Validation of adopting vaginal natural orifice transluminal endoscopic surgery for risk-reducing salpingo-oophorectomy for women with germline BRCA1/2 pathogenic variants analysis from conventional procedure
Article information
Abstract
Objective
Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is less invasive than conventional transabdominal laparoscopic surgery for benign gynecological indications. When adopting this procedure for risk-reducing salpingo-oophorectomy (RRSO) in women with hereditary breast and ovarian cancer (HBOC), the ventral side of the uterus becomes a blind area, which is a challenge. To clarify the effects of this blind area on the treatment outcome of HBOC, we examined the clinical data of RRSO using conventional procedures for women with germline BRCA1/2 pathogenic variants who were treated at our institution.
Methods
A retrospective chart review was performed. The clinical data of patients who underwent RRSO using the conventional procedure between September 2011 and July 2024 were extracted. All included patients were preoperatively examined using vaginal ultrasonography, contrast-enhanced pelvic magnetic resonance imaging, and carcinoma antigen-125 level measurements to exclude ovarian cancer development.
Results
A total of 267 patients underwent RRSO at our institution. The mean age at RRSO was 50.1 years. Five cases of occult invasive cancer (1.9%) and 10 cases of serous tubal intraepithelial carcinoma (3.7%) were identified postoperatively. One patient (0.37%) showed macroscopic peritoneal dissemination in the omentum. None of the 252 patients without occult cancer developed peritoneal cancer during the mean observational time of 62.4 months. No patient presented with peritoneal lesions ventral to the uterus.
Conclusion
Macroscopic tumors on the peritoneum ventral to the uterus were rare when strict preoperative screening for ovarian cancer was performed. vNOTES can be safely adopted for RRSO in patients with HBOC, without evident disadvantages.
Introduction
Women carrying germline pathogenic variants (GPV) of the BRCA1 or BRCA2 genes have an increased risk of developing breast or ovarian cancer (OC). Women in the general population have a 1.3% lifetime risk of developing OC, but this risk increases to 44% and 17% for women aged up to 80 years old with a BRCA1 and BRCA2 GPV, respectively [1]. Risk-reducing salpingo-oophorectomy (RRSO) can decrease OC-specific mortality and overall mortality by approximately 80% and 70% for women with BRCA1 or BRCA2 GPV, respectively [2–5]. Thus, RRSO has been routinely performed in women with BRCA1/2 GPV.
Vaginal natural orifice transluminal endoscopic surgery (vNOTES) has emerged as the preferred procedure for benign gynecological indications and has gained widespread use in recent years [6]. The NOTABLE trial demonstrated that adnexectomy using vNOTES is non-inferior to laparoscopy and reduces operating times and postoperative pain [7]. Moreover, a comparison between vNOTES and single-port access surgery through the umbilicus revealed that the vNOTES group reported lower postoperative pain scores within 12 hours after surgery and required less use of postoperative analgesic medications [8]. vNOTES is less invasive than the transperitoneal approach in terms of cosmetic and postoperative pain.
Recently, the feasibility of performing RRSO via vNOTES has been demonstrated in limited case series and video-based technical reports [9,10]. These studies confirmed the procedural applicability of vNOTES in adnexal surgery. However, there remains a paucity of data regarding its oncological validity, particularly in the context of hereditary breast and ovarian cancers. To date, no study has provided robust clinical evidence supporting the safety and effectiveness of vNOTES in RRSO. Therefore, further investigation is necessary to validate its use in high-risk populations.
According to the National Comprehensive Cancer Network guidelines, RRSO performed using minimally invasive laparoscopic surgery should include surveys of the upper abdomen, bowel surfaces, omentum, appendix, and pelvic organs [11]. Transabdominal laparoscopic surgery simplifies the survey of the entire abdominal cavity and is particularly superior for observing the upper abdomen, except for the anterior abdominal wall around the umbilicus. However, in adnexectomy using vNOTES, the ventral side of the uterus, including the bladder surface, is inaccessible, because access to the abdominal cavity is established dorsal to the uterus. Does inaccessibility of the ventral peritoneum to the uterus affect the outcome of RRSO with BRCA GPV via vNOTES? Does this technique offer advantages that outweigh this disadvantage? We addressed these questions by examining the clinical data of women with BRCA GPV who underwent RRSO at our institution. This study aimed to demonstrate the validity of vNOTES based on the outcomes of conventional RRSO. While previous research has indicated the superiority of vNOTES in terms of perioperative outcomes in adnexal surgery, this study investigated its applicability in RRSO. In particular, we examined the impact of the potential disadvantage of not visualizing the ventral side of the uterus when applying vNOTES to RRSO.
Materials and methods
The clinical data of patients who underwent RRSO using the conventional approach between September 2011 and July 2024 were extracted, and a retrospective chart review was performed. This study was approved by our Institutional Review Board (IRB) (2023-GB-079). Informed consent was obtained from all participants. This study was conducted in accordance with the relevant guidelines and regulations of our IRB.
1. Patients
Since RRSO was not covered by the national insurance system, it was approved at our institution for clinical research in 2011. The inclusion criteria were as follows: 1) genetic confirmation of BRCA1 or BRCA2 GPV and consent to undergo RRSO; 2) no desire to bear a child; 3) an understanding of the complications associated with RRSO and the possible symptoms of surgical menopause; 4) an understanding of the financial cost; and 5) an understanding that RRSO is performed as part of clinical research. All patients underwent transvaginal ultrasonography, cytological examination of the uterine cervix and endometrium, contrast-enhanced pelvic magnetic resonance imaging (MRI), and serum carcinoma antigen-125 (CA-125) level measurements approximately 1 month preoperatively. Based on these evaluations, those with suspected ovarian, fallopian tube, or uterine cancer were excluded and treated for the indicated diseases under the coverage of the national insurance system. If MRI was contraindicated, computed tomography was performed. To examine the incidence of peritoneal cancer after RRSO, all patients underwent yearly transvaginal ultrasonography, CA-125 level measurement, and uterine cervical and endometrial cytology if they had not undergone hysterectomy.
2. Surgical procedures
The surgical procedures performed during RRSO included peritoneal washing, cytology, and removal of the ovaries, fallopian tubes, and mesosalpinx. If the adnexa showed adhesions, the peritoneum attached to the adnexa was removed. Transabdominal laparoscopy is the standard procedure for RRSO. After the instruments were placed, the ascitic fluid was aspirated. If ascites were not present, peritoneal washing with 30–50 mL saline was performed, followed by aspiration. Therefore, peritoneal washing cytology was performed immediately and the diagnosis was reported intraoperatively. If the diagnosis of ascites was positive or suspicious of malignancy, a biopsy of the omentum was additionally performed during the surgery to determine micrometastasis. RRSO specimens were collected for histological microscopic examination, which was conducted based on the sectioning and extensive examination of the fimbriated end (SEE-FIM) protocol [10]. As per the protocol, the ovaries and fallopian tubes were sectioned at 2–3-mm intervals and submitted for histological examination. If atypical cells were observed, immunohistochemical staining for the cellular tumor antigen p53 and KI-67 was performed.
Results
In total, 267 patients underwent RRSO at our institution between September 2011 and August 2024. Of the 267 women, 142 had BRCA1 GPV, 124 had BRCA2 GPV, and 1 had BRCA1 and BRCA2 GPV (Table 1). The mean age at RRSO was 50.1 years. Among these women, approximately 90% of them had a history of breast cancer, and more than one-third had a family history of ovarian cancer. Since the introduction of laparoscopic surgery in 2013, open surgery has become the primary procedure. Nine patients underwent RRSO via open surgery, while the remaining 258 patients underwent RRSO via transabdominal laparoscopic surgery. No major peri- or postoperative complications (Clavien-Dindo classification II or worse) were observed. Occult cancer was detected postoperatively in 15 patients (5.6%). No malignant lesions were observed on the preoperative images. Five invasive cancers and 10 serous tubal intraepithelial carcinomas (STICs) were detected. Among the five invasive cancers, three originated from the fallopian tube and two from the ovary and fallopian tube. All 10 patients with STIC had negative peritoneal cytology results. Adjuvant chemotherapy was administered to one patient. However, none of the patients experienced a recurrence. The pathological subtype of the five invasive cancers was high-grade serous carcinoma. A macroscopic tumor on the omentum was observed in one patient during RRSO, but SEE-FIM examination revealed no microscopic tumors in the ovaries or fallopian tubes. The patient was diagnosed with peritoneal cancer and had received chemotherapy, including platinum and taxane, before undergoing RRSO. Preoperative MRI imaging revealed a tumor on the omentum. Hysterectomy and omentectomy were subsequently performed for peritoneal staging. Of the 15 patients, one with occult invasive cancer had a suspected malignancy based on intraoperative cytology of the ascites. Of the 252 patients without occult cancer, 11 had serous tubal intraepithelial lesions and seven had p53 accumulation in the fimbriae. However, none of the patients showed abnormal cytology during RRSO and none developed peritoneal cancer during the mean observational time of 62.4 months (median, 59 months).
Patient characteristics
Discussion
In this retrospective study, patients with clinically suspected ovarian cancer were excluded based on preoperative transvaginal ultrasonography, contrast-enhanced pelvic MRI, and CA-125 level measurements. Under strict criteria, only one case showed a peritoneal lesion on the omentum, which was revealed on preoperative MRI. No macroscopic malignant lesions were found during RRSO in the 252 cases without malignant lesions in the ovaries or fallopian tubes. Furthermore, none of the patients developed peritoneal cancer postoperatively. These results indicate that if the absence of occult cancer is confirmed by the SEE-FIM protocol, the development of peritoneal dissemination in women with BRCA1/2 GPV is extremely rare. However, it should be acknowledged that current preoperative imaging modalities, including transvaginal ultrasound, contrast-enhanced MRI, and CA-125, have limited sensitivity in detecting microscopic or early-stage peritoneal dissemination. Although our strict screening protocol appeared to be effective in excluding advanced malignancies, it may not fully rule out early occult disease.
Adnexectomy for benign indications via vNOTES is non-inferior to laparoscopy and reduces the operating time and postoperative pain, as revealed by the NOTABLE trial [7]. vNOTES has a cosmetic advantage over transabdominal laparoscopic surgery because it does not leave any abdominal scars. Moreover, most women with BRCA1/2 GPV undergo mastectomy or a risk-reducing mastectomy for breast cancer. Patients who undergo mastectomy can opt to undergo breast reconstruction using a deep inferior epigastric perforator (DIEP) flap. A flap from the lower belly was used to rebuild the breast. Therefore, women who wish to undergo breast reconstruction using the DIEP flap must keep their abdominal tissues intact. In these cases, vNOTES is a promising option. In vNOTES for RRSO, the major concern is limitation of the pelvic wall visual field, particularly on the ventral side of the uterus. In vNOTES, the upper abdomen, bowel surfaces, omentum, appendix, and ventral abdominal wall around the umbilicus can be surveyed, which is a blind area in transabdominal laparoscopic surgery (Fig. 1). The characteristics of the two procedures are summarized in Table 2. In this study, we further clarified whether this limitation affected the treatment outcomes of women undergoing RRSO. Another technical consideration in vNOTES is the collection of the peritoneal fluid for cytological analysis. Upon colpotomy, the ascites may immediately drain into the vaginal cavity. If this fluid is collected from the vaginal side, it may be contaminated with squamous epithelial cells from the vaginal mucosa, which interferes with accurate cytological interpretation. Therefore, peritoneal fluid must be collected directly from the abdominal cavity. In cases without visible ascites, peritoneal washing should be performed before further dissection to ensure reliable cytological evaluation.
Abdominal wall around umbilicus. (A) Right diaphragm; (B) left diaphragm; (C) upper abdomen; (D) abdominal wall around the umbilicus.
Comparison of the character of transabdominal laparoscopic surgery and vNOTES data in this table are cited from previously published studies and not derived from our current cohort
Of the 267 patients who underwent RRSO at our institution, 14 were diagnosed postoperatively and one was diagnosed intraoperatively. Some of these cases have been previously reported [12]. Preoperative screening using transvaginal ultrasonography, contrast-enhanced pelvic magnetic MRI, and CA-125 level measurements can exclude certain OCs with peritoneal dissemination. In fact, we excluded one patient with OC with peritoneal dissemination who was treated as having International Federation of Gynecology and Obstetrics stage IIIB OC. What is the possibility of overlooking peritoneal lesions during RRSO? In this study, 252 patients without malignant lesions according to the SEE-FIM protocol did not undergo any adjuvant therapy because their peritoneal cytology was negative for cancer. No patients developed peritoneal cancer during the mean observation time of 62.4 months after RRSO. This indicates that peritoneal dissemination is extremely rare in patients without abnormal peritoneal cytology or negative SEE-FIM findings. Our results are consistent with those of a previous report indicating that random peritoneal and omental biopsies during the RRSO do not increase the detection rate of occult cancers [13].
RRSO was performed in patients who did not use OC. Additional treatment is required if occult lesions are detected during or after the RRSO. Staging surgery with retroperitoneal lymph node dissection is the standard treatment strategy for OC without peritoneal dissemination. Primary debulking surgery was performed in patients with peritoneal dissemination [11]. However, RRSO requires approximately 1 hour and cannot be extended to accommodate surgical procedures for incidentally diagnosed OC. Examining the extent of abdominal cavity dissemination is crucial; however, the required treatment cannot be administered sufficiently during RRSO. Thus, the date of the OC operation must be scheduled later. If peritoneal cytology is positive for malignancy or macroscopic cancer is detected, conversion to transabdominal laparoscopic surgery to enable the survey of the entire abdomen may be considered, even if RRSO was initially performed via vNOTES.
This study was limited by its retrospective nature and the relatively small sample size of patients enrolled from a single institution. However, we believe that our study sufficiently demonstrates the advantages of RRSO using vNOTES. The strength of this study is the strict preoperative screening modality implemented via vaginal ultrasonography, contrast-enhanced pelvic MRI, and measurement of CA-125 levels to exclude patients with ovarian cancer.
Our study presents important findings that support RRSO using vNOTES. Macroscopic tumors are rarely detected if strict preoperative screening for OC is performed. No macroscopic peritoneal lesions were observed on the ventral side of the uterus. Therefore, we conclude that RRSO using vNOTES can be less invasive and preserve abdominal tissue intact for women undergoing breast reconstruction using a DIEP flap in the future. Thus, vNOTES can be safely adopted for RRSO in hereditary breast and ovarian cancer without any evident disadvantages. A multicenter prospective study is necessary to confirm the safety and effectiveness of vNOTES for RRSO.
Notes
Conflicts of interest
The authors declare no competing interests.
Ethics approval
This study was approved by the Institutional Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (approval number: 2023-GB-079).
Patient consent
Informed consent was obtained from all participants.
Funding information
None.