Pathologic findings and clinical outcomes in women undergoing risk-reducing surgery to prevent ovarian and fallopian tube carcinoma: A large prospective single institution experience☆
Introduction
Ovarian, fallopian tube, and primary peritoneal carcinoma (collectively referred to as OC) remains one of the leading causes of cancer death in US women, with >22,000 new OC cases and over 14,000 deaths from the disease estimated in 2018 [1]. Approximately 20% of unselected ovarian carcinoma is hereditary and therefore potentially preventable [2]. Women with inherited BRCA1 mutations have a 44–54% risk and BRCA2 mutations have a 17–23% risk of developing OC during their lifetimes [3,4]. Surveillance for OC with transvaginal ultrasound and CA-125 blood tests does not ensure early detection [5] or decrease OC-related mortality [5,6].
Other mutations within genes of the BRCA-Fanconi Anemia pathway and involved in homologous recombination DNA repair (HRR) confer an increased risk of OC, including BRIP1, RAD51C, and RAD51D [[7], [8], [9], [10], [11]]. Mutations in BRCA-Fanconi Anemia genes PALB2 and BARD1 may also increase the risk of OC, although more research is needed [2,10,11]. In addition, mutations in mismatch repair (MMR) genes associated with Lynch Syndrome increase OC risk, including MLH1, MSH2, and MSH6; while the role of PMS2 in ovarian cancer risk is controversial [[12], [13], [14]].
Risk-reducing surgery is an effective strategy for mitigating OC occurrence in women with inherited mutations. Risk-reducing salpingo-oophorectomy (RRSO) reduces OC risk by up to 96% and all-cause mortality by up to 77% in BRCA1 and BRCA2 mutation carriers [15,16]. It is crucial to provide women at high risk of OC with information about risk-reducing surgery given the high mortality of OC. In light of the cancer prevention efficacy of RRSO, National Comprehensive Care Network (NCCN) guidelines state that women with BRCA1 and BRCA2 mutations should be offered RRSO after childbearing, between the ages of 35–40 for those with BRCA1 mutations, and 40–45 for those with BRCA2 mutations [17]. NCCN also advises consideration of RRSO for those with mutations in BRIP1, RAD51C, and RAD51D after childbearing or between 45 and 50 years of age [17]. These guidelines do not currently recommend RRSO for women with mutations in PALB2 and BARD1, citing insufficient evidence of OC risk, though RRSO recommendations for any gene should take into account the individual's family history of ovarian cancer [17].
Some women are diagnosed with an occult invasive or intraepithelial neoplasm at the time of RRSO. Adherence to a high-risk pathology protocol for processing specimens that includes complete serial sectioning of the fallopian tubes, such as the Sectioning and Extensively Examining the FIMbriated End (SEE-FIM) protocol [18], increases the likelihood that occult neoplasms are detected. Previous smaller studies using such a pathology protocol have demonstrated a 4–15% [[19], [20], [21], [22], [23], [24], [25], [26], [27]] rate of occult neoplasm at the time of RRSO, compared to rates of 0–3.1% in prior studies that did not include complete serial sectioning, as previously summarized [19].
A large multi-institutional study (GOG-199) that proscribed serial sectioning at 2–3 mm intervals of the entire fallopian tubes for women undergoing RRSO, reported a surprisingly low rate of fallopian tube intra-epithelial neoplasms (otherwise known as serous intraepithelial carcinomas or STICs) in BRCA1 and BRCA2 mutation carriers (4 of 557, 0.7%). The rate of compliance to this protocol was documented in pathology reports in only 85% of cases, raising concerns about consistency and adequacy of pathological sampling across centers [28].
The objective of our study was to elucidate the rate of occult neoplasia in women undergoing RRSO for genetic risk of OC, using detailed and standardized surgical and pathological protocols in the largest single-institution prospective study to date. Our study also includes a relatively large cohort of women with mutations in genes other than BRCA1/2, a population on which has not been previously reported. We correlate these findings with clinical factors such as age, type of genetic mutation, and history of breast carcinoma. We describe the type of neoplasms found, present follow-up data after diagnosis of occult neoplasm, and include a group of women with negative or unknown genetic testing as a comparison.
Section snippets
Methods
This prospective, observational study was conducted at a single tertiary care center. Women consented to be included in an IRB approved gynecologic oncology tissue bank prior to surgical intervention. The study spans January 1999 until December 2017, a time wherein all fallopian tubes and ovaries from risk-reducing surgeries were serially sectioned at 2–3 mm intervals per a high-risk pathology protocol. Our surgical protocol at risk-reducing surgery included visual inspection of the entire
Results
A total of 644 women underwent risk-reducing surgery. Demographics of the patient population are provided in Table 1. There were 413 mutation carriers (413/644, 64.1%), with the majority of mutation carriers (371/413, 89.8%) having pathogenic BRCA1 or BRCA2 mutations, 192/413 (46.5%) with BRCA1, 177 (42.9%) with BRCA2, and 2/413 (0.5%) with both BRCA1 and BRCA2 mutations. The two women with BRCA1 and BRCA2 mutations were analyzed in the BRCA1 mutation group. There were 27 (6.5%) women with
Discussion
Our study found an overall 4.1% rate of occult neoplasm in mutation carriers undergoing risk-reducing surgery, with the highest frequency in BRCA1 mutation carriers (14/194, 7.2%). The rates for BRCA2 mutation carriers (2/177, 1.1%, chi square, p = .004) and other HRR gene mutations (1/27, 3.7%, chi square, p = .50) were lower in comparison to BRCA1. Notably, those with occult invasive neoplasms were all BRCA1 mutation carriers. The rate of occult neoplasms for BRCA1 and BRCA2 mutation carriers
Author contributions
Dr. Rush and Dr. Norquist had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have provided critical revision of the manuscript for important intellectual content, participated in manuscript writing, and all agree upon the submitted version. Nancy Kelley Jensen fund for Gynecologic Oncology Research (BMN).
Study conceptualization, formal analysis, investigation, methodology, visualization,
Declaration of competing interest
Dr. Elizabeth Swisher has received grant support via the National Institutes of Health, 1R01CA131965. Otherwise, there are no conflicts of interest or disclosures from any of the other authors.
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Cited by (0)
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This study was funded by the National Institutes of Health 1R01CA131965 (EMS) and the Wendy Feuer Research Fund for Prevention and Treatment of Ovarian Cancer.
Funding source: Nancy Kelley Jensen fund for Gynecologic Oncology Research (BMN).
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Present address: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, UW Health Hospital & Clinics, University of Wisconsin – Madison.