutations. However, there is no management strategy for isolated precursors detected at RRSO, and the role of subsequent surgery or chemotherapy in preventing serous carcinoma remains unclear. Surgical menopause due to RRSO provides a variety of problems related to patients' quality of life, and the risks and benefits of hormone replacement are under investigation, especially for women without a previous history of breast cancer. An additional surgical option, salpingectomy with delayed oophorectomy, has been proposed to prevent surgical menopause. The number of opportunistic salpingectomies at the time of surgery for benign disease to prevent the future occurrence of HGSC has increased worldwide. Thus, the changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and therapeutic approaches.

Health Care Provider Adherence to Surgical Guidelines for Risk-Reducing Salpingo-Oophorectomy.

OBJECTIVE: To evaluate health care provider adherence to the surgical protocol endorsed by the National Comprehensive Cancer Network and the American College of Obstetricians and Gynecologists at the time of risk-reducing salpingo-oophorectomy and compare adherence between gynecologic oncologists and obstetrician-gynecologists (ob-gyns). METHODS: In this multicenter retrospective cohort study, women were included if they had a pathogenic BRCA mutation and underwent risk-reducing salpingo-oophorectomy between 2011 and 2017. Adherence was defined as completing all of the following: collection of washings, complete resection of the fallopian tube, and performing the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) pathologic protocol. RESULTS: Of 290 patients who met inclusion criteria, 160 patients were treated by 18 gynecologic oncologists and 130 patients by 75 ob-gyns. Surgery was performed at 10 different hospitals throughout a single metropolitan area. Demographic and clinical characteristics were similar between groups. Overall, 199 cases (69%) were adherent to the surgical protocol. Gynecologic oncologists were more than twice as likely to fully adhere to the full surgical protocol as ob-gyns (91% vs 41%, P<.01). Specifically, gynecologic oncologists were more likely to resect the entire tube (99% vs 95%, P=.03), to have followed the SEE-FIM protocol (98% vs 82%, P<.01), and collect washings (94% vs 49%, P<.01). Complication rates did not differ between groups. Occult neoplasia was diagnosed in 11 patients (3.8%). The incidence of occult neoplasia was 6.3% in gynecologic oncology patients and 0.8% in obstetrics and gynecology patients (P=.03). CONCLUSION: Despite clear surgical guidelines, only two thirds of all health care providers were fully adherent to guidelines. Gynecologic oncologists were more likely to follow surgical guidelines compared with general ob-gyns and more likely to diagnose occult neoplasia despite similar patient populations. Rates of risk-reducing surgery will likely continue to increase as genetic testing becomes more widespread, highlighting the importance of health care provider education for this procedure. Centralized care or referral to subspecialists for risk-reducing salpingo-oophorectomy may be warranted.

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Objective: To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction and Synthesis: Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality. Main Outcomes and Measures: Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions. Results: For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy. Conclusions and Relevance: Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.

Retrospective study of a 16 year cohort of BRCA1 and BRCA2 carriers presenting for RRSO: Prevalence of invasive and in-situ carcinoma, with follow-up.

OBJECTIVES: Carriers of BRCA1 and BRCA2 mutations are at increased risk of high grade serous carcinoma and are therefore offered risk-reducing salpingo-oophorectomy (RRSO) by 40-45 years. Most of these carcinomas are believed to arise in the fallopian tube from serous tubal intraepithelial carcinoma (STIC). We conducted a retrospective study on the prevalence of high grade serous carcinoma and STIC in BRCA1/2 carriers presenting for RRSO, and their follow-up. METHODS: Consecutive BRCA1/2 carriers presenting for an RRSO at Erasmus MC (2000-2016) were studied. SEE-FIM pathology protocol was followed from 2010 onwards. For the cases with carcinoma and/or STIC, the histology was reviewed and immunohistochemistry (p53 & MIB-1) was performed. Next Generation Targeted Sequencing (NGTS) for TP53 mutation was used to establish clonality in 2 cases. RESULTS: Of the 527 included patients, 68% were BRCA1, 31.6% were BRCA2, and 0.4% carried both mutations. The prevalence of high grade serous carcinoma was 2.3% (12/527); 59% of these were of tubal origin. High grade serous carcinoma was more common in patients operated on after the recommended age (p = 0.03). Isolated STIC was present in 0.8% (4/527). Two BRCA1 carriers with isolated STIC at RRSO developed peritoneal serous carcinoma >7 years later. Identical TP53 mutations in the peritoneal serous carcinoma and the preceding STIC established their clonal origin. CONCLUSIONS: High grade serous carcinoma is more common in BRCA1/2 carriers presenting for RRSO after the recommended age, and is more often of tubal origin. Longer follow up of patients with STIC at RRSO should be considered.

Distinctive psychological and social experiences of women choosing prophylactic oophorectomy for cancer prevention.

Women known to have significantly elevated ovarian cancer risk due to genetic mutations or family history can reduce this risk by surgically removing both ovaries and fallopian tubes (RRBSO, risk-reducing bilateral salpingo-oophorectomy). We used interpretive phenomenological analysis (IPA) to explore the psychosocial experiences of women who chose RRBSO for cancer prevention. We extended the traditional use of IPA to compare the experiences of women who chose RRBSO for cancer prevention to those of women who underwent similar gynecologic surgery for benign indications. The analysis resulted in three superordinate themes describing women's psychosocial experiences related to RRBSO: (a) psychological facets of cancer risk (b) social support and (c) shared medical decision making. Findings illustrate that women choosing RRBSO for cancer prevention experience heightened psychosocial challenges before and after surgery compared to women undergoing surgery for benign indication. Furthermore, they may need distinct types of information and support from healthcare providers.

The Use of Opportunistic Salpingectomy at the Time of Benign Hysterectomy.

STUDY OBJECTIVE: To delineate the use of opportunistic salpingectomy over the study period, to examine factors associated with its use, and to evaluate whether salpingectomy was associated with perioperative complications. DESIGN: A retrospective cross-sectional study (Canadian Task Force classification II-2). SETTING: The Michigan Surgical Quality Collaborative. PATIENTS: Women undergoing ovarian-conserving hysterectomy for benign indications from January 2013 through April 2015. INTERVENTIONS: The primary outcome was the performance of opportunistic salpingectomy with ovarian preservation during benign hysterectomy. The change in the rate of salpingectomy was examined at 4-month intervals to assess a period effect over the study period. Multivariate logistic regression was performed to evaluate independent effects of patient, operative, and period factors. Perioperative outcomes were compared using propensity score matching. MEASUREMENTS AND MAIN RESULTS: There were 10 676 (55.9%) ovarian-conserving hysterectomies among 19 090 benign hysterectomies in the Michigan Surgical Quality Collaborative in the study period. The rate of opportunistic salpingectomy was 45.8% (n = 4890). Rates of opportunistic salpingectomy increased over the study period from 27.5% to 61.6% (p < .001), demonstrating a strong period effect in the consecutive 4-month period analysis. Salpingectomy was more likely with the laparoscopic approach (odds ratio = 3.48; 95% confidence interval, 3.15-3.85) and among women younger than 60 years of age (odds ratio = 1.60; 95% CI, 1.34-1.92). There was substantial variation in salpingectomy across hospital sites, ranging from 3.6% to 79.9%. Salpingectomy was associated with a 12-minute increase in operative time (p < .001), but there were no differences in the estimated blood loss or perioperative complications. CONCLUSION: The rates of salpingectomy increased significantly over the study period. The laparoscopic approach and younger age are associated with an increased probability of salpingectomy. Salpingectomy is not associated with increased blood loss or perioperative complications.

No. 344-Opportunistic Salpingectomy and Other Methods of Risk Reduction for Ovarian/Fallopian Tube/Peritoneal Cancer in the General Population.

OBJECTIVE: This guideline reviews the potential benefits of opportunistic salpingectomy to prevent the development of high grade serous cancers (HGSC) of the ovary/fallopian tube/peritoneum based on current evidence supporting the fallopian tube origin of disease. INTENDED USERS: Gynaecologists, obstetricians, family doctors, registered nurses, nurse practitioners, residents, and health care providers. TARGET POPULATION: Adult women (18 and older): OPTIONS: Women considering hysterectomy who wish to retain their ovaries in situ have traditionally also retained their fallopian tubes. In addition, women undergoing permanent surgical sterilization have usually undergone tubal ligation using various methods rather than undergoing surgical removal of the entire fallopian tube. EVIDENCE: For the sections "Evidence Supporting the Hypothesis That HGSC Originates in the Fallopian Tube" and "Current Literature on the Effects and Safety of Opportunistic Salpingectomy," relevant studies were searched in PubMed, Medline, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials: "high grade serous cancers ovary," "fallopian tube," "peritoneum," "opportunistic salpingectomy," "epithelial ovarian cancers," "origin," "tubal carcinoma in situ," "BRCA mutation," "prophylactic salpingectomy," "inflammation," "clear cell," and "endometrioid." The initial search was performed in March 2015 with a final literature search in March 2016. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. The total number of studies identified was 458, and 56 studies were included in this review. For the section "Other Factors Influencing the Risk of Developing "Ovarian" Cancers" a general Medline search was carried out using the terms "ovarian neoplasm" and "prevention." The search included papers published from December 2005 to March 2016. Meta-analyses were preferentially selected except where no such review was found. Additional searches for each subheading were also conducted (e.g., "ovarian neoplasm" and "tubal ligation.") Additional significant articles were identified through cross-referencing the identified reviews. For the search for "ovarian neoplasm" and "prevention," 10 meta-analyses were identified. For the search for "ovarian neoplasm" and "tubal ligation," an additional 4 meta-analyses were identified. VALIDATION METHODS: The content and recommendations were drafted and agreed on by the principal authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the SOGC approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation methodology framework (Table 1). The interpretation of strong and weak recommendations is described in Table 2. The summary of findings is available on request. BENEFITS, HARMS, AND/OR COSTS: The addition of opportunistic salpingectomy to a planned hysterectomy or permanent sterilization did not increase rates of hospital readmission (OR 0.91, 95% CI 0.75 to 1.10 and OR 0.8, 95% CI 0.56 to 1.21, respectively) or blood transfusions (OR 0.86, 95% CI 0.67 to 1.10 and OR 0.75, 95% CI 0.32 to 1.73, respectively) but did increase the overall operating time (by 16 minutes and 10 minutes, respectively) in a retrospective review of 43 931 women. The risk of repeat surgery for tubal pathology among women with retained fallopian tubes after hysterectomy was at least doubled (OR 2.13, 95% CI 1.88 to 2.42 in a population-based study of 170 000 women). If general gynaecologists were to consider removal of fallopian tubes at the time of every hysterectomy and sterilization procedure with referral of all patients with HGSC for hereditary cancer counselling and genetic testing, experts project a potential reduction in the rate of HGSC by 40% over the next 20 years. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Gynecologic Oncology of Canada and SOGC. SUMMARY STATEMENTS: RECOMMENDATIONS.

Assessing the Risk of Occult Cancer and 30-day Morbidity in Women Undergoing Risk-reducing Surgery: A Prospective Experience.

STUDY OBJECTIVE: To investigate the incidence and predictive factors of 30-day surgery-related morbidity and occult precancerous and cancerous conditions for women undergoing risk-reducing surgery. DESIGN: A prospective study (Canadian Task Force classification II-1). SETTING: A gynecologic oncology referral center. PATIENTS: Breast-related cancer antigen (BRCA) mutation carriers and BRCAX patients (those with a significant family history of breast and ovarian cancer). INTERVENTIONS: Minimally invasive risk-reduction surgery. MEASUREMENTS AND MAIN RESULTS: Overall, 85 women underwent risk-reducing surgery: 30 (35%) and 55 (65%) had hysterectomy plus bilateral salpingo-oophorectomy (BSO) and BSO alone, respectively. Overall, in 6 (7%) patients, the final pathology revealed unexpected cancer: 3 early-stage ovarian/fallopian tube cancers, 2 advanced-stage ovarian cancers (stage IIIA and IIIB), and 1 serous endometrial carcinoma. Additionally, 3 (3.6%) patients had incidental finding of serous tubal intraepithelial carcinoma. Four (4.7%) postoperative complications within 30 days from surgery were registered, including fever (n = 3) and postoperative ileus (n = 1); no severe (grade 3 or more) complications were observed. All complications were managed conservatively. The presence of occult cancer was the only factor predicting the development of postoperative complications (p = .02). CONCLUSION: Minimally invasive risk-reducing surgery is a safe and effective strategy to manage BRCA mutation carriers. Patients should benefit from an appropriate counseling about the high prevalence of undiagnosed cancers observed at the time of surgery.

Interventions to reduce the risk of ovarian and fallopian tube cancer: A European Menopause and Andropause Society Postition Statement.

BACKGROUND: Ovarian cancer is a leading cause of female gynecological cancer-related death, and there are no effective screening procedures or early diagnostic approaches. AIMS: To examine risk factors and risk-reducing strategies for both sporadic and familial tumors. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: In women with a genetic predisposition to ovarian cancer, salpingo-oophorectomy reduces the risk of ovarian malignancy, and to a lesser degree of breast cancer. Opportunistic bilateral salpingo-oophorectomy and bilateral salpingectomy may also prevent epithelial ovarian cancer. In premenopausal women, bilateral salpingectomy should be preferred to tubal ligation, and be performed when hysterectomy is carried out for benign uterine disease. Hysterectomy and the use of combined oral contraceptives and non-steroid anti-inflammatory drugs are also recognized to reduce the risk of ovarian cancer, as do the prevention of obesity and smoking cessation.

Role of Fallopian Tubes in the Development of Ovarian Cancer.

Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth cause of cancer death in women in the United States. The most common and lethal histologic subtype of epithelial ovarian cancer is high-grade serous carcinoma (HGSC), which generally presents at an advanced stage. HGSC may be associated with BRCA1 and BRCA2 mutations. Historically, HGSC was believed to originate from the ovarian epithelial cells. However, more recent evidence supports the idea that most ovarian cancers originate in the fallopian tube epithelium in both high-risk women and in the general population. Serous tubal intraepithelial carcinomas may ultimately evolve into ovarian or peritoneal cancer. As a result, prophylactic salpingectomy with conservation of the ovaries has become an increasingly more common practice for premenopausal women undergoing risk-reducing surgery. Because the fallopian tube is now recognized as the most common potential site of origin of ovarian carcinoma, there is ongoing research to explore molecular and genetic factors that may be critical in the development of this disease. Further research is needed to identify novel opportunities for early detection and screening of ovarian cancer with the ultimate goal of increasing overall survival.