Prophylactic salpingectomy and prophylactic ... - Gacetas SEGO

Surgical Oncology 24 (2015) 335e344

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Prophylactic salpingectomy and prophylactic salpingoophorectomy for adnexal high-grade serous epithelial carcinoma: A reappraisal ~a b, Alvaro Tejerizo García a, M.Reyes Oliver Perez a, *, Javier Magrin nez Lopez a Jesus Salvador Jime a b

Division of Gynaecologic Oncology, 12 de Octubre University Hospital, Madrid, Spain Division of Gynaecologic Surgery, Mayo Clinic, AZ, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 July 2015 Received in revised form 27 September 2015 Accepted 30 September 2015

At present, there is no effective screening of ovarian cancer. Primary prevention may be the only strategy to decrease the mortality from ovarian cancer, not only in women at high risk but also at low risk. Several recent studies have identified the distal fimbriae end of the fallopian tubes as primary precursor of High-grade serous carcinoma. Serous tubal intraepithelial carcinomas and occult invasive serous carcinomas have been identified in 2e17% of the fallopian tubes of BRCA1/2 positive women undergoing risk-reducing salpingo-oophorectomy. Removal of the fallopian tubes with ovarian preservation has been suggested as a reasonable strategy that could reduce the risk of developing ovarian carcinoma in both low and high-risk women. It has been proposed after childbearing in women at high risk to be followed by bilateral oophorectomy at a later date. Bilateral salpingectomy is also suggested for low risk women, at the time of other benign gynaecologic surgery as a primary preventive strategy. Some studies have shown a risk reduction of ovarian cancer in women with bilateral prophylactic salpingectomy. Current research regarding bilateral salpingoophorectomy as primary prevention approach of ovarian cancer is reviewed here. In addition, the potential use of bilateral salpingectomy as prevention approach of ovarian cancer is discussed. © 2015 Elsevier Ltd. All rights reserved.

Keywords: High grade serous carcinoma Serous tubal intraepithelial carcinomas BRCA 1 /2 mutation carriers Salpingectomy and ovarian cancer

1. Introduction Ovarian cancer is the second most common gynaecologic malignancy in developed countries, with a 1e2% lifetime risk of developing the disease. Worldwide, more than 100,000 women die each year of ovarian cancer, making it the fifth most common cause of cancer death in women in the Western world and the most lethal gynaecological malignancy, with an overall 5-year survival of 45% [1,2].

List of abbreviations: US, United States; EOC, Epithelial Ovarian Carcinoma; HGSC, High grade serous carcinoma; TVS, transvaginal ultrasound; STIC, Serous Tubal Intraepithelial Carcinomas; RRSO, Risk-reducing Salpingo-oophorectomy; SEE-FIM, Sectioning and Extensively Examining of the Fimbriated end; HR, Hazard Ratio; OTPC, Ovarian Fallopian tube or Peritoneal Cancer; BC, Breast Cancer; PBS, Prophylactic bilateral salpingectomy; RR, Relative Risk; CHD, Coronary heart disease. * Corresponding author. Division of Gynaecologic Oncology, 12 de Octubre University Hospital, Av. Cordoba s/n 28041, Madrid, Spain. E-mail address: [email protected] (M.Reyes Oliver Perez). http://dx.doi.org/10.1016/j.suronc.2015.09.008 0960-7404/© 2015 Elsevier Ltd. All rights reserved.

In the United States (US), there are approximately 22,000 new cases and 14,000 cancer-related deaths each year from ovarian cancer, making it the most common cause of gynaecologic cancer death. In Europe, the corresponding figures are 66,700 and 41,900, respectively [1,3]. Epithelial ovarian carcinoma (EOC) is the most common histologic type (80e85%) and serous is the most common subtype (75% of EOC) [1]. High-grade serous carcinoma (HGSC) is associated with high mortality perhaps from its surface development and early intraperitoneal spread.

2. Early detection of ovarian cancer EOC is diagnosed at an advanced stage in 60% of patients, with a 5-year survival as low as 25% when advanced stages are considered. However, when the disease is diagnosed at early stage, the 5-year survival is over 90% [1]. Pelvic/transvaginal ultrasound imaging of the ovaries and serum CA 125 antigen have been studied with the aim of establishing

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strategies for early detection of ovarian cancer. However at the present there is no evidence that serial ultrasound scanning or measurements of Ca 125 reduce mortality from EOC. 2.1. CA 125 antigen The first prospective ovarian cancer screening study using CA 125 was published in 1992 by Einhorn et al. They detected 175 women with high CA 125 levels of 5550 Swedish women aged over 50. Of them, six were found to have ovarian cancer. Skates et al. demonstrated that elevated CA 125 levels in women without ovarian cancer had a flat or static profile or decreased with time, whereas levels associated with malignancy tended to rise. Successive studies showed that CA 125 at a fixed cut-off of 35 U/mL had a low sensitivity for Stage 1 disease [1,4]. 2.2. Transvaginal ultrasound (TVS) In the University of Kentucky ovarian cancer screening trial, annual TVS screening was performed on 25,327 women. The reported sensitivity for primary EOC was 81%, specificity of 98.7%, positive predictive value of 14.01%, and negative predictive value of 99.9%, with 9.3 operations carried out per case detected. Serum CA 125 levels were increased (>35 U/mL) at the time of detection in 13 of 15 (87%) patients who had Stage 3 EOC but in only three of 15 (20%) patients who had Stage 1 or 2 [1,4]. The results agreed with those obtained in the Japanese Shizuoka Cohort Study of Ovarian Cancer Screening [5]. 2.3. CA 125 vs. TVS The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial [6], a randomized controlled trial of 78216 women aged 55e74 years assigned to undergo either annual screening with CA 125 (using a cut-off of 35 U/mL) and TVS vs. no screening (usual care), found no difference in mortality between both groups but a significant increase in morbidity (5.1%) in the screened group, mainly from unnecessary surgery due to false-positive ultrasound findings. Preliminary results from the United Kingdom Collaborative Trial of Ovarian Cancer Screening [7] which targeted similar women, reported potentially improved results using an algorithm-based CA125 testing with secondary TVU examination (multimodal screening) to ultrasound screening alone. For the detection of primary invasive ovarian cancers, multimodal screening had a sensitivity of 89%, as compared to the sensitivity of the ultrasound-based strategy, which was 75%. At the present there is no evidence that serial ultrasound scanning or measurements of Ca 125 reduce mortality from EOC. There is no evidence of an effective screening system to diagnose ovarian cancer at an early stage. 3. The fallopian tube, the primary precursor of HGSC Classically, the origin of the HGSC was thought to result from the invagination of the germinal epithelium from the ovarian surface. However, most histopathological studies have not largely confirmed the existence of HGSC precursors in the germinal epithelium, but the belief has persisted with the view that the rapid growth of HGSC may destroy the precursors from which it arose [8]. The germinal epithelium theory has been recently challenged by two observations. First, the identification of serous tubal intraepithelial carcinomas (STIC) and occult invasive serous carcinomas in the fimbriated end of the fallopian tubes examined from women with germ line mutations in the BRCA1/2 genes who undergo riskreducing salpingo-oophorectomy (RRSO). These lesions

morphologically and molecularly resemble HGSC. Second, tubal mucosal involvement with STIC or invasive carcinoma has been observed in 60e75% of sporadic (non hereditary) ovarian, fallopian tube and primary peritoneal HGSC [9,10]. Thus, STICs have been suggested to be a putative precursor to ovarian and peritoneal serous carcinoma. 3.1. Early molecular changes in the fallopian tube: P53 signatures Several studies have established a relationship between early serous carcinoma in the fimbria and overexpression of p53 and TP53 mutations. It has been defined the term “P-53 signatures” as a linear stretch of al least 12 consecutive, morphologically benign, intensely p53 inmunorreactive secretory cells with a low proliferative index [2,4,11]. Although these lesions are found more frequently in association with STICs, they have also been described in normal appearing fallopian tubes of women without STICs or carcinoma (67% vs. 20e32%) [2,11e13]. Around 50% of p53 signatures contain TP53 mutations. The majority exhibit evidence of DNA damage by immunoreaction for gamma-H2AX [2,13,14]. Thus, P53 signatures probably represent early clonal expansion short of neoplastic proliferation. The similarity of gene expression signatures of fallopian tube epithelium and HSCG, and the coexistence of STIC with identical TP53 mutations to those in tumours classified as ovarian in origin are consistent with the idea that the distal fallopian tube is an important site for the initiation of HSCG. Jarboe et al. described a morphologic continuum of epithelial changes taking place in the distal fallopian tube. The transition is as follows: normal fallopian tube epithelium, overexpression of p53, STIC, and finally, invasive serous carcinoma [4,14]. P53 signatures are found in both women with and without BRCA1/2 mutations at the same frequency (10e38% vs. 17e33%) [12,14]. That similar frequency of p53 signatures in both groups suggests that the initiation of DNA damage and p53 accumulation is independent of BRCA mutation status, though a germ line BRCA mutation promotes the risk of transition from a p53 signature to malignancy [15]. Bowtell proposed a model with a different sequence of events: early p53 loss, followed by BRCA loss, leading to a deficiency in homologous recombination repair of DNA double-strand breaks, which initiates chromosomal instability and widespread copy number changes that are consistent features of HGSC. Copy number change can be a driver of molecular subtype specification and results in global changes in gene expression. Subsequent mutations provide further advantages for tumour growth but may not be molecular subtype specific [2,14]. However, because p53 immunostaining can occur in both normal and neoplastic epithelium, additional biomarkers staining may improve the rate of detection of serous carcinomas. Inmunostaining for MIB-1 (Ki67) is helpful to detect proliferative cells. The combination of a high index of both MIB-1 and p53 in the same epithelial area correlated strongly with atypia and serous neoplasia [11]. 3.2. Fimbrial origin of HGSC: STIC The distal fallopian tube, eg, fimbria, seems to be the dominant site of origin for early malignancies. No Cancer has been described in the intramural portion of the tube. Medeiros et al. propose three explanations why the Fimbria is the most likely place to generate HCSG. First, the fimbria contains a larger surface area than the more proximal tube, which increases the risk simply by surface area. Second, fimbrial involvement reflects potential differences between the mucosa of the fimbria as compared to the remaining


mucosa of the tube. Third, the fimbrial mucosa is exposed to the peritoneal cavity, is in close proximity to the ovarian surface, and merges with the serosal mesothelium, forming a ‘‘mullerianmesothelial’’ junction [11,16]. Protocols that extensively examine the fimbria will maximize the detection of early tubal epithelial carcinoma in patients at risk for ovarian cancer. In 2005, the Sectioning and Extensively Examining of the Fimbriated end protocol (SEE-FIM protocol) was instituted at Brigham and Women's Hospital and specified more thorough sectioning of the fimbriated end [16,17]. The protocol dictated the amputation of the fimbria from the proximal tube and divided in at least four longitudinal sections and the submitting the remaining tube for histologic review. An increased rate (up to 17%) of early cancer detection was noted with more extensive sectioning [13,14,18]. Mahe et al. [19] examined deeper sections from 56 cases of pelvic carcinoma in which the initial H&E sections of the fallopian tubes were negative for STIC. Of them, 4 cases of STIC were identified after examination of multiple deeper sections of the fallopian tubes. A follow-up study showed that the frequency of STICs detection increased from 35% to 50% in patients with primary peritoneal serous carcinoma when random sampling was replaced by the SEE-FIM protocol [10]. Although, tubal mucosal involvement with STIC or invasive carcinoma has been observed in 60e75% of non-hereditary ovarian, fallopian tube and primary peritoneal HGSC [9,10], there are few studies reporting the identification of STIC and occult invasive serous carcinomas in the fallopian tubes from low risk women undergoing surgery for benign disease. 3.3. Histological detection of STIC Rabban et al. [20] reported on the results of a prospective study in low risk population using a systematic protocol of examination sectioning of the fallopian tubes removed during surgery for benign indications STIC was identified in the fallopian tubes of 4 of 522 patients (0.7%), and one of them was associated with an occult ovarian carcinoma. Because of study design limitations, their findings cannot be directly translated to estimate the incidence of STIC in the general population but two important observations are worth to emphasize. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women and in addition three of the STICs would have gone undetected using the current standard protocol of tube sampling (only a single random section of the tube). Thus, systematic examination of the fallopian tube fimbriae in low-risk women will indeed identify cases of early-stage tubal cancer that would otherwise have not been recognized. 4. Prophylactic salpingo-oophorectomy in high-risk women Familial predisposition has been described in 5e10% of women who develop ovarian cancer. Most of them are associated with mutations in the BRCA1 and BRCA2 genes. Women with deleterious germline mutations in the BRCA1/2 genes have a lifetime (to 70 years of age) risk of ovarian cancer which ranges from 36% to 63% for BRCA 1 mutation carriers and from 10% to 27% for BRCA2 mutation carriers. In addition they have a lifetime risk of breast cancer of 56e84% [10,21e24]. Accordingly, once childbearing is completed, RRSO is recommended to reduce their risk of ovarian and breast cancer. 4.1. Surgical technique of RRSO The peritoneum lateral to the infundibulopelvic ligament is divided to identify the ureter. A peritoneal window is created

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between the ureter and the infundibulopelvic ligament and the latter is divided. The peritoneal attachments of the adnexa are divided and the ovarian ligament and the fallopian tube are transected flush with the uterus. 4.2. Occult carcinoma at RRSO in BRCA mutation carriers: incidence As summarized in Table 1, the reported incidence of occult neoplasia identified at the time of RRSO in germline BRCA1/2 mutation carriers ranges from 2 to 17% [10,17e19,25e28]. That wide range can be explained by the different methodology of the studies, type of patients included, and the histopathological analysis technique used to review the tubes. The Gynaecologic Oncologic Group (GOG-199) [28] recently reported the largest series of known BRCA carriers reported to date. A non-randomized prospective study was carried out following a standardized surgical and pathological protocol. A total of 25 (2.6%) occult neoplasms in 966 RRSOs were identified, including 4.6% in BRCA1 mutation carriers, 3.5% in BRCA2 mutation carriers, and 0.5% in noncarriers. Also, results of the Gynaecologic Oncologic Group showed that women with abnormal CA-125 serum levels or abnormal TVS are more likely to have invasive neoplasms at RRSO. On the other hand, a history of invasive breast cancer has been associated with a reduced risk of occult carcinoma [27]. 4.2.1. BRCA 1 vs. BRCA2 incidence The incidence of occult neoplasia seems to be higher in women with a BRCA1 mutation compared to BRCA2. While in BRCA1 mutation carriers the prevalence of occult neoplasm ranges from 4% to 9%, in BRCA2 mutation carriers the prevalence is around 3% [17,28]. Powell et al. [26] describe a total of 10 occult neoplasia in a cohort of 111 women; all occult ovarian carcinomas were detected in BRCA1 patients, whereas all BRCA2 carcinomas involved only the fallopian tube. Colgan et al. found five occult carcinomas (8.3%) in a series of 60 consecutive prophylactic RRSO; all five had BRCA1 mutations [29]. 4.2.2. Age of diagnosis As is shown in Table 1, the age at diagnosis of occult carcinoma ranges from 38 to 73 years of age. Most occult carcinomas are found in women over 45 years of age. In the study carried out by Powell et al. [27] the odds of finding occult carcinoma was 4 times greater (odds ratio, 4.3; 95% confidence interval, 1.06e20.7) in women older than 50 than in younger ones (P ¼ 0.023). Callahan et al. [10] concluded that age over 44 years at the time of the RRSO was significantly associated with the identification of occult tubal neoplasia. Finally, none of the women with occult neoplasms from the study of the Gynaecologic Oncologic Group was younger than 42 years, concluding that occult neoplasm prevalence is higher among older post-menopausal women [28]. 4.2.3. Stage at diagnosis Most of the occult neoplasms identified at RRSO are early stage and many are non-invasive high-grade intraepithelial neoplasias. Rebeck et al. [30] reported six women with ovarian cancer diagnosed at time of RRSO and all were stage I. Scheuer et al. [31] found two occult carcinomas in 90 women (2.2%) undergoing prophylactic surgery: one early-stage ovarian neoplasm and one earlystage fallopian tube neoplasm. Both had preoperative negative transvaginal ultrasounds. In 2006, Powell et al. [18] detected seven malignancies (10.4%) in 67 patients, six of which were microscopic. In the GOP -199 [28] fourteen of 25 neoplasms were stage 0 to II, including five ovarian and nine tubal malignancies (four were STICs).

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Table 1 Incidence of Early pelvic serous carcinoma in RRSO from BRCA1/2 mutation carriers. Author (year)

Colgan et al. [29] (2001) Leeper et al. [58] (2002) Olivier et al. [59] (2004) 16 Powell et al. [18] (2005) Finch et al. [32] (2006) Medeiros el al [16] (2006) Connor et al. [17] (2014) Powell et al. [27] (2011) Rebbeck et al. [30] (2002) Sherman et al. [28] (2014)

N

OC at RRSO n (%)

Ovarian involvement n (%)

Tubal involvement n (%)

Fimbria involvement n (%)

BRCA1 carriers n (%)

BRCA2 carriers n (%)

Age at diagnosis mean (range)

Stage at diagnosis

Positive PW n (%)

60

5 (8)

3/5 (60)

2/5 (40)

NA

5/5(100)

0/5(0)

51.2 (40e65)

5 ES

NA

30

5 (17)

2/5 (40)

3/5 (60)

NA

3/5 (60)

1/5 (20)

54 (47e65)

5 ES

3 (60)

90

5 (5.5)

3/5 (60)

3/5 (60)

NA

5/5 (100)

0 (0)

42.2 (33e49)

NA

41

7 (17.1)

3/7 (42.8)

4/7 (57.1)

NA

2/7 (28.5)

5/7 (71.4)

50.7 (42e54)

3 ES 2 AS NA

11(2.2)

7/11 (63.6)

3 (27.27)

NA

9/11 (81.81)

2 (18.18)

47.7 (38e68)

5 (38.5)

4/5 (80)

5/5(100)

4/5 (80)

NA

NA

490 13

1/7 (14.2)

NA

3ES 4AS NA

NA 5 (20)

349

19 (5.4)

7/19(36)

18/19 (94)

NA

14/19 (73.6)

5 (26.3)

51(41e76)

NA

8/19 (42)

111

10 (9.1)

3/11 (27)

9/11 (81)

NA

8/11 (72)

2/11 (18)

51 (43e59)

NA

3/11 (27)

259

6 (2.3)

2/6 (33)

NA

NA

NA

NA

NA

6ES

NA

966

25 (2.6)

10/25 (40)

10/25 (40)

NA

15/25 (60)

8/25 (32)

53.2 (42e73)

8 ES 2 AS

NA

NA: Not available; ES: Early Stage (0-II); Advanced Stage (IIIeIV); OC: Occult carcinoma.

4.3. Survival Regarding the long-term outcome of BRCA1/2 mutation carriers found to have unsuspected invasive carcinomas or intraepithelial neoplasia/STIC at the time of RRSO, Powell et al. [25] studied 15 subjects who had invasive carcinoma and 17 who had STIC. They detected 8 recurrences (25%), with a median disease free interval of 32.5 months (range 25e83 months). Compared to women with invasive carcinoma, the recurrence rate was significantly lower in women with non-invasive neoplasia or STIC (1/17, 6%, P ¼ 0.01). BRCA mutation carriers who have undergone RRSO with negative pathology have a 4e5% risk of developing peritoneal serous cancer on follow-up up to 20 years. As a result of recurrence of a previous non-identified ovarian cancer or the subsequent development of primary peritoneal cancer [17,25]. 4.4. Impact of RRSO in BRCA mutation carriers for adnexal, peritoneal and breast cancer Several authors have compared the reduction in Breast, ovarian, tubal and peritoneal cancers in BRCA1/2 carriers for patients with and without RRSO. As shown in Table 2, the reduction in ovarian, tubal or peritoneal cancer (OTPC) is about 80%, while the reduction for breast cancer ranges from 40 to 70%. One reason could be the patient's age at the time of the RRSO for breast cancer risk reduction. It has been suggested there is no apparent benefit for breast cancer risk reduction when it is performed after age 50 [23]. Finch et al. [32] entered a total of 1828 BRCA1/2 mutation carriers in a prospective study and followed them until diagnosis of OTPC or death. In patients without RRSO, there were 32 (4.08%) incident ovarian cancers and in RRSO patients with negative pathology there were 7 (0.7%) patients who developed peritoneal cancer within 3 years from RRSO. The overall reduction in ovarian cancer risk was estimated at 80%. These results agree with those obtained by Kauff et al. [24] in their prospective study with a mean follow up of 24. 2 months. The reduced risk of OTPC reported by Rebbeck et al. [30] was higher and estimated at 96%, and the reduction of breast cancer risk was estimated at 53%. Their conclusion was based on 2 patients with papillary serous peritoneal carcinoma, diagnosed at 3.8 and 8.6 years after RRSO.

The largest prospective study was carried out by Domchek et al. [23] in a cohort of 2482 women with BRCA1/2 mutations. They calculated the risk and mortality reduction stratified by mutation type and prior cancer status. In BRCA1 mutation carriers, RRSO was associated with a 70% reduction in the risk of ovarian cancer in patients without a history of breast cancer while the reduction was 85% in those with prior breast cancer. RRSO was associated with a significantly decreased risk of breast cancer in BRCA 1 (37% reduction) and BRCA2 (64% reduction) mutation carriers. RRSO was also associated with lower all cause mortality (76% reduction), breast cancer specific mortality (90% reduction) and ovarian cancer specific mortality (95% reduction). Marchetti et al. [33] published a meta-analysis of 3 prospective studies, with a total of 9192 patients and a mean follow up of 4 years. The reduction risk for peritoneal cancer after RRSO was 81% (Hazard Ratio (HR) ¼ 0.19 (95% CI: 0.13e0.27)), significantly greater for BRCA 1 carriers (HR ¼ 0.20; 95% CI: 0.12e0.32, p < 0.00001). There was also a benefit for all-causes mortality incidence. These results are consistent with Rebbeck et al. metaanalysis [22] reporting an 80% reduction in OTPC risk and a 50% reduction in breast cancer risk associated with RRSO in BRCA1/2 mutation carriers. 4.5. Impact of RRSO in quality of life of BRCA mutation carriers Several studies have analysed the impact on quality of life and health of RRSO in high risk women, particularly when it is done prior to natural menopause. Included aspects are general health, cancer worry, menopausal symptoms, sexual functioning and satisfaction with the decision made. In the short term, overall quality of life for all patients after RRSO is comparable to that of the general population and to that of the high risk population that prefer only screening. Nonetheless when RRSO is performed prior to natural menopause, due to the sudden and severe decrease of estrogen and androgen levels, vasomotor symptoms related to surgical menopause and changes in sexual functioning are noticeable. Hot flashes, night sweats and sweating and a decline in sexual function it is frequently referred after RRSO in premenopausal women. Vaginal dryness and dyspareunia, and less pleasure and


339

Table 2 Risk Reduction of Ovarian/Tubal/peritoneal and Breast cancer in women at risk (BRCA1/2) underwent to RRSO vs. No RRSSO. Author (year)

Study design

Time of follow up

N

Kauff et al. [24] (2002) Kauff et al. [60] (2008) Rebeck et al. [30](2002) Domchek et al. [22] (2010) Finch et al. [32] (2006)

PC

24.2 months

PC

3 years

1079

RC

8 years

551

PC

3 years

2482

PC

3.5years

1828

170

Group

Diagnosis of BC during follow up

Diagnosis OTPC during follow up

Time to the diagnosis after RRSO (mean)

Reduction in BC risk

Reduction in OTPC risk

A: 98 B: 72 A: 509 B: 570 A: 551 B: 292 A: 465 B: 1092 A: 1045 B: 783

3/98 (3%) 8/72 (11%) 19/303 (6.27%) 28/294 (9.5%) 21/99 (21.2%) 60/142 (42.3%) 39/336 (11.6) 223/1034 (21.6) NA NA

1/98 (1.02%) 4/72 (22.2%) 3/509 (0.58%) 12/283 (4.24%) 2/259 (0.8%) 58/292 (19%) 6/465 (1.3% 63/1092 (5.8%) 7/1034 (0.7%) 32/783 (4.08)

16.3 months. NA 37 months 16 months 3.8 and 8.6 years 8.8 years NA NA 3 years NA

68% HR ¼ 0.3; 95% CI, 0.08e1.20 72% HR ¼ 0.28; 95% CI, 0.08e0.92 53% HR ¼ 0.47; 95% CI, 0.29e0.77 46% HR ¼ 0.54; 95% CI, 0.37e0.79 NA

85% HR ¼ 0.15; 95% CI, 0.02e1.31 85% HR ¼ 0.15; 95% CI, 0.04e0.56 96% HR ¼ 0.04; 95% CI, 0.01e0.16 72% HR ¼ 0.28, 95% CI, 0.12e0.69 80% HR ¼ 0.20; 95% CI, 0.07e0.58

BC: Breast cancer; OTPC: Ovarian/Tubal/peritoneal cancer PC: Prospective cohort study; RC: Retrospective cohort study; NA: Not available; A: Patients with RRSO; B: Patients without RRSO; CI: Confidence interval.

satisfaction during sexual activity are noted. Hormone replacement therapy can be an option for BRCA carriers without prior breast cancer after RRSO when performed prior to menopause. However, it mitigates some but not all of these symptoms. Despite the impact of RRSO, BRCA mutation carriers report high levels of satisfaction with their decision. RRSO Women reported fewer cancer-related worries than women having only screening [34e37]. Long term studies on the impact on health of RRSO in high risk women are not available. 5. Prophylactic salpingogoophorectomy in low risk women Hysterectomy is the most frequently performed gynaecological surgical intervention among women of reproductive age. Between 4% and 18% of patients with ovarian cancer have undergone a previous hysterectomy for benign conditions with ovarian conservation [38]. Because of this, elective bilateral salpingooophorectomy has been routinely offered to women 40 years or older at the time of hysterectomy to prevent the development of ovarian cancer risk. Bilateral salpingo-oophorectomy is performed in 40% of benign hysterectomies among women aged 40e44 years; 60%, among women aged 45e50 years; and 78%, among women aged 50e55 years [39,40]. The decision to perform an elective bilateral prophylactic salpingoophorectomy at the time of hysterectomy must be carefully evaluated. On the one hand, concomitant oophorectomy significantly reduces the likelihood of reoperation for benign ovarian pathology and the risk of ovarian cancer. On the other hand, several recent studies have shown that prophylactic salpingogoophorectomy could have negative effects on mortality and morbidity in patients at low risk of ovarian cancer, especially when performed in premenopausal women. 5.1. Impact of oophorectomy in premenopausal women Several small studies have shown that bilateral oophorectomy at the time of surgery for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease and lung cancer, especially when the oophorectomy is performed before 45 years of age [39,41,42]. The largest prospective study, with the longest follow-up (24 years), to examine the effect of bilateral oophorectomy on health outcomes in general population was carried out by Parker et al. [41] with a total of 29,380 women participants of the Nurses' Health Study who had a hysterectomy with or without bilateral

oophorectomy for benign disease. Concurrent bilateral oophorectomy was associated with a higher risk of all-cause mortality when compared with ovarian conservation. Furthermore, prophylactic oophorectomy did not improve survival at any age. This risk was significantly higher among women younger than 50 years of age at the time of surgery (HR 1.40, 95% CI 1.01e1.96). Oophorectomy was associated with an increased risk of coronary heart disease; this increase was statistically significant for all women (HR 1.17, 95% CI 1.02e1.35) and for those before age 45 years (HR 1.26, 95% CI 1.04e1.54). The risk of stroke was increased for women younger than 50 years of age at the time of surgery (HR 2.19, 95% CI 1.16e4.14). When adjusted for age, death from stroke was reduced 6% per year of delayed menopause. Although the risks of breast (HR 0.75, 95% CI 0.68e0.84) and ovarian cancer (HR 0.04, 95% CI 0.01e0.09) decreased after oophorectomy, lung cancer incidence (HR1.26, 95% CI 1.02e1.56), and total cancer mortality (HR1.17, 95% CI 1.04e1.32) increased. The risk of breast cancer was lower among women having oophorectomy before the age of 45 years (HR 0.62, 95% CI 0.53e0.74). Also, data from the Mayo Clinic Cohort Studies [37,43] showed an association between either unilateral or bilateral oophorectomy in premenopausal women and increased risks of Parkinsonism, dementia, cognitive impairment, anxiety, and depression. When bilateral oophorectomy was performed, the increased risk of cognitive impairment or dementia was restricted to the stratum of women who underwent oophorectomy before age 49 years and were not given estrogen until at least age 50. For both unilateral and bilateral oophorectomy, the association was age-dependent, and the risks increased with younger age at surgery.

5.2. Impact of oophorectomy in postmenopausal women During the reproductive years, the ovaries produce estradiol, testosterone, and androstenedione. After menopause, the ovary continues to produce androstenedione and testosterone in significant amounts until age 80. These androgens are converted in fat, muscle, and skin into estrone, the primary estrogen in postmenopausal women. Oophorectomy in postmenopausal women has been associated to osteoporotic fractures [39]. The Women's Health Initiative Observational Study [40] is the other large retrospective study that have evaluated the effect of bilateral prophylactic oophorectomy on mortality and morbility in 25,448 women who underwent hysterectomy with or without adnexectomy. Contrary to the results obtained in the Nurses' Health Study [41], this study reported a decreased risk of ovarian cancer with adnexectomy, but it was not associated with a decrease of the incidence of breast and lung cancer. There were no adverse effects

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on cardiovascular health, hip fracture, cancer or total mortality. The different results in the study are justified by the authors because of the Women's Health Initiative Observational Study was and older cohort at study enrolment (mean age, 63 vs 51 years) and with a shorter follow-up (8 years). In 2007 Parker et al. [39] published the results of a computer model to calculate risk estimates for mortality from the five conditions that seem to be related to ovarian hormones: coronary heart disease (CHD), ovarian cancer, breast cancer, stroke and hip fracture. For women who have a hysterectomy at ages 50 to 54 the probability of surviving to age 80 was 62.46% with ovarian conservation compared with 53.88% if oophorectomy was performed. This 8.6% difference in survival was primarily because of fewer women dying of CHD (15.95% vs. 7.57%) and hip fracture (4.96% vs. 3.38%), far outweighing the 0.47% mortality rate from ovarian cancer after simple hysterectomy for benign disease. If surgery occurs between age 55 and 59, the survival advantage is 3.92%. After age 64, there was no significant difference in survival. They concluded that for women younger than 65, oophorectomy increases the risk of dying from CHD and after age 65 oophorectomy increases mortality primarily due to hip fracture. Due to the low risk of ovarian cancer in the general population and the risk of bilateral oophorectomy in terms of quality of life and mortality from other causes, the authors concluded the procedure may not be justified, especially in women younger than 65 years. 5.3. Prophylactic salpingectomy for ovarian cancer in high and low risk women Because the fallopian tube is postulated as the precursor of HGSC, it has been proposed to perform prophylactic bilateral salpingectomy once fertility is not an issue as an option for prevention of ovarian cancer, allowing women to maintain their own ovarian function and avoiding the negative effects of oophorectomy in both premenopausal and postmenopausal women, especially under 65. 5.4. Salpingectomy: surgical technique Because no cancer has even been reported in the intramural portion of the tube, removal of the isthmic, ampullary and the entire fimbrial portions constitute an adequate prophylactic salpingectomy. Complete preservation of the infundibulopelvic and utero-ovarian ligaments will ensure maintenance of the ovarian function. The tubo-ovarian ligament is first divided at the fimbria, the distal part of the fallopian tube, followed by division of the mesosalpinx along the mesenteric border of the tube while keeping on the fallopian tube under gentle traction. Once the mesosalpinx is divided the tube is transected flush with the uterine cornua, avoiding injury to the utero-ovarian ligament. This procedure can be easily performed with the use of a vessel-sealing device, monopolar cautery or scissors, or bipolar cautery and scissors. (Fig. 2). 5.5. Ovarian function post e salpingectomy One argument against PBS in premenopausal women is the potential risk of ovarian blood supply impairment, which can reduce ovarian function and subsequently result in an earlier menopause. The tubal artery arises from the ovarian artery before entering the ovary, and then continues along the mesenteric border of the fallopian tube, to anastomose with the uterine artery at the uterine cornua (Fig. 1). However investigations on ovarian function after salpingectomy have not observed any alterations in ovarian blood flow or ovarian function. A retrospective comparison of the ovarian function in 79 pre-

menopausal women undergoing hysterectomy versus 79 premenopausal women undergoing hysterectomy and bilateral salpingectomy, for benign disease was reported by Morelli et al. [44]. There was no difference in ovarian function between both groups, as measured by anti-Mullerian hormone, follicle stimulating hormone, antral follicle count, mean ovarian diameter, and peak systolic velocity at 3 months post-operative and compared with preoperative values. There was also no difference in operative time, postoperative stay, time to return to normal activity, and postoperative haemoglobin between the two groups. These results are consistent with other studies [38]. Findley et al. [45] reported the results of a pilot randomized controlled trial on the short term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve. . They prospectively included 30 premenopausal women, randomized to undergo hysterectomy and concurrent salpingectomy (n ¼ 15) compared with hysterectomy without salpingectomy (n ¼ 15). Ovarian function was estimated by the measurement of Antimüllerian hormone preoperatively, 4e6 weeks postoperatively, and 3 months postoperatively. There were not significant difference in the mean levels of Antimüllerian hormone at baseline, 4e6 weeks postoperatively or 3 months postoperatively among women with salpingectomy versus no salpingectomy. A recent study reported the results of a randomized controlled trial of the effects of laparoscopic bilateral prophylactic salpingectomy with a wide excision of the mesosalpinx [46]. One hundred eighty-six women undergoing laparoscopic surgery for uterine myoma or tubal surgical sterilization were randomly divided to standard salpingectomy or wide mesosalpinx excision. Ovarian function was estimated by the measurement prior to and 3 months after surgery, antimullerian hormone, FSH, three-dimensional antral follicle count, vascular index, flow index, and vascular-flow index for each patient. No significant difference was observed between groups. The authors concluded that even when the surgical excision includes the removal of the entire mesosalpinx, salpingectomy does not damage the ovarian reserve. However, there are no data regarding the impact on the start of menopause. No large case controlled or epidemiological studies exist to provide concrete evidence for a potential early menopause after prophylactic salpingectomy.

5.6. Sequalae of fallopian tube preservation after hysterectomy or tubal ligation Preservation of the fallopian tubes in premenopausal women at time of hysterectomy or tubal ligation significantly increases the risk of developing symptomatic benign tubal pathologies [47]. Potential complications due to tubal remnants are hydrosalpinx, tubal pregnancy, torsion, chronic pelvic inflammatory disease, salpingitis, pyosalpinx, tubal prolapse, tubo-ovarian abscess, benign and malignant tubal tumours. The lifetime risk of hydrosalpinx after hysterectomy or tubal ligation has been estimated to be 7.8%. These patients have at least a doubled risk of subsequent salpingectomy due to benign pathology as reported by Guldberg et al. [48]. In a follow-up study, Repassy et al. [49] identified 82 patients who had undergone hysterectomy followed by a second operation for an adnexal condition. In 35.5% of patients, hydrosalpinx was the reason for the second operation. Recently, Vorwergk et al. [47] reported a retrospective cohort study including 540 premenopausal patients after laparoscopically assisted vaginal hysterectomy alone (413 patients) or with PBS (127 patients). There was a higher incidence of benign adnexal pathologies (26.9 vs. 13.9%; P ¼ 0.02), and a higher rate of surgical re-intervention (12.56 vs. 4.16%; P ¼ 0.04) in the hysterectomy alone group.


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Fig. 1. Vascularization of ovarian and fallopian tube.

Fig. 2. Surgical procedure of salpingectomy: 1. Section of tuboovarian ligament. 2. Section of mesosalpinx, as close as possible to the fallopian tube. 3. Section of fallopian tube from the uterus.

5.7. Surgical outcome and short-term postoperative complications of salpingectomy Bilateral salpingectomy has been probed to be a safe procedure [50e52]. The first prospective study on the feasibility and postoperative outcome of laparoscopic hysterectomy with and without bilateral salpingectomy was carried out by Berlit et al. [50]. A total of 25 patients were prospectively enrolled to undergo laparoscopic hysterectomy with bilateral salpingectomy and compared with a retrospective cohort of 25 patients who underwent laparoscopic hysterectomy without bilateral salpingectomy. There were no statistically significant differences concerning overall hospital stay, duration of surgery and blood loss. These results agree with those recently published by Mining et al. [51]. A cohort of consecutive premenopausal women who had undergone hysterectomy plus bilateral salpingectomy (n ¼ 97) because of benign indication was compared with a cohort of

consecutive premenopausal women who had undergone simple hysterectomy (n ¼ 71) for benign conditions. The average operative time, estimated blood loss, intraoperative complications and mean length of hospitalization were similar between groups. There were no significant differences in terms of the incidence of postoperative complications, emergency visits after readmission, and hospital readmission between both groups of patients.

5.8. Impact of prophylactic salpingectomy (PBS) in risk reducing of ovarian carcinoma 5.8.1. Prophylactic salpingectomy in high-risk women Because of the impact of RRSO in the quality of life of BRCA mutation carriers and the effect of oophorectomy on premenopausal women, PBS has been proposed as primary prevention strategy in premenopausal BRCA mutation carriers, completing bilateral oophorectomy when natural menopause occurs or after 50 years of age. However, there are no studies in BRCA mutation

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carriers evaluating the impact of prophylactic bilateral salpingectomy for the reduction risk of OTPC. Some have studied the relationship between bilateral tubal ligation and risk reduction of ovarian cancer in BRCA mutation carriers. The largest study with a total of 2281 BRCA1 and 1038 BRCA2 carriers established that tubal ligation is associated with a reduced risk of ovarian cancer (HR, 0.43; 95% CI, 0.24e0.75; P ¼ 0.003) [53]. This positive trend has been seen in other studies with a lesser number of patients [54]. Performing a prospective randomized trial comparing both prophylactic strategies in BRCA mutation carriers may have ethical conflicts, given the lack of data on risk reduction of ovarian cancer with PBS. On the other hand bilateral oophorectomy decreases breast cancer risk when performed before 45e50.

oophorectomy ($12,626.84 ± $13.11) but more effective at 21.12 ± 0.02 years compared with 21.10 ± 0.03 and 20.94 ± 0.03 years, representing average gains of 1 week and 2 months, respectively. For surgical sterilization, salpingectomy was more costly ($9719.52 ± $3.74) than tubal ligation ($9339.48 ± $26.74) but more effective at 22.45 ± 0.02 years compared with 22.43 ± 0.02 years (average gain of 1 week) with an incremental cost-effectiveness ratio of $27,278 per year of life gained. They concluded that opportunistic salpingectomy should be considered for all women undergoing these surgical procedures. In conclusion, bilateral salpingectomy is probably an effective prevention strategy to reduce the incidence of ovarian cancer in a low risk population but more prospective population-based cohort studies are necessary to establish long-term risks and benefits.

5.8.2. Opportunistic salpingectomy in low-risk women In US, about 600,000 hysterectomies and over 700,000 tubal ligation are carried out each year in premenopausal women. It has been suggested that performing prophylactic bilateral salpingectomy (PBS) at time of hysterectomy and replacing tubal ligation could be a primary prevention strategy for ovarian cancer in the general population. Nonetheless there are a few studies reporting on the impact of PBS in reducing the risk of ovarian carcinoma in general population. The reduction of ovarian cancer risk in women with a history of tubal ligation or hysterectomy has been reported repeatedly, mostly on small populations. In 2011, Cibula et al. [54] published a meta-analysis of the relationship between tubal ligation and the risk of ovarian cancer. They strictly selected 13 studies for analysis and showed a reduced risk of EOC by 34%. The risk reduction was most profound in endometrioid type cancer (Relative risk (RR) 1⁄4 0.40, 95% CI 0.30e0.53), lower yet still present in serous carcinomas (RR 1⁄4 0.73, 95% CI 0.63e0.85) and not present for mucinous tumours. These results are consistent with those obtained in the meta-analysis carried out by Rice et al. [55], with an approximately 26e30% reduction in ovarian cancer risk observed among women who had a tubal ligation or hysterectomy compared to women who never had a tubal ligation or hysterectomy. Also, the reported reduction of ovarian cancer risk was stronger for endometrioid tumours compared to serous tumours. Interestingly, they obtained a similar RR among BRCA carriers (RR ¼ 0.64, 95% CI: 0.43e0.96 vs. RR ¼ 0.70, 95% CI: 0.64e0.76). Recently a nationwide population based study [56], including a total of 5,7005,84 Swedish women, reported a statistically significantly lower risk for ovarian cancer among women with previous salpingectomy, with a 35% reduction risk of ovarian cancer (HR ¼ 0.65, 95% CI ¼ 0.52e0.81). The most pronounced protective effect was observed among women with bilateral salpingectomy, with a 50% decrease in ovarian cancer risk compared to unilateral salpingectomy (HR ¼ 0.35, 95% CI ¼ 0.17e0.73, and 0.71, 95% CI ¼ 0.56e0.91, respectively). In addition, statistically significant risk reductions were observed among women with previous hysterectomy (HR ¼ 0.79, 95% CI ¼ 0.70e0.88), tubal ligation (HR ¼ 0.72, 95% CI ¼ 0.64e0.81), and hysterectomy with PBS (HR ¼ 0.06, 95% CI ¼ 0.03e0.12). In the absence of more prospective studies, some have conducted a cost-effectiveness analysis of opportunistic salpingectomy with mathematical simulation model in a hypothetical cohort of Canadian women undergoing hysterectomy for benign gynaecologic conditions or surgical sterilization [57]. Salpingectomy would reduce ovarian cancer risk by 38.1% (95% confidence interval [CI] 36.5e41.3%) and 29.2% (95% CI 28.0e31.4%) compared with hysterectomy alone or tubal ligation, respectively. Salpingectomy with hysterectomy was less costly ($11,044.32 ± $1.56) than hysterectomy alone ($11,206.52 ± $29.81) or with bilateral salpingo-

6. Conclusions Because there are no screening tools for ovarian cancer, primary prevention appears to be a potentially successful approach to decrease the high mortality associated with this disease, both in, high and low risk women. Removal of the fallopian tubes by itself, without oophorectomy, may reduce the risk of developing ovarian carcinoma in both low and high-risk women since the fallopian tubes are the primary precursors of ovarian and peritoneal serous carcinoma in some patients. The benefits of this strategy remain to be proven. Delaying oophorectomy after PBS in high-risk women will favourably lengthen their premenopausal status. It remains to be determined the benefit and risk of ovarian conservation, the benefit of subsequent oophorectomy, at what time should it be performed if proven to be beneficial, and does ovarian conservation before age 50 increases breast cancer risk or should it be considered only in patients with prophylactic mastectomies. Some of these questions can only be answered with a randomized clinical trial: PBS with delayed oophorectomy vs. RRSO. Search strategy and selection criteria References for this review were identified through searches of PubMed with the search terms “High grade serous carcinoma”, “Serous tubal intraepithelial carcinomas”, “BRCA1/2 mutation carriers”, “Risk-reducing Salpingo-oophorectomy”, “Prophylactic bilateral salpingectomy” and “ovarian cancer” from 2000 until February 2015. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review. Role of funding source The authors have no financial support to report. Conflict of interest statement The authors have nothing to disclose. Author's contributions rez carried out the review of literature, drafted the MR Oliver Pe manuscript, performed tables and figures, and revised it critically for important intellectual content ~a designed the manuscript, helped to review of litera J Magrin ture, drafted the manuscript and revised it critically for important intellectual content A Tejerizo Garcia helped to draft the manuscript and revised it critically for important intellectual content


pez helped to draft the manuscript and revised it JS Jimenez Lo critically for important intellectual content

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All authors read and approved the final version of the manuscript to be published and are agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated.

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