The pathologic and clinical outcomes of risk-reducing salpingo-oophorectomy in asymptomatic carriers of homologous recombination repair gene mutation.

Risk-reducing salpingo-oophorectomy (RRSO) reduces the number of deaths resulting from ovarian, tubal, and breast cancers among carriers of BRCA1/2 pathogenic variants/likely pathogenic variants (PV/LPV). As a result, RRSO has emerged the preferred management strategy for these women [ 1 2 ]. The lifetime risk of ovarian, tubal, and primary peritoneal carcinomas in BRCA PV/LPV carriers has led to the recommendation of RRSO at age 35–40 years for BRCA1 PV/LPV and age 40–45 years for BRCA2 PV/LPV carriers [ 3 ]. Recently, additional genes have been identified that are associated with increased ovarian cancer risk, including BRIP1 , RAD51C , and RAD51D . These genes are associated with a lower risk of ovarian cancer than BRCA1 and BRCA2 , but the risk is significantly higher than in the general population, with lifetime risks ranging from 6 to 15% [ 4 ]. RRSO for women with PV/LPV in BRIP1 , RAD51C , and RAD51D is recommended after childbearing or between 45 and 50 years of age [ 4 ]. Evidence suggests that RRSO is associated with a remarkable reduction of up to 95% in the anticipated risk of ovarian cancer [ 5 ]. However, a subset of asymptomatic women undergoing RRSO was diagnosed with invasive or intraepithelial neoplasms. The importance of implementation of a standardized tissue processing protocol during RRSO was emphasized from a large multi-institutional study (Gynecologic Oncology Group-199) that ovaries and fallopian tubes be sectioned at 2- to 3-mm intervals and entirely submitted for histologic examination [ 6 ]. According to prior research, it has been reported that a range of 0.6% to 27% of RRSO samples may exhibit the presence of high-grade serous ovarian carcinoma [ 7 8 ]. This broad range may result from differences in the age at RRSO, adherence of tissue processing protocol, proportion of contributing factors such as family history of breast and ovarian cancer, oral contraceptives use and hormone therapy use, and the comprehensiveness of histopathologic analysis [ 6 9 ]. The aim of this study was to investigate the incidence of incidental intraepithelial and invasive cancer germline homologous recombination repair (HRR) gene PV/LPV following RRSO and to demonstrate the pathological consequences and clinical implications of the procedure. Furthermore, our study investigated the cumulative risk of primary peritoneal carcinomatosis (PPC) in HRR PV/LPV population in Korea.

A total of 255 women with HRR gene PV/LPV underwent risk-reducing surgery. Characteristics of the patients who underwent RRSO are demonstrated in Table 1 . The majority of PV/LPV carriers (252/255, 98.8%) had pathogenic BRCA1 or BRCA2 PV/LPV, 129/255 (50.6%) with BRCA1 , 121/255 (49.8%) with BRCA2 , and 2/243 (0.7%) with both BRCA1 and BRCA2 mutations. There were 3 (1.2%) women with other HRR mutations, 1 (0.4%) with RAD51D , and 2 (0.8%) with BRIP1 . Values are presented as median (interquartile range) or number (%). BMI, body mass index; BSO, bilateral salpingo-oophorectomy; CA-125, cancer antigen 125; HR, homologous recombination; OC, oral contraceptive; POFT, peritoneal, ovarian, and fallopian tubal; RRSO, risk-reducing salpingo-oophorectomy; USO, unilateral salpingo-oophorectomy. The median age was 47 years (range, 31–75) and median BMI was 23.3 kg/m 2 (range, 12.5–32.8). The 128 (50.2%) patients were premenopausal state before RRSO. The 218 (85.5%) PV/LPV carriers were in the normal range preoperative CA 125 level. The 237 (97.5%) of women underwent bilateral salpingo-oophorectomy, and concomitant hysterectomy was performed in 31 (12.2%) patients. Breast cancer was previously diagnosed in 181 (71.0%) of patients and other cancer was 17 (6.8%). Pelvic washings were performed for cytological examination in all neoplasm cases (n=166, Table 2 ). Of the 166 women, 4 (1.2%) were positive for malignant cells in peritoneal cytology. Four of 5 invasive occult neoplasms had neoplastic cells present on cytology. Nine (3.5%) women had concomitant endometrial biopsy, no one reported pathologic findings. Values are presented as number (%). RRSO, risk-reducing salpingo-oophorectomy; STIC, serous tubal intraepithelial carcinoma. Of the 255 PV/LPV carriers who underwent risk-reducing surgery, 9 (3.5%) were found to have an occult neoplasm, including STIC, fallopian tubal cancer, and ovarian cancer. Of the 9 patients with occult neoplasm, 6 women (2.3%) had invasive carcinoma in overall population, while another 3 (1.2%) patients were diagnosed with STIC ( Tables 3 , 4 , 5 ). Of those women whose neoplasm did not arise from the fallopian tube, 3 patients had high-grade serous ovarian carcinoma. Furthermore, one patient incidentally identified metastatic breast cancer in the left ovary, even though there were no suspicious findings in the CT scan. The individual who has been diagnosed with estrogen receptor positive, progesterone receptor positive, and human epidermal growth factor receptor 2-low metastatic intraductal carcinoma, has undergone mastectomy and chemotherapy and is currently receiving ongoing treatment. Microscopic findings of the occult neoplasms were summarized in Fig. 1 . BC, breast cancer; FIGO, International Federation of Gynecology and Obstetrics; F/U, follow-up; HGSOC, high-grade serous ovarian cancer; LPV, likely pathogenic variant; NED, no evidence of disease; PPC, primary peritoneal carcinomatosis; PV, pathologic variant; RRSO, risk-reducing salpingo-oophorectomy; STIC, serous tubal intraepithelial carcinoma. F/U, follow-up; LPV, likely pathogenic variant; PPC, primary peritoneal carcinomatosis; PV, pathologic variant; RRSO, risk-reducing salpingo-oophorectomy; STIC, serous tubal intraepithelial carcinoma. F/U, follow-up; LPV, likely pathogenic variant; PPC, primary peritoneal carcinomatosis; PV, pathologic variant; RRSO, risk-reducing salpingo-oophorectomy; STIC, serous tubal intraepithelial carcinoma. CA-125, cancer antigen 125; H&E, hematoxylin and eosin; RRSO, risk-reducing salpingo-oophorectomy; STIC, serous tubal intraepithelial carcinoma. Clinical characteristics of women with occult neoplasms are described in Tables 3 - 5 . All 5 invasive carcinomas were discovered in 5 women with BRCA1 PV/LPV carriers and in 1 woman with BRCA2 PV/LPV carriers. All fallopian tube neoplasms were serous in histology. During the median follow-up period was 36.7 months (interquartile range, 25.9–71.4), 1 (0.4%) BRCA1 PV carrier without any prior precursor lesions at RRSO developed PPC after 30.1 months. Following primary cytoreductive surgery and adjuvant chemotherapy, the patient is currently receiving PARP inhibitors as a frontline maintenance treatment without evidence of disease. One patient who was incidentally diagnosed with PPC during RRSO underwent primary cytoreductive surgery and received adjuvant chemotherapy. Her first disease-free interval was 30.4 months, and following complete secondary cytoreductive surgery and intraperitoneal chemotherapy, she remains disease-free at 60 months with PARP inhibitor maintenance therapy.

In this study, 255 women underwent RRSO, while 3.5% of HRR gene pathogenic variant carriers developed occult neoplasms. The present study represents the largest cohort of asymptomatic Asian women who underwent RRSO, encompassing not only BRCA carriers but also individuals with PV/LPV in other HRR genes ( Table S1 ) [ 11 12 13 14 15 ]. In the previous study, which included 3,121 non-Asian women, 3.7% (115 women) had STIC, and the corresponding risk for peritoneal carcinomatosis was 0.3% [ 16 ]. This finding is consistent with our data, suggesting future studies to explore conducting a meta-analysis or multicenter study targeting Asian cohorts. STIC is the widely accepted precursor lesion, comprehensive tubal sectioning yields higher detection rates of occult neoplasia including STIC. In addition, recent data suggests STIC can progress to an invasive carcinoma and metastasize [ 17 18 19 ]. Since the detection that STIC is the premalignant lesion of high-grade serous ovarian cancer in women with a BRCA mutation, the significance of RRSO until the guideline-recommended age and comprehensive histopathologic examination of the fallopian tubes obtained has increased [ 14 ]. Some women are diagnosed with a latent invasive or intraepithelial neoplasm at the time of RRSO. Some of the cases with occult neoplasms have been reported previously [ 20 21 ]. Women receiving RRSO should be consulted before surgery to identify potential neoplasms and the possibility of requiring further treatment. One study of 122 BRCA PV/LPV women who underwent RRSO found latent cancer in 6% at the time of surgery [ 22 ]. According to another study, microscopic occult cancer of the ovary or fallopian tube might be identified following RRSO. Powell et al. [ 8 ] reported that 7 malignancies (10.4%) were found in 67 patients, 6 of which were microscopic. We detected 9 occult neoplasms in 255 patients (3.5%), 8 (3.1%) of which were microscopic except PPC. Therefore, mostly detected neoplasm were detected microscopically from the postoperative pathological evaluation. Re-operation might be needed for the staging surgery for the women with microscopic occult neoplasm. This needs to be discussed with patients preoperatively. In previous study, Blok et al. [ 7 ] reported of the 527 included patients, the prevalence of high-grade serous carcinoma was 12/527 (2.3%), and isolated STIC was present in 4/527 (0.8%). In addition, Nomura et al. [ 11 ] described that invasive or intraepithelial ovarian/fallopian tubal neoplasms were detected in 6 (5.2%) of the 117 women who underwent RRSO. In this study, none of the women with occult intraepithelial neoplasms of the fallopian tube succumbed to their disease, nor had a recurrence or subsequent diagnosis of primary peritoneal carcinoma, consistent with a previous study [ 20 ]. The current study includes a relatively large cohort of women with germline HR gene PV/LPV, a population on which previously reported incidental intraepithelial and invasive cancer. Interestingly, we identified the novel finding of metastatic breast cancer after RRSO in the patient 8. Because most of this study population, 73.3% (178/243), were women with breast cancer. Ovarian metastasis of breast cancer is rare and usually bilateral, and often seen in premenopausal hormone receptor-positive young women [ 23 ]. In this study, metastatic breast cancer after RRSO was identified in the left ovary unilaterally. Our pathology findings represent the importance of utilizing strict surgery and pathology protocols at the time of risk-reducing surgery. No mortality was identified in this surgical series. And this suggests the potential survival benefit from RRSO. Women with BRCA PV/LPV have survival benefit from the intraperitoneal chemotherapy compared to conventional intravenous chemotherapy [ 24 25 ]. In patient who were diagnosed with PPC, recurrent disease was identified in the peritoneal cavity with disease free interval of 61 months. Survival benefit of secondary cytoreductive surgery in platinum sensitive recurrent ovarian cancer has been stablished [ 26 ]. So, in cases of recurrent disease in women with RRSO, secondary cytoreductive surgery with IV/IP chemotherapy could be considered as one of the optional therapeutic strategies for the maximal survival benefit. In this study, a single individual (0.4%) carrying a BRCA1 pathogenic variant, who showed no precursor lesions at the time of RRSO, developed PPC after 30.1 months. While a previous study found that those with STIC at RRSO had a significantly higher hazard ratio (33.9; 95% confidence interval, 15.6–73.9; p<0.001) for peritoneal carcinomatosis, our results indicate a risk for PPC even in those without STIC [ 16 ]. This underscores the need to inform patients postoperatively about the risk of peritoneal carcinomatosis based on pathology reports and information of the absolute cancer risk at 5 and 10 years after RRSO should be included in the consultation. Moreover, adherence to the SEE-FIM protocol and thorough assessment by an experienced pathologist are crucial to avoid missing STIC. This study had several limitations, including a limited sample size and a relatively short observation follow-up period. Additional research is needed to conduct a large-scale, comprehensive long-term follow-up and assess the long-term surgical outcomes in women who underwent RRSO [ 27 ]. Second, there is a potential for selection bias due to the retrospective study design. Third, the lack of pelvic washing cytology in about one-third is also a weakness of this our study. Pelvic washings were obtained in nearly two-thirds of cases and all cases of occult neoplasm [ 27 ]. Pelvic washings were cytologically malignant in 3 cases with neoplasm; no false positives were identified as has been reported in another study [ 28 ]. Therefore, pelvic washing was recommended when performing RRSO surgery. In conclusion, patients with germline HRR gene PV/LPV had a 3.5% incidence of occult neoplasms at the time of RRSO. Despite the absence of precursor lesions during RRSO, there was a cumulative risk of peritoneal carcinomatosis development, suggesting the need for long-term surveillance irrespective of precursor lesions at the time of RRSO. These study findings can inform counseling strategies for RRSO in women with germline HRR gene PV/LPV.

This study retrospectively collected data from women who underwent RRSO for germline HRR PV/LPV at National Cancer Center Korea from January 2006 to December 2022 were identified. Enrolled patients were eligible if they were diagnosed with germline BRCA1/2 or other HRR gene PV/LPV (PALB2 , ATM , ATR , CHEK2 , BRIP1 , BARD , FANCL , NBM , RAD51C , and RAD51D ). However, patients who underwent bilateral salpingo-oophorectomy with the aim of endocrine ablation for the therapeutic benefit of breast cancer were excluded in this study. These breast patients with mutations for endocrine ablation were not enrolled. We collected relevant clinical data including age at RRSO, body mass index (BMI), parity, BRCA status, histology of breast cancer, family history of breast and peritoneal, epithelial ovarian, and fallopian tubal cancers, oral contraceptive use, preoperative cancer antigen 125 (CA-125) levels and preoperative radiologic imaging with computed tomography (CT) scans or ultrasonography for this cohort. During follow-up period, the incidence of PPC was evaluated and the incidence of incidental finding of neoplasm was detected at the time of surgery or in subsequent pathological examination of the tissue. Risk-reducing bilateral salpingo-oophorectomies were performed by laparoscopy or robot-assisted laparoscopy with adherence of surgical principle of RRSO based on the National Comprehensive Cancer Network (NCCN) guidelines [ 4 ]. The surgical removal of bilateral ovaries, fallopian tubes, and mesosalpinges was a standard protocol, and the specific details of the procedure could vary slightly based on the patient's surgical history. Washing cytology of the abdominopelvic cavity was performed in most cases at the beginning of the procedure and fallopian tubes were removed at the uterine insertion. Following the NCCN guidelines, more than 2 cm of the infundibulopelvic ligament with adjacent peritoneum were surgically resected for the microscopic evaluation of occult neoplasm. All submitted slides were carefully reviewed by gynecological pathologist and p53 and Ki-67 immunohistochemistry staining were performed. Following RRSO, the implementation of surveillance for screening of PPC in patients diagnosed with occult neoplasms involves conducting examinations every 6 months, with serum CA-125 assessments and ultrasonography check-ups. Additionally, patients without occult neoplasms were also included in regular follow-up consultations. Germline variants were analyzed based on the recently updated American College of Medical Genetics and Genomics and Association of Molecular Pathology guidelines, which provide a 5-tier classification system [ 10 ]. This study considered pathological variants classified as ‘pathogenic’ or ‘likely pathogenic’ according to guidelines. Other reports considered wild-type BRCA. The primary outcome of this study was to evaluate the incidence of occult neoplasm including serous tubal intraepithelial carcinoma (STIC), occult carcinoma in addition to abnormal expression of p53 or Ki-67. The secondary outcome assessed in the study was the incidence of patients who developed PPC after undergoing RRSO. The follow-up period began on the day of surgery and continued until the final follow-up visit. Continuous data were demonstrated as median and range, and categorical data were demonstrated as absolute numbers and percentages. Follow-up period were demonstrated as median and interquartile range. Statistical analysis was performed using IBM SPSS Statistics® version 25 (IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Boards of the participating institutions and conducted in accordance with the principles of the Declaration of Helsinki (National Cancer Center: NCC2022-0222). The requirement for informed consent was waived.