Abstract
Background:
Germline BRCA1 or BRCA2 mutation carriers have a lifetime risk of ovarian cancer of up to 46%. Opportunistic salpingectomy has been advocated as a risk-reducing strategy due to increasing recognition of tubal origin yet evidence of efficacy in this high-risk population is limited.
Case:
This is a case of a woman with a BRCA1 mutation who underwent prophylactic mastectomy and bilateral salpingectomy with ovarian retention prior to the age of 40. She did not undergo an oophorectomy and subsequently developed stage IV high-grade serous ovarian cancer 4 years after her initial surgery.
Conclusion:
More research is needed to determine the role of prophylactic salpingectomy with delayed oophorectomy, optimal timing of completion oophorectomy and the risks and benefits compared with upfront risk-reducing salpingo-oophorectomy.
Precis
Delay of oophorectomy after prophylactic salpingectomy may adversely affect ovarian cancer risk in BRCA-mutant carriers.
INTRODUCTION
Ovarian cancer is the leading cause of mortality due to gynecologic malignancy, with an estimated 13,980 deaths per year in the United States.1 Due to the nonspecific symptoms of early-stage ovarian cancer, most patients present with advanced-stage disease; and although most patients will experience remission after combined surgical and chemotherapeutic management, recurrence is usually inevitable. Several germline mutations are known to increase the lifetime risk of ovarian cancer development.2 Approximately 18% of all ovarian cancers are associated with a pathogenic germline BRCA1 or BRCA2 mutation. Patients with these mutations have an increased lifetime risk of ovarian cancer by up to 46% and 27%, respectively, through 70 years of age.2
Professional societies such as the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) have recommended bilateral risk-reducing salpingo-oopherectomy (RRSO) after completion of childbearing (or by the age of 40 for BRCA1 mutation carriers and the age of 45 for BRCA2 mutation carriers) as the primary recommendation for women with these germline mutations.3 This recommendation is based on studies that have demonstrated at least an 80% risk reduction in the development of ovarian cancer.4,5 Compliance with this recommendation, however, has been relatively limited due to concerns about sexual dysfunction, unplanned sterility, premature menopause, with suboptimal quality of life due to vasomotor symptoms, and cardiovascular events.6 Many efforts have been made to develop and establish surveillance methods to address these compliance issues, particularly for patients with such high risk for ovarian cancer.
Current disease theory hypothesizes that the majority of serous tumors originate in the distal fallopian tube, with likely progression from a serous tubal intraepithelial carcinoma (STIC) lesion to high-grade serous ovarian cancer.7 These findings have prompted new approaches to the timing of oophorectomy and whether it should be performed at the time of bilateral salpingectomy or as an interval procedure after bilateral salpingectomy. Furthermore, recent articles have discussed the biological and pathological plausibility of achieving significant risk reduction with bilateral salpingectomy alone, thereby avoiding the hormonal depravation of bilateral oophorectomy. Although no studies have demonstrated that bilateral salpingectomy without oophorectomy is a safe alternative in these patients, trials are underway in germline BRCA mutation carriers undergoing prophylactic bilateral salpingectomy without oophorectomy. We present a case of a woman with a deleterious BRCA1 mutation who underwent a prophylactic mastectomy and bilateral salpingectomy with ovarian retention prior to the age 40. She did not have her ovaries removed after the age of 40 and subsequently developed stage IV high-grade serous ovarian cancer.
CASE
The patient is a 42-year-old known BRCA1 gene mutation carrier who presented to our center due to an elevated serum CA-125 level and concerning transvaginal ultrasound findings. The patient has signed consent for the publication of details of her case. Her family history was significant for breast and ovarian cancers in her grandmother, ovarian cancer in her mother at the age of 55 years, and breast cancer in her maternal second cousin at the age of 50 years. The patient’s BRCA1 germline mutation was diagnosed when she was 35 years old. At age 38, she underwent a prophylactic bilateral mastectomy and bilateral risk-reducing salpingectomy. She was counseled regarding standard treatment of risk-reducing salpingo-oophorectomy (RRSO); however, she expressed concern about surgical menopause and desired prophylactic salpingectomy with delayed oophorectomy (PSDO). At her two preoperative visits, she was counseled that although she could undergo her risk-reduction surgery in two steps, she remained at an increased risk for ovarian cancer during the interval between the two surgeries. She was also recommended to complete her risk-reducing surgery by age 40. She underwent periodic surveillance with clinical examination during the interval, during which time her serum CA-125 level remained in the single digits for 4 years.
Approximately 4 months after turning 42 years of age, her CA-125 level rose to 65 mIU/mL. A transvaginal ultrasound was reportedly unremarkable. A month later, her CA-125 level rose to 139 mIU/mL, and a repeat transvaginal ultrasound identified symmetrically enlarged bilateral ovaries. Magnetic resonance imaging (MRI) of the pelvis identified complex cystic bilateral adnexal masses suspicious for malignancy. A computed tomography (CT) scan of the abdomen and pelvis demonstrated mixed cystic and solid ovarian masses (Figure 1) and a nodular appearance of the bowel mesentery and omentum, consistent with carcinomatosis. There were capsular implants at the hepatic dome and supradiaphragmatic adenopathy (Figures 2 and 3). The patient reported feeling well, with only symptoms of bloating.
Figure 1:
Axial contrast-enhanced computed tomography image shows bilateral complex cystic and solid adnexal masses (white arrows). Peritoneal thickening and nodularity are also noted (black arrow).
Figure 2:
Coronal contrast-enhanced computed tomography image. Black arrow indicates hepatic dome capsular implant with mass effect on the liver parenchyma. The adnexal masses are also visible (white arrows).
Figure 3:
Sagittal computed tomography image. Black arrow indicates mildly enlarged right supradiaphragmatic lymph node. The hepatic capsular implant is also visible (white arrow).
The patient presented to our center with a presumed diagnosis of advanced ovarian cancer. She underwent a laparotomy, which revealed high-grade serous ovarian carcinoma. She underwent a total abdominal hysterectomy, bilateral oophorectomy, omentectomy, splenectomy, right diaphragm peritonectomy, partial hepatectomy, appendectomy, right supradiaphragmatic lymphadenectomy, pelvic lymphadenectomy, rectosigmoid resection and anastomosis, resulting in a complete gross resection. The patient was discharged on postoperative day 5. Final pathology revealed International Federation of Gynecology and Obstetrics (FIGO) stage IVB ovarian cancerwith positive supradiaphragmatic lymph nodes. The patient is currently undergoing postoperative chemotherapy with plans for poly (ADP-ribose) polymerase (PARP) maintenance.
DISCUSSION
Women with genetic germline mutations involving the BRCA1 and 2 tumor suppressor genes are at significant risk for developing lethal cancers at a younger, premenopausal age, necessitating risk-reducing interventions such as prophylactic mastectomy and RRSO.8 While RRSO is associated with a significant reduction in the risk of ovarian cancer development among women with a background predisposition to the disease, adherence to such risk-reducing recommendations is often limited, likely due to the medical, psychological, and quality of life implications associated with surgical menopause.
Women with these background predispositions to ovarian cancer have expressed their desire for RRSO alternatives, as reported by the Facing Our Risk of Cancer Empowered (FORCE) trial, an online survey that assessed the opinions of women with BRCA mutations with regard to PSDO. Approximately one third (34.3%) of eligible high-risk women who participated in the survey expressed that they were “definitely interested” in PSDO, accepting the possible risk of delay in cancer diagnosis without a standard RRSO.9
A recent study by Negben et al. included a prospective pilot study for women with BRCA germline mutations given the option of undergoing RRSO or delaying oophorectomy until the age of 40 for BRCA1 and 45 for BRCA2 mutations. The study’s primary endpoints included acceptability, surgical outcomes, quality of life, and psychological outcomes with PSDO. The study found no increased rate of surgical complications, overall satisfaction with procedure choice, and decreased cancer worry and anxiety after the procedure.10 The study supports patient interest in alternatives to RRSO; however, it did not assess risk reduction of cancer development with PSDO.
A review of the literature identified only one other case of development of high-grade serous ovarian cancer with metastasis after prophylactic bilateral salpingectomy. Sato et al. reported a case of FIGO stage IV ovarian cancer in a 51-year-old woman who had undergone a bilateral salpingectomy and unilateral oophorectomy for a benign indication 3 years earlier. However, there was no comment on the patient’s genetic makeup, so it is unknown whether or not she had a BRCA mutation.11
Harmsen et al. reported 36 cases of women who had undergone RRSO and were later diagnosed with peritoneal carcinomatosis. Thirty-one were BRCA1-mutation carriers and 5 were BRCA2-mutation carriers. The median age at RRSO was 52 years, and the median age of peritoneal carcinomatosis diagnosis was 60 years. None of the women in this study had undergone PSDO and subsequently developed high-grade ovarian cancer.12
Our case emphasizes the need for more research on the optimal timing of RRSO, the role of PSDO, and the risks and benefits of not having a completion oophorectomy after bilateral salpingectomy. PSDO is still an experimental intervention, with no formal guidelines regarding timing of oophorectomy. Until then, oophorectomy should continue to be recommended for women with BRCA mutations who have completed childbearing, with considerations for age, as supported by RRSO management guidelines. Current clinical trials regarding PSDO that may change counseling in the future are ongoing in the US and Europe (Table 1). In our case, it is unclear if her carcinoma arose from retained fallopian tissue in her ovaries after bilateral salpingectomy, a phenomenon proposed by some,13 or due to some other, complex proposed biological process.
Table 1.
Clinical Trials Evaluating ISDO in Women with Germline BRCA mutations
| Clinical Trial | Location | Study Design | Primary Aim | Status |
|---|---|---|---|---|
|
WISP Trial Surgery in Preventing Ovarian Cancer in Patients with Genetic Mutations (NCT02760849) |
US, multicenter | ISDO vs RRSO Non-randomized Prospective Cohort |
Sexual function Quality of life |
Recruiting |
|
TUBA Trial Early Salpingectomy (Tubectomy) with Delayed Oophorectomy to Improve Quality of Life as an Alternative to Risk-reducing Salpingo-oophorectomy in BRCA1/2 Gene Mutation Carriers (NCT02321228) |
Netherlands, multicenter | ISDO vs RRSO Non-randomized Prospective Cohort Study |
Quality of life Menopause-related changes |
Recruiting |
| Prophylactic Salpingectomy with Delayed Oophorectomy (NCT01907789) | US, multicenter | ISDO vs RRSO Non-randomized Prospective Cohort |
Number of participants who complete oophorectomy after primary salpingectomy | Active, not recruiting |
|
PROTECTOR Trial Preventing Ovarian Cancer through Early Excision of Tubes and Late Ovarian Removal (protector.org.uk) |
UK, multicenter | ISDO vs RRSO vs no intervention Non-randomized Prospective Cohort |
Sexual function Quality of life |
Recruiting |
Information acquired with assistance of https://www.clinicaltrials.gov/
ISDO, interval salpingectomy with delayed oophorectomy; RRSO, risk-reducing salpingo-oophorectomy
Our case also reiterates the need for sustained efforts to research and develop optimal screening modalities for the prediction of ovarian cancer, especially in high-risk women, as this patient developed stage IV disease despite adhering to a surveillance protocol after salpingectomy. A recently published prospective cohort study by Gronwald et al. looked at women with BRCA1 mutation to evaluate the risk of death from ovarian cancer and type of surgical or screening intervention used.14 Women enrolled in an ultrasound screening program had the worst survival rates. No studies have evaluated screening protocols for women who have had risk-reducing surgery.
Future studies will hopefully help us formulate appropriate care plans to better counsel our patients with regard to the delicate balance between risk reduction for ovarian cancer and concerns about quality of life after oophorectomy.
Supplementary Material
Teaching Points.
More research is needed about the safety and efficacy of prophylactic salpingectomy with delayed oophorectomy in the high-risk population.
High-risk women undergoing salpingectomy should be extensively counseled about the optimal timing of completion oophorectomy..
Risk-reducing salpingo-oophorectomy is still the gold standard intervention recommended for women with germline mutations predisposinge to the development of ovarian cancer.
Funding:
Drs. Broach and Chi are funded in part by the National Institutes of Health/National Cancer Institute Memorial Sloan Kettering Cancer Center Cancer Support Grant (P30 CA008748).
Footnotes
Financial Disclosure:
Outside the submitted work, Dr. Chi reports personal fees from Bovie Medical Co. (Medical Advisory Board and stock options), Apyx Medical Corp. (Medical Advisory Board and stock options), C Surgeries (shareholder), and Biom ‘Up, (Medical Advisory Board). The other authors did not report any potential conflicts of interest.
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