The incidence and clinical outcomes following prophylactic risk-reducing salpingo-oophorectomy in BRCA mutation carriers: a single-center retrospective study

1. Introduction

Epithelial ovarian cancer (EOC) is the primary reason of mortality in gynecological malignancies, with a 5-year survival rate of 47% [1]. The most prevalent histological type is high-grade serous carcinoma (HGSC), accounting for 70–80% of cases [2]. It is estimated that approximately 10% of ovarian carcinomas, particularly HGSC, are attributable to hereditary factors [2]. It is well known that more than 90% of all hereditary EOC cases are related to BRCA pathogenic variants [3]. The risk of occuring EOC is 36–53% for BRCA1 mutation carriers and 11–25% for BRCA2 mutation carriers [4]. It is estimated that approximately 50% of HGSC cases are associated with a defect in Homologous Recombination, which primarily depends on the function of the BRCA1-2 DNA repair proteins. In recent years, there has been significant attention on the utilisation of poly (ADP)-ribose polymerase (PARP) inhibitor drugs, such as olaparib, niraparib and rucaparib, in the context of maintenance therapy following the response to platinum-based chemotherapy as a first-line treatment. These studies have demonstrated a notable prolongation in survival rates for patients diagnosed with homologous recombination deficiency (HRD), particularly those with a mutation in the BRCA1 or BRCA2 genes [5]. Current findings indicate that high-grade serous ovarian carcinomas have the potential to originate from the fallopian tube [6]. The most effective method of prevention is a timely risk-reducing salpingo-oophorectomy (RRSO), which has been shown to reduce the risk of EOC by up to 96% [7]. In accordance with the guidelines established by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), the recommendation for the administration of RRSO is between 35 and 40 years of age, subsequent to the completion of childbearing in BRCA1 mutation carriers [8]. In patients with a pathogenic variant in the BRCA2 gene, causing later onset of ovarian cancer, RRSO may be postponed until 40–45 years of age [8]. The principal pathological findings documented in cases of prophylactic removal of adnexa are serous tubal intraepithelial lesions (STIL), serous tubal intraepithelial carcinoma (STIC) and occult invasive cancer (OC) [9]. STIC is a precursor lesion mostly appears in the distal part of the fallopian tube and fimbria and leads to the occurring of HGSC [3, 10]. The STIC, STIL and OC are determined by applying the Sectioning and Extensively Examining the Fimbriated end of the fallopian tube (SEE-FIM) protocol. This protocol has been applied in the patients with BRCA pathogenic variants by resection and transversal sectioning of the fimbria and remaning tube at 2–3 mm intervals [9]. Prior to the development of STIC, detected by the SEE-FIM protocol, three precursor lesions, characterised by Secretory cell outgrowth (SCOUT), p53 signature and STIL, were hypothesised to play potential roles in the pathogenesis. As demonstrated in earlier research, the incidental identification of these precursor lesions does not appear to be linked to primary peritoneal or ovarian cancer during follow-up [9, 11, 12, 13]. The incidence of OCs varies from 1.9 to 5.6%, and the incidence of STICs varies from 0.8 to 9.8% at the time of the RRSO in patients with BRCA mutation carriers [9, 14, 15, 16]. Conversely, in a large cohort study conducted in the Netherlands, the results of RRSO conducted on 2557 patients with BRCA mutations were evaluated [17]. The study identified a low proportion (n = 28, 1.0%) of asymptomatic patients with HGSC; nonetheless, the data concerning the remaining patients remains unclear [17]. However, the clinical impact of STIC is not yet fully understood.

The goal of this paper was to ascertain the prevalence of pre-cancerous lesions, Secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial lesion (STIL), serous tubal intraepithelial carcinoma (STIC) and occult invasive cancer (OC), in patients with pathogenic variants of the BRCA1 and/or BRCA2 genes. Additionally, the study aspire to evaluating clinical outcomes and the risk of developing primary peritoneal carcinoma (PPC) in the follow-up period.

2. Materials and methods

3. Results

Between January 2021 and November 2024, a total of 63 patients with BRCA mutation carriers underwent RRSO were enrolled in this study. It was ascertained that none of the patients had a prior medical history of oophoro- or salpingectomy. Twenty-nine women (46.0%) were BRCA1, 33 (52.3%) were BRCA2, and 1 (1.5%) was BRCA10+2 mutation carriers.

Table 1 presents comparisons of the demographic and clinical characteristics of the patients. The mean age at risk-reducing surgery was 45.9 years and the majority of patients were between the ages of 40 and 49. The mean age for BRCA1 was 48.7 years (range 37–67 years), 48.1 years for BRCA2 (range 34–71 years) and for BRCA1+2 mutation carrier, it was 41. The first patient was subjected to RRSO at the age of 67 due to a history of operated breast cancer and a BRCA1 pathogenic variant. The operation revealed a purely cystic formation measuring approximately 7 cm in diameter, originating from the left adnexa. Furthermore, the patient’s CA-125 value was found to be within normal limits. (CA-125: 15 IU/mL). Frozen section reported as benign. The final pathology revealed follicle cyst. The second patient exhibited a BRCA2 pathogenic variant and a personal and family history of breast cancer. At the age of 71, RRSO was performed due to the presence of a heterogenous cystic mass containing fatty and calcific areas measuring approximately 5 cm in size, originating from the right adnexa. The CA-125 level was 25 IU/mL. Frozen section reported as benign. The final pathology revealed mature cystic teratoma. At the time of the surgery, 45 women (71.4%) were postmenopausal caused by iatrogenic induced or spontaneous and 18 women (28.5%) were premenopausal. Of the 63 patients, five were nulliparous.

Fifty-three (84.1%) patients had personal history of breast cancer and 2 (3.1%) patients without previous personal history of breast cancer underwent prophylactic bilateral mastectomy before RRSO, while the remaining patients did not have a history of breast cancer in the past (Table 1). The breast cancer history in the family was detected in 11 (37.9%) BRCA1 mutation carriers, in 14 (42.4%) BRCA2 mutation carriers and also the patient with both BRCA1 and BRCA2 mutation carrier had a family history of breast cancer. A family history of ovarian cancer was only detected in BRCA1 mutation carriers (n = 11, 37.9%). 22 of 63 patients (34.9%) were tamoxifen users (current and former) and 35 had never used tamoxifen or any other medications.

The mean preoperative CA-125 level was 14.2 IU/mL for the patients with BRCA1 mutation, 14.6 IU/mL for the patients with BRCA2 mutation and 12.0 IU/mL for the patient with both BRCA1 and BRCA2 mutation (Table 1). All patients underwent TVUSG imaging prior to RRSO. Suspicious features were observed in 2 cases (3.1%). The first case was an asymptomatic 61 years old, BRCA1 carrier, with solid and well-circumscribed measuring 5 × 6.5 cm mass on the right adnexal mass lobe and CA-125 level was 15 IU/mL. Intraoperatively, the presence of the pelvic kidney was observed. In the second case (52 years old, BRCA2 carrier), TVUSG demonstrated 3–4 cystic structures within the left ovary and 7 × 6 cm cyst within right ovary. CA-125 was 33 IU/mL and intraoperatively, suspicious deposits seen in the pouch of Douglas were biopsied and sent for frozen section with the bilateral salpingo-oophorectomy specimen. Frozen section reported as benign. The final pathology revealed follicle cyst and endosalpingiosis. The peritoneal washing was negative for all the patients. Majority of the patients (n = 33, 52.3%) underwent total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO) and cytology with or without omental biopsy. The histopathological results of the hysterectomy specimens were reported as chronic cervicitis, leiomyoma, adenomyosis, atrophic endometrium, endometrial polyp, proliferative endometrium and simple endometrial hyperplasia (without atypia).

Table 2 shows the details of histopathologic findings for each groups. In total 10 (15.8%) SCOUTs were detected in our study at the time of the RRSO; 5 of them (17.2%) were BRCA1 mutation carriers and the remaining patients were (15.1%) BRCA2 mutation carriers. The p53 signature was observed in 4 (6.3%) patients (BRCA1: n = 2, 6.8% and BRCA2: n = 2, 6.0%). Isolated STIL lesions were diagnosed in 3 (4.7%) patients, 2 (6.8%) occurred among women carrying BRCA1 mutation and the last one (3.0%) with BRCA2 mutation. Isolated STIC was observed in 1 (1.5%) patient with both BRCA1 and BRCA2 carrier had history of breast cancer surgery. At the time of the RRSO, the age was 41 years. CA-125 level was 12 IU/mL, examination of the pelvis and TVUSG were negative. Restaging surgery was not performed and adjuvant chemotherapy was not given but the patient was followed closely. All the patients were subjected to transvaginal ultrasound scanning and CA-125 level assessment every 6 months and primary peritoneal carcinoma (PPC) did not occur at all. None of the patients were diagnosed OC at the final pathological examination.

4. Discussion

High-grade serous carcinoma represents the most prevalent histological subtype of epithelial ovarian carcinoma, with approximately 10% of cases being associated with mutations in the BRCA1 and BRCA2 genes [3]. A significant proportion of HGSC cases are thought to originate in the fallopian tubes [26], with STIC being the precursor lesion, leading to the recommendation of standardised and detailed tubal sampling using the SEE-FIM protocol [27]; the average duration of STIC progression to HGSC is 6.5 years [26]. A variety of pre-neoplastic lesions, including p53 signature and STIL lesions, have been identified on histological examination of the fallopian tubes [27]. The temporal relationship between these lesions and HGSCs remains a subject of debate [27].

In recent study, the mean age at risk-reducing surgery was 45.9 years (range, 34–71 years) which was higher than the international guidelines but this result was similar to that obtained by Lee et al. [23], who searched 63 patients with BRCA mutation and found that the median age was 46.5 years. Additionally, our study showed that only 5 (7.9%) patients with BRCA1 mutation carriers were nulliparous which means the majority of women want to undergo risk-reducing surgery after completed childbearing, that’s why they may delay surgery. Another possible reason is concern about negative hormonal influence, quality of life and health [23].

In light of the most recent findings on the association between STICs and HSGCs among patients who had pathogenic variants in BRCA1-2 genes [9], previous trials have indicated that the incidence of STIC in cases of BRCA1-2 mutations ranges from 0.8 to 2.3% [14, 15]. Additionally, the incidence of HGSCs was about 1–2.5% [15, 17]. In the present result, the incidence of isolated STIC was 1.5%, which shows resemblance to previous studies which had in a similar regarding the number of included patients [3, 9, 14, 28, 29].

It is evident that the potential risk of developing PPC arising from the STIC in carriers of the BRCA1-2 gene is, as yet, unclear [9]. In the present result, the STIC lesion was detected in 1 (1.5%) case and was not undergone restaging. The PPC did not occur during follow-up of the 23 month. There have been several studies that support our findings. Similarly, the study by Abay et al. [3] showed that 1 (2.0%) patient with BRCA1 mutation had STIC and did not undergo restaging as well but 8 cycles of chemotherapy were given after RRSO and PPC development was not observed during the 20 months follow-up period. According to these data demonstrated that the short-term follow-up period may not be sufficiently prolonged to allow for the occurrence of PPC in both studies. On the other hand, Saccardi et al. [9], in the long-time follow-up period (median 54.5 months), detected STICs in 4 (2.6%) patients. A close monitoring process was implemented for all patients at six-month intervals; however, no patient exhibited the development of PPC. Furthermore, the study published by Kang et al. [12] in 2023 revealed that no patient diagnosed with STIC developed PPC about 8 years follow-up period. On the contrary, in a large cohort meta-analysis conducted in the Netherlands, 2519 patients underwent RRSO and were subsequently followed up for a mean period of 13 years [30]. In 19 cases, despite the absence of pathology detected during RRSO, HGSC developed in a mean timeframe of 8 years. Notably, five of the eight patients diagnosed with STIC also developed HGSC at an average of 8 years. In a further meta-analysis encompassing 17 studies with a total sample size of 3121 patients, STIC was observed in 115 patients [7]. In the group with STIC, PPC cancer (n = 15, 13%) developed in a mean of 4.5 years, and similarly in the group without STIC, PPC cancer (n = 12, 0.4%) developed in a mean of 4.5 years. A similar observation was made in a UK study, where 3 patients (0.3%) developed PPC within 4–10 years after RRSO performed in 891 patients [31].

An additional purpose of the current trial was to ascertain the incidence of OC. In the present sample, the presence of OC was not identified. While there have been several studies that contrast to our findings. Kang et al. [12] found OC in 4 (3.3%) patients despite no evidence of malignancy on preoperative examination. Abay et al. [3] revealed OC was detected only in 1 (2.0%) case. Saccardi et al. [9] demonstrated 3 (2.0%) patients had OC, in particular 2 tubal cancers and 1 ovarian cancer, was consistent with those reported by Ricciardi et al. [32].

Undoubtedly, following the detection of STIC, the challenge is to determine the most suitable treatment to prevent the potential recurrence or progression of the disease [9]. Following the diagnosis of STIC in RRSO, a plethora of management strategies have been posited. Nevertheless, there remains a paucity of robust evidence to support the efficacy of restaging, chemotherapy or close monitoring [9].

Van der Hoeven et al. [33] enrolled combination of 15 studies and demonstrated that 82 patients were diagnosed STIC. Thirteen of them (16.0%) underwent restaging surgery, only 3 of them (4.0%) received chemotherapy and the remaining patients (n = 36, 44.0%) followed closely. Recurrence disease occurred in four of the 36 patients who did not receive chemotherapy or undergo staging surgery following their initial RRSO. As a result, this study suggested that chemotherapy or restaging surgery was related to a lower risk of recurrence [33]. Wethington et al. [28] observed there was not found difference for the recurrence rate between restaging surgery for the diagnosis of STIC or after follow-up only. 12 patients were diagnosed with isolated STIC. The patients were treated in one of two ways: hysterectomy and omentectomy were performed on seven patients, while lymphadenectomy of the pelvic or para-aortic regions was carried out on 11 patients. It is noteworthy that adjuvant chemotherapy was not given to all patients. During a follow-up period of 28 months (range, 16–44 months), the recurrence rate was found to be similar in both groups, with no statistically significant difference observed. In other research published by Ricciardi et al. [32], the isolated STIC lesions were observed in 7 cases, of whom four did not undergo restaging surgery. Notably, adjuvant chemotherapy was not given to all patients. After a 30-month (9–84) follow-up period, oncological outcomes were found to be similar between the two groups.

Although there have been reports of an increased risk of pelvic peritoneal cancer in patients diagnosed with STIC, it is important to note that this risk also exists in patients with benign pathology [3]. Zakhour et al. [34] included 257 patients with BRCA mutation underwent RRSO. They observed 9 cases of STIC with an incidence rate of 3.5%, and 2 of which were pelvic serous carcinoma. Conversely, three patients with benign pathology progressed to serous carcinoma of the pelvis. These findings are in line with previous literatures, Minig et al. [35], and Powell et al. [36] observed one patient with normal histopathological findings developed PPC. Another endpoint of Minig’s study only one patient had positive cytology among 3 patients diagnosed STIC and surgical staging was performed in this patient. None of these 3 patients went on to develop PPC while followed up [35]. Powell et al. [37] conducted a study in which patients diagnosed with STIC were divided into three distinct groups: staging surgery, adjuvant chemotherapy and no treatment. In this study, only three out of seventeen patients received chemotherapy, while only nine out of seventeen patients underwent surgical staging. However, the outcomes were favourable for all patients diagnosed with STIC, regardless of whether they received chemotherapy, operated or not treated [37].

In addition to STIC, three other lesions must be considered: p53 status, SCOUT and STIL. As these lesions have only been recognised in recent times, further research is required to ascertain their clinical significance. It is also possible that they may play a role in the pathogenesis of EOC [11].

There are several strengths of the current study including (1) uniform SEE-FIM protocol was used for all cases (2) all RRSO specimens were examined by expert gynecological pathologists (3) A rigorous selection process was employed to identify suitable patients. Only patients with pathogenic variants in BRCA1-2 genes and negative sign of cancer by TVUSG screening were chosen. Notwithstanding the aforementioned strengths, it is important to acknowledge the limitations of the present study, which are inherent to its retrospective nature, a single center, not a randomized trial, short period of follow-up, small number of cases.

5. Conclusions

Overall, no significantly different outcomes or reduced rates of subsequent PPC after RRSO were reported in the main trials that compared restaging surgery, adjuvant chemotherapy or close follow-up in patients with STIC [9]. It should be remembered that there is still a risk of occurring PPC. In conclusion, on the basis of the result of our study and on the evidence of previous publications, the implementation of a prolonged follow-up in patients detected with the isolated STIC should be thought as a possible strategy for management. Undeniably, larger prospective case series with adequate patients and longer follow-up can define the advantages of RRSO in order to establish more certain recommendations and to define management.

Availability of data and materials

The data underpinning the finding of this study can be obtained from the corresponding author, NY, upon a reasonable request.

Author contributions

NY—project development; management/editing. TS—data collection; data analysis; manuscript writing. AAÖ—management/editing. MCT—management/editing. LA—management/editing. LT—data collection. KM—data collection; data analysis. AES—data collection; data analysis. HA—management/editing. GS—pathologic examination; data analysis. GA—pathologic examination; data analysis.

Ethics approval and consent to participate

The study protocol was approved by the institutional Ethics Committee of Ege University Faculty of Medicine (approval number: 25-2T/45). Consents were obtained from all participants included in the study.

Acknowledgement

We would like to thank the members of gynecological oncology, pathology and genetics team of Ege University Faculty of Medicine for collaboration and supports.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.