Overall, 65% (77) of the 119 patients had a complementary hysterectomy, which represents 78% of patients who had their uterus in place at the time of RRSO. Twenty-two patients (18%) retained their uterus, and 20 patients (17%) already had a previous hysterectomy. With regard to the surgical approach, laparoscopically assisted vaginal hysterectomy (LAVH) + RRSO was performed in 38 patients (32%), whereas 39 patients (33%) underwent a total abdominal hysterectomy (TAH) + RRSO. The remaining 42 patients (35%) had a laparoscopically assisted RRSO only.
Mean blood loss was similar for LAVH + RRSO and TAH + RRSO (103 mL [range, 20–500 mL] and 117 mL [range, 20–750 mL], respectively) but was significantly less for LRRSO (laparoscopically RRSO; 41 mL [range, 5–300 mL]) (P < 0.01). Mean operative time was similar for LRRSO and TAH + RRSO (76 minutes [range, 30–154 minutes] and 78 minutes [range, 40–225 minutes], respectively) but was significantly longer for LAVH + RRSO (102 minutes [range, 84–135 minutes]) (P < 0.01). Mean hospital stay was 1 day for RRSO only and 2.4 days for patients undergoing hysterectomy (P < 0.001; Table 3).
There were 6 complications (5%), five of which occurred in patients who underwent TAH + RRSO (2 hematomas, 2 cardiac arrhythmias, and 1 iatrogenic cystotomy). Two patients in the laparotomy group required a blood transfusion. The other complication, a hematoma, was in a patient who underwent only laparoscopic RRSO (LRRSO). There was no statistical difference between TAH + RRSO and only LRRSO (P > 0.5).
Four women developed breast cancer after RRSO, three of which had already had a breast cancer before RRSO. Of the 57 women (48%) without breast cancer before RRSO, only one patient developed breast cancer (1.8%). A stage II high-grade serous ovarian cancer (0.8%) was discovered at the time of surgery in a 41-year-old woman. Fallopian tube atypias were identified on final pathology in 8 cases (6.7%). The tubal atypias noted on final pathology were not significant enough to consider them tubal intraepithelial carcinomas (TICs). All were followed conservatively and none have recurred. One patient (0.8%) developed a serous peritoneal carcinoma 5 years after RRSO and died of her disease 2 years later. The patient had negative pelvic cytologic findings. In retrospect, at the time of the recurrence, it was noted that the tubes had not been thoroughly serially sampled. Archival material from the tubes and ovaries were retrospectively serially sampled and immunohistochemistry was performed. No evidence of TICs or precancerous changes was identified.
The current report represents, to our knowledge, the largest single-institution study in French Canadian families with high-risk breast and ovarian cancer. We studied 119 patients over a 10-year period. In our study, RRSO was associated with significant protection against BRCA1- and BRCA2-associated gynecologic cancers.
Forty-three patients (36%) were either not tested or had a negative BRCA mutation test result. These patients had a strong family history of breast or ovarian cancer or a personal history of breast cancer and were included for RRSO in our study. The discussion as to whether there is a benefit for RRSO in women without an identified BRCA1 or BRCA2 mutation remains unsettled. A study from Memorial Sloan-Kettering Cancer Center to address the role of RRSO in BRCA-negative women prospectively evaluated the incidence of breast and ovarian cancer in 165 BRCA-negative patients. During the 3.4 years of follow-up, women from these families had a 3-fold increased risk of breast cancer compared with population rates (standardized incidence ratio, 3.13; 95% confidence interval, 1.88–4.89). However, there was no significantly increased risk of ovarian cancer in this cohort (standardized incidence ratio, 3.13; 95% confidence interval, 1.88–4.89).10 A retrospective study has suggested that RRSO is protective against breast cancer at all levels of risk.11 Further, these women remain potentially at high risk because they could be carriers of other mutations that were either untested or yet undiscovered.12 Finally, the American College of Obstetricians and Gynecologists Practice Bulletin, Hereditary Breast and Ovarian Syndrome, stated that women with a personal or family history who have tested negative for BRCA mutation should be managed based on their family history.3
Only one patient (0.8%) developed a peritoneal carcinoma after RRSO. This risk is independent of RRSO. A multicentric cohort with 555 patients who underwent an RRSO showed an incidence of peritoneal carcinoma of 4.3% at 20 years after the surgery.13
Although we had 8 patients with fallopian tube atypias, these could not be classified as in situ or invasive carcinoma, which is in disagreement with the literature that reported rates of in situ or invasive fallopian tube occult carcinoma ranging from 2% to 10% after RRSO.14,15 Epithelial carcinomas arising in the tubal mucosa can present in 2 ways: The first is the classically described tumor that is confined largely to the tube and expands outward, with invasion of the muscularis. The second is the more recently described pattern in which the tumor commonly arises in the fimbria and spreads rapidly to the peritoneal and ovarian surfaces, that when restricted to the tubal mucosa is called serous TICs; these tumors are usually p53 positive. Also found, but more unusual, are endometrioid intraepithelial carcinomas. Early carcinomas of the tube are virtually always located in the fimbria or ampulla.16 Thereby, the distal tube is potentially the origin of high-grade serous tumors and may account for malignancies previously attributed to the ovaries or peritoneum.17 In 1996, the University of California San Francisco Gynecologic Oncology Program instituted a surgical-pathologic RRSO protocol that was composed of bilateral salpingo-oophorectomy and removal of entire fallopian tube (open or laparoscopic), cytologic examination of peritoneal washings, and serial sectioning of entire fallopian tubes and ovaries at 2-mm intervals and microscopic examination of all sections. The authors concluded that a rigorous operative and pathologic protocol for RRSO increases the detection rate of occult ovarian malignancy in BRCA mutation carriers nearly 7-fold.15 Powell et al,18 in a report of 111 consecutive BRCA-positive women who had RRSO with rigorous surgical protocol with meticulous pathologic review, yielded an overall detection rate of 9.1% for occult gynecological carcinoma in BRCA mutation carriers, followed by a multidisciplinary team at a single institution.
We believe the retrospective character of our study limited the detection rate for occult gynecological carcinoma, and it is a probable flaw of our study (although we had 8 fallopian tube atypias, not classified as TICs or invasive carcinomas). As of today, there is little doubt, if any, about the importance of a rigorous surgical protocol with meticulous pathological review for BRCA-positive women.
Women with breast cancer who are identified with BRCA1 or BRCA2 mutation have a 40% to 50% risk of developing a second breast cancer.19 A history of breast cancer was present in 62 patients (52%) in our cohort. Four patients developed a new breast cancer during the study period. Of them, 3 patients had a breast cancer recurrence, 2 patients were BRCA1 mutation carrier, and the other one was not tested. One patient had never had a breast cancer before RRSO, and she was a BRCA2 mutation carrier. Between the 76 BRCA1 or BRCA2 known mutation-positive patients from our study, only three developed a recurrence or a new breast cancer (the other patient was not tested). These results suggest a protective effect of RRSO, in agreement with the literature, which shows a protective effect with a 40% to 60% reduction of breast cancer risk after RRSO in BRCA1 and BRCA2 mutation carriers.20,21
In our study, the mean age of RRSO was 49 years. Simard et al12 found the mean age for ovarian cancer in a French Canadian population with BRCA1- and BRCA2-positive mutations to be 52.8 years and 56.1 years, respectively. Other studies also found the mean age of ovarian cancer to be approximately 50 years for women with BRCA1 mutations and 60 years for those with BRCA2 mutations.22,23 The literature suggests that the ideal age for RRSO is approximately 35 to 40 years to prevent breast and ovarian cancer in women who have completed their childbearing.24 However, a high percentage of patients will seek genetic evaluation only after a diagnosis of cancer. In the study of Kauff et al,25 the mean age for RRSO was 47.7 years. The same was observed in the study of Finch et al,13 where the mean age of RRSO was 46.4 years. The only way to identify BRCA mutation carriers earlier is by a thorough familial history taking. All health professionals should be alerted to the criteria for referral for BRCA testing.24
Almost 80% of our patients who had their uterus in place chose to undergo a complementary hysterectomy at the time of RRSO. One explanation for our elevated proportion of hysterectomies could be the high proportion of patients who had been treated for breast cancer and who were taking tamoxifen. There are pros and cons when deciding whether or not a complementary hysterectomy should be performed. In our study, there was no statistical difference in morbidity between patients who underwent TAH + RRSO versus RRSO alone. This result may be in part explained by our low morbidity rate in general (5%). One such explanation for our low rate of complications than would be expected is the large known experience of our center with laparoscopic surgeries and vaginal hysterectomies, which represented altogether 67% (80 patients) of our cohort. In the literature, the morbidity associated with an additional hysterectomy is higher than with RRSO alone, in the range of 10%.26 A possible association with an increase in the risk of uterine serous papillary carcinoma in these women has been suggested.27 Hysterectomy also allows a more complete removal of the fallopian tube, which can be the putative origin of serous ovarian cancer in BRCA1 or BRCA2 mutation carriers. However, this is a theoretical risk, once there has never been reported a case in the literature of a cancer in the cornual portion of the fallopian tube.28 In women taking tamoxifen, which is associated with an increased risk of polyps and endometrial cancer, hysterectomy may be appropriate.29 Finally, patients with concomitant benign conditions, such as menorrhagia, fibroids, or uterine prolapse, could also benefit from a hysterectomy. As of today, routine performance of prophylactic hysterectomy remains discretionary, and the decision should be individualized.30
Regardless of some limitations inherent to the retrospective and observational study design, our study confirms the high efficacy of RRSO for the prevention of ovarian, fallopian tube, and breast cancer in a high-risk French Canadian population; and the surgical morbidity of the procedure is low.
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Keywords:Copyright © 2012 by IGCS and ESGO
Risk-reducing salpingo-oophorectomy; BRCA; Prophylactic salpingo-oophorectomy; Prophylactic surgery; Ovarian cancer prevention