Sweta Dhakal, Yunxi Zheng, and Xiaofang Yi＊

1Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China

2Department of Obstetrics and Gynecology, Shanghai Medical College,Fudan University, Shanghai 200011, China

3Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China

Current Updates on Salpingectomy for the Prevention of Ovarian Cancer and Its Practice Patterns Worldwide

Sweta Dhakal1,2,3, Yunxi Zheng1,2,3, and Xiaofang Yi1,2,3＊

1Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China

2Department of Obstetrics and Gynecology, Shanghai Medical College,Fudan University, Shanghai 200011, China

3Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China

ovarian cancer; salpingectomy; prevention; clinician opinion

A paradigm shift of the origin of ovarian cancer to fallopian tube has brought more focus on bilateral salpingectomy as a preventive method for ovarian cancer. Bilateral salpingectomy has shown a dramatic reduction in the risk of ovarian cancer. Bilateral salpingo-oophorectomy has been a long-used practice to prevent ovarian cancer, but it brings surgical menopause and an increased mortality rate to women undergoing such a surgery at the age of ＜47.5. With the prophylactic bilateral salpingectomy, however, the ovarian function remains unaltered. Recent studies have shown that prophylactic salpingectomy was helpful not only in preventing high-grade serous type ovarian cancer, but also in decreasing adnexal pathologies. With the publication of committee opinion, more practitioners have accepted this proposal, but some are more concerned about its disadvantages. This review illustrates the latest updates on salpingectomy as a preventive method for ovarian cancer, including its advantages and disadvantages, clinicians’ opinions, public opinions, so as to find out Obstetricians’ and Gynecologists’ practice pattern related to opportunistic salpingectomy worldwide.

O VARIAN cancer is the fifth leading cancer in women and of all gynecological neoplasms,and it has the highest mortality rate.1In the USA, it is estimated that 22 280 new cases will be diagnosed with ovarian cancer in 2016 and 14 240 deaths are expected.2

In an annual screening with CA125 and trans-vaginal ultrasound in 35 000 women among which, 70% of screen-detected ovarian cancer women were reported with an advanced stage of disease.3The aggressiveness of this disease is a matter of concern for its early detection, treatment and prevention. The risk of ovarian cancer increases in women who have ovulated more over their lifetime, like those who never have children,whose ovulation started at a younger age, who reached menopause late, and those with a family history of ovarian cancer and being breast cancer mutation (BRCA)carriers. It was found that the use of oral contraceptive pills lowered the risk of ovarian cancer withOR=0.70(95%CI0.52-0.94) in hospital studies andOR=0.66(95%CI0.55-0.78) in population studies.4The presence of serous intraepithelial neoplasm in the fallopian tube in women with BRCA1 and BRCA2 mutations who had undergone bilateral salpingo-oophorectomy (BSO)has brought more curiosity to researchers. Due to the site of tumor being the ovary, fallopian tubes were always neglected. After the lesion was discovered in women with heredity predisposition, various studies started emerging stating about the cells origin of ovarian cancer shifting from the ovary to the fallopian tube.5-6Since the focus was taken on the fallopian tube,a few clinicians started conducting bilateral salpingectomy in women undergoing hysterectomy for benign causes, and even in women with genetic mutation who deny for BSO, and this resulted in significant decrease in ovarian cancer. Bilateral salpingectomy, unlike BSO,does not hamper the quality of life. Ovarian blood supply and ovarian function remain unaltered if the surgery is performed cautiously. Clinicians still hesitate to discuss with patients about the benefit of bilateral salpingectomy. And many clinicians are still unaware about the new cancer pathogenesis and the risk reducing strategy.

Our objective of this study is to review the latest studies done on salpingectomy as a preventive method for ovarian cancer, including the advantages and disadvantages, latest clinician opinions, public opinions on this matter, and to find out Obstetricians’ and Gynecologists’practice patterns related to opportunistic salpingectomy worldwide.

THE ORIGIN OF OVARIAN CANCER, IS IT THE FALLOPIAN TUBE?

The origin and pathogenesis of ovarian cancer are poorly understood. Evidence from different research hints that the origin of ovarian cancer is from the fallopian tube rather than the ovary. According to the dualistic model of carcinogenesis, epithelial ovarian cancer has been divided into two categories: type I and type Ⅱ. Type Ⅰ tumors include low-grade serous, low-grade endometrioid, clear cell, and mucinous carcinomas; whereas type Ⅱ tumors consist of high-grade serous carcinomas, high-grade endometrioid carcinomas, malignant mixed mesodermal tumors, and undifferentiated carcinomas. Type Ⅰ tumors are genetically stable and undergo KRAS, BRAF, PTEN,PIK3CA, CTNNB1, ARID1A and PPP2RIA mutations, but rarely TP53 mutation; Type Ⅱ tumors are mainly high grade serous carcinoma (HGSC), highly unstable, and undergo TP53 mutation. BRCA inactivation occurs in up to 40%-50% of HGCS, but it has not been reported in typeⅠ tumors.7It has been proposed that low-grade and highgrade serous tumors arise from the implantation of the epithelium from the fallopian tube but not the ovary. During ovulation, fimbria comes close in contact with ovary, and tubal epithelial cells are implanted on the disrupted ovarian surface and thus to form cortical inclusion cysts.6Endometrioid and clear cell tumors are associated with endometrial tissue implanted in the ovaryviaretrograde menstruation.8Mucinous and transitional tumors are said to arise from the transitional-type epithelium nests at tubal-epithelial junction.5-6

HGSC is the most common subtype of ovarian cancer,and we will be discussing in detail about its fallopian origin.Firstly, the gene expression of HGSC is closely related to fallopian tube rather than ovarian epithelial surface. Immunohistochemical study showed that HGSC expressed PAX8, a müllerian marker, but not calretinin, a mesothelium marker,6whereas ovarian surface epithelium is mesothelium in origin. HGSC shows TP53 mutation, and normal fallopian tubes also show TP53 signatures with TP53 mutation occasionally occurring.6Secondly, serous tubal intraepithelial carcinoma (STIC) was identified in a specimen of women with hereditary predisposition to ovarian cancer.9Previously fallopian tube was not carefully examined in ovarian cancer patients, so lesions in the fallopian tube were missed. After careful examination, it was found that STICs were even seen in 50%-60% of women without known BRCA mutation.10-11Concomitant presence of TP53 mutation in women with STIC and HGSC made it clear that HGSC might have arisen from the fallopian tube but notfrom the ovary. STIC and HGSC also co-expressed p16,FAS, Rsf-1 and cyclin E1.12Like other precancerous lesions,STIC also showed short telomere.13Dysplastic lesion in the fallopian tube was commonly found in the fimbriated end of the fallopian tube rather than in other segments.14Furthermore, Kimet al15have provided further evidence of the fallopian tube as the source of HGSC in their mouse model. They found that, HGSC developed in mice that underwent bilateral oophorectomy and had fallopian tubes intact, but did not develop in mice that underwent bilateral salpingectomy and had ovaries intact. Not only HGSC but also other epithelial ovarian cancers are thought to be derived from the fallopian tube and endometrium, but not directly from the ovary. With all this evidence, it is possible to relate fallopian tube to be the origin of ovarian cancer,mainly for the high-grade serous type.

EVIDENCE SHOWING THE BENEFITS OF PROPHYLACTIC BILATERAL SALPINGECTOMY

In consideration of this paradigm shift of the origin of ovarian cancer to fallopian tube, clinicians started to try prophylactic bilateral salpingectomy to prevent ovarian cancer. Initially in 2014, Lessard-Andersonet al16studied the effect of excisional tubal sterilization technique on the risk of serous epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), in which, from 1966 to 2009, 194 cases of EOC and PPC and 388 cases of the control group were included. The rates of tubal sterilization were 72%(14/194) in the study group and 11.9% (46/388) in the control group. Among those who had tubal sterilization,excisional tubal sterilization was received by 36% (5/14)of the study group and 55% (25/46) of the control group,and complete salpingectomy was received by 13% (6/46)of the control group and 0 case in the study group. Excisional tubal sterilization alone showed 63% decrease in the risk of EOC and PPC. Then in 2015, Madsenet al17further studied the effect of bilateral salpingectomy on reducing the risk of epithelial ovarian cancer, comprising 13 241 cases with epithelial ovarian cancer and 194 689 cases of the control group. In the disease group, 89 underwent unilateral salpingectomy and 17 underwent bilateral salpingectomy. In the control group, 1382 underwent unilateral salpingectomy and 411 underwent bilateral salpingectomy.Bilateral salpingectomy was associated with 42% decrease in the risk of epithelial ovarian cancer; but in the unilateral salpingectomy group, the risk reduction was smaller and not significant. Even though there was limited number of bilateral salpingectomy cases, it was associated with a decreased risk of epithelial ovarian cancer. Further Falconeret al18studied a cohort of women in Sweden from 1973 to 1996 and followed through 2009, with the mean age of 35.9 years and mean follow-up of 23.1 years, including 98 026 females who had hysterectomy. Among them,37 348 had hysterectomy with BSO, 34 433 had salpingectomy, and 81 658 had sterilization. Women with hysterectomy and concomitant salpingectomy constituted a small group (n=2646) and were excluded from analysis. A significant reduction in the risk of ovarian cancer was seen in women undergoing salpingectomy. Those who underwent unilateral salpingectomy showed a reduction withHR=0.71(95%CI=0.56 to 0.91), and those who had bilateral salpingectomy showed 50% of reduction in the risk of ovarian cancer withHR=0.35 (95%CI=0.17 to 0.73). Kwonet al19further focused on the risk of ovarian cancer in patients who underwent hysterectomy alone, who had hysterectomy with salpingectomy and who had hysterectomy with BSO for benign gynecologic conditions or surgical sterilization. In total, 28 000 cases underwent hysterectomy; 270 cases were diagnosed with ovarian cancer after hysterectomy alone; 167 cases were diagnosed with ovarian cancer after hysterectomy with salpingectomy, which showed a 38.1% reduction in the risk of ovarian cancer in women who underwent hysterectomy with salpingectomy compared to those with hysterectomy alone. Hysterectomy with BSO showed a dramatic decrease in ovarian cancer with the reduction of 88.1%. But when death due to premenopausal BSO was compared, 934 cases died after BSO and 8 cases died after salpingectomy. Kwon even compared the risk of ovarian cancer between the two sterilization groups: there was a 29.2% reduction in ovarian cancer posterior to salpingectomy, compared to tubal ligation. Vorwergket al20researched in 540 premenopausal women undergoing hysterectomy for benign causes.Among them, 127 patients underwent prophylactic bilateral salpingectomy. Postoperatively, in 60 women who did not undergo prophylactic bilateral salpingectomy, the occurrence of adnexal pathologies was noted, in which 33 cases had ovarian cyst, 18 adnexitis, 8 hydrosalpinx and 1 pyosalpinx. Hysterectomy related surgical interventions were higher in the group who did not undergo prophylactic bilateral salpingectomy. Study showed that, preservation of fallopian tube in premenopausal women increased the risk of adnexal pathologies and even increased the risk of re-surgery. Bilateral salpingectomy not only can reduce ovarian cancer but also can reduce some benign ovarian and fallopian tube diseases.

Tubal ligation has widely been performed for permanent contraception. Previously, tubal ligation has also shown some reduction in the risk of ovarian cancer, especially the ovarian endometrioid subtype.21Cibulaet al22conducted research on tubal ligation and the risk of ovarian cancer, which reported an overallHR=0.69 (95%CI=0.64 to 0.75). Riceet al23studied the risk of ovarian cancer with tubal ligation, which showedHR=0.67 (95%CI=0.49-0.90)when tubal ligation was done at the age of ＜35. Though these two studies showed reductions in the risk of ovarian cancer, emerging theories on initial fimbrial involvement in ovarian cancer make us suspicious about its prevention of high-grade serous type ovarian cancer. Daniset al24compared salpingectomy and tubal ligation in respect to estimated blood loss, duration of surgery and complications.He involved 64 patients who had undergone tubal ligation and 16 patients with salpingectomy; no difference was found between these two groups.

Even though BSO has shown to reduce the risk of ovarian cancer, it also affect the quality of life. Women were more osteoporotic, more prone to coronary artery diseases,and hypoactive sexual desire was noticed. In a Nurse Health Study, it suggested that oophorectomy before age 47.5 may be associated with increased risk of death from cardiovascular disease and even increased risk of dementia and cognitive impairment.25-28

Kwonet al29concluded that in BRCA carriers, bilateral salpingectomy with delayed oophorectomy was effective in terms of quality-adjusted life expectancy.

EVIDENCE SHOWING THE RISKS WITH PROPHYLACTIC BILATERAL SALPINGECTOMY

Even at knowing the reduction in the risk of ovarian cancer by bilateral salpingectomy, whether or not to carry it out as a preventive method is a big question.What about its side effect? Actually this question was first addressed in animal models. Zhaoet al30experimented on monkeys to see their ovarian function after bilateral (B/L) salpingectomy. The result showed all salpingectomized monkeys had at least one corpus luteum with a distinct stigma on one ovary, same as the result of sham-operated monkeys, and no demonstrable endocrine changes were seen. Halmeet al31experimented on nine rabbits undergoing B/L salpingectomy and other nine undergoing sham operation. They found there were no significant difference in progesterone level, the means of the number and the weight of corpus luteum.Further research was done to show the effect of salpingectomy on ovarian function, Morelliet al32enrolled 79 patients who underwent only total abdominal hysterectomy (TAH) and other 79 patients who underwent TAH with salpingectomy. Their study revealed no statistical difference between the two groups in terms of anti-mullerian hormone (AMH), follicle stimulating hormone(FSH), antral follicle counts (AFC) and mean ovarian diameters. Then Findlayet al33further focused on hormonal changes and blood loss by salpingectomy. In this research, 15 patients underwent laparoscopic hysterectomy, and another 15 patients received laparoscopic hysterectomy plus salpingectomy; no difference in AMH,mean operation time and mean blood loss was found between the two groups. Recently, Atalayet al34compared the ovarian function between the group receiving TAH plus bilateral salpingectomy (TAH-BS) and the group receiving total laparoscopic hysterectomy plus bilateral salpingectomy (TLH-BS). The ovarian function was evaluated before and 6 months after the surgery.Postoperatively luteinizing hormone (LH), FSH and inhibin B decreased in both groups. A significant decrease was seen in AMH and ovarian function in the TAH-BS group compared to the TLH-BS group. Since this research was based on two different surgical procedures,we cannot conclude if hysterectomy or salpingectomy alone decreases the ovarian function. To show the effect of salpingectomy on artificial reproductive technology,Daret al35evaluated ovarian function before and after salpingectomy. It showed no significant changes in human menopausal gonadotropin (HMG) used in the cycles,pre-ovulatory concentration of estrogen, the number of oocytes retrieved and the quality of the embryo. After salpingectomy, implantation rate was 23.07% and clinical pregnancy rate was 19.23% in patients who underwentin vitrofertilization (IVF). Qinet al36also analyzed 13 studies and concluded that salpingectomy did not affect ovarian function, ovarian response to gonadotropin stimulation, or the outcome of IVF embryo transfer(IVF-ET) in the short run. It may, however, impair ovarian reserve in the long run. As mentioned above, animal models and all other research showed no significant change in hormone level and ovarian function when salpingectomy was performed carefully. Although bilateral salpingectomy is much more reliable to prevent various ovarian diseases, we have to be cautious about the risk that is brought up by the surgery, such as bleeding,leaking, infection, more cost, more hospital days and post-surgery morbidity. Since no definitive long term effect has been researched, more studies are needed tofind the long term effect of bilateral salpingectomy.

RECENT PERCEPTION ON THE PRACTICE OF BILATERAL SALPINGECTOMY

Even though it is almost clear that bilateral salpingectomy might prevent the development of ovarian cancer, it has always been a controversial matter. Do patients want bilateral salpingectomy as preventive method or permanent contraception? Do Obstetricians and Gynecologists want to recommend bilateral salpingectomy as a preventive method or permanent contraception?

As patients’ compliance, in a study on the public perception of 100 women done by Kanget al,37regarding knowledge about ovarian cancer and bilateral salpingectomy, 71% of the females did not have any knowledge about the risk of ovarian cancer; 87% did not have any information about bilateral salpingectomy; 98% wanted to get informed about the benefit of bilateral salpingectomy while going through any gynecological surgery. The limitation of this study was the small number of participants and the location of urban areas where it was conducted. Thus,clinicians should discuss with patients about the benefits of bilateral salpingectomy before undergoing any gynecological surgeries for benign causes, and raise awareness of patients about the risk of ovarian cancer.

A statement released in 2011 by the Society of Gynecologic Oncology of Canada encouraged physicians to discuss with patients about the pros and cons of prophylactic bilateral salpingectomy at the time of hysterectomy or tubal ligation.38American College of Obstetrics and Gynecology Committee published their opinion in 2015,39and suggested that surgeons should inform patients about the advantages of bilateral salpingectomy before performing hysterectomy in high-risk patients who deny oophorectomy and permanent sterilization. In addition, they considered bilateral salpingectomy to be an effective method for contraception. They even mentioned that minimal invasive technique should be confined just to salpingectomy, and vaginal hysterectomy should not be replaced by laparoscopic hysterectomy.

With regard to society opinion, committee opinion and the benefits of bilateral salpingectomy, a lot of clinicians started performing this procedure. Regarding clinicians’opinions, lot of survey started blooming out. In 2013, Gillet al40reported that 54.3% of clinicians performed bilateral salpingectomy during hysterectomy for benign causes,among which, 75% intended to reduce the risk of ovarian cancer, 49.1% to avoid repeated surgery, 48.3% to avoid the risk of developing hydro-salpinx, and 30.2% to decrease the risk of pelvic pain. Among the remaining patients who did not perform salpingectomy, 69.4% mentioned that there was no benefit for decreasing the risk of ovarian cancer, 40% believed it increased operative time, 34.1%thought there would be increased intraoperative complications, and 23.5% did not believe it would decrease the risk of ovarian cancer. This survey also questioned clinicians about their perception on the use of salpingectomy as a permanent sterilization procedure. The result revealed 58.3% of clinicians believed that salpingectomy was the most effective permanent form of sterilization for women older than 35. Another survey done in Canada by Readeet al,41involved 757 physicians, and only 192 physicians responded the survey. The result showed 55% of the clinicians did not perform salpingectomy, and among them,51% believed that there was no benefit, 36% thought it increasing surgical morbidity, 19% believed it increasing operative time, and 8% regarded it increasing surgical complexity. Earlier, most clinicians were unaware of the benefit of bilateral salpingectomy; but in recent years, clinicians started performing it worldwide. In 2015, a similar survey was done in Australia. Totally, 1490 clinicians were questioned about the opportunistic bilateral salpingectomy(OBS) during gynecological surgeries for benign causes,and only 382 clinicians responded. Finally, 269 clinicians would discuss or perform OBS in the women with a low risk of ovarian cancer before undergoing any gynecological surgery for benign causes. In addition, 96% of clinicians during counseling for abdominal hysterectomy and 76% before laparoscopic hysterectomy, would offer or discuss OBS.42In a survey done in Italy by Venturellaet al,43most of the clinicians performed bilateral salpingectomy. There were 391 out of 477 clinicians who performed prophylactic bilateral salpingectomy, and among them, 371 performed to reduce the risk of ovarian and peritoneal cancers; 86 out of 477 clinicians did not perform salpingectomy, and among them, 47 thought that there was no benefit, 24 thought there was a risk of repetitive surgery, 19 believed it increasing the risk of intraoperative complications, 14 considered it increasing operative time, and 9 disbelieved the fact of reducing the risk of peritoneal and ovarian cancers. The clinicians were asked if they had information on the paradigm shift of the pathogenesis of ovarian cancer and the possibility of salpingectomy as a risk reducing strategy. The result displayed that, 65.44% of the clinicians were aware of the literature and safety data published, 20.95% knew about the literature but were unaware of the safety data published, 7.55% had heard it in the conference, 4.53% had never heard about prophylactic bilateral salpingectomy and 1.51% were asked about it bypatients. Lately, on this topic, Garciaet al44showed the increasing rate in the practice of salpingectomy recent years in the United Sates. Patients aged over 18 years old were involved. From June 2011 to May 2014, among 12 143 patients receiving hysterectomy, 7498 underwent hysterectomy with salpingectomy, and the rate of salpingectomy was increased from 14.7% to 72.7%. According to the clinicians’ view, 54.0% did not have any barriers performing, 36.0% reported difficulty in accessing fallopian tube, 3.0% believed it increased complications, 2.1%did not mention, 2.1% had no evidence found, 0.7% believed it potentially decreased ovarian reserve, 0.7% complained of increased operating room time, 0.7% thought it increased counseling time, and 0.7% lack of equipment to perform salpingectomy. The change in the trend towards the use of salpingectomy is seen, and clinicians are more aware of the fact about the benefit of salpingectomy in current days. Garciaet al44even reported that, the median estimated blood loss was lower, and even the operating time was shorter, in the salpingectomy group when compared with the group of hysterectomy alone. The only limitation of this study was the selection bias due to the low response rate of the clinicians. Clinicians’ opinions have been compared below (Table 1). Due to a decrease in the trend of total vaginal hysterectomy and an increase in trend of laparoscopic assisted vaginal hysterectomy, more bilateral salpingectomy is being performed worldwide. A large population based study conducted by Mikhailet al45compared the current practice of concurrent bilateral salpingectomy during total vaginal hysterectomy (TVH) with laparoscopic-assisted vaginal hysterctomy (LAVH) in the United States. It was found that, from 1998 to 2004,bilateral salpingectomy during TVH increased from 2‰to 14‰, with 42.8% annual increase, and it remained stable from 2004. Moreover, the rate of bilateral salpingectomy with LAVH increased nearly 15% each year during the entire study period.

In conclusion, in premenopausal women who undergo hysterectomy for benign uterine pathologies, bilateral salpingectomy could reduce the lifetime risk of developing HGSC. It not only helped in reducing ovarian cancer, but also helped in reducing adnexal pathologies. There was no difference in the values of AMH, FSH, LH, AFC, and mean ovarian diameter between the patients undergoing hysterectomy and the patients undergoing hysterectomy with bilateral salpingectomy, which indicates that ovarian function remained unaltered when bilateral salpingectomy was performed carefully. Bilateral salpingectomy might give a better quality of life, as it avoids the risk of premature menopause.The proportion of clinicians who incorporated bilateral salpingectomy varys from 45% to 86% in various countries.And 90% of clinicians performed the procedure to reduce the risk of ovarian cancer. There is still a small percentage of clinicians that are unaware about the new pathogenesis of ovarian cancer and about the role of bilateral salpingectomy in preventing ovarian cancer. More awareness is needed in clinicians and the public about the benefit of bilateral salpingectomy during a gynecological surgery for a benign reason in high-risk patients, such as those who has a family history of ovarian cancer, BRCA carriers who deny for BSO, and those who want permanent contraception. In the future, better research design is needed to show the long-term effect of bilateral salpingectomy on preventing ovarian cancer, as well as preserving ovarian function.

Table 1.Summary of studies based on clinicians’ views on BS

Conflict of Interest Statement

All authors have no conflict of interests to disclose.

1. Mc Alpine JN, Hanley GE, Woo MM, Tone AA, Rozenberg N,Swenerton KD. Opportunistic salpingectomy: uptake, risks,and complications of a regional initiative for ovarian cancer prevention. Am J Obstet Gynecol 2014; 210(5):471.e1-471.e11. doi: 10.1016/j.ajog.2014.01.003.

2. American Cancer Society: Cancer Facts and Figures 2016.Atlanta: American Cancer Society; 2016 [cited 2017 Jan 14]. Available from: http://www.cancer.org/Research/CancerFactsStatistics/cancerfactsfigures2016/cancerfactsand figures2016.

3. Partridge E, Kreimer AR, Greenlee RT, Williams C, Xu JL.Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 2009; 113(4):775-82.doi: 10.1097/AOG.0b013e31819cda77.

4. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992; 136(10):1212-20.

5. Kurman RJ, Shih IeM. Molecular pathogenesis and extra ovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol 2011; 42(7):918-31. doi: 10.1016/j.humpath.2011.03.003.

6. Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer—a proposed unifying theory. Am J Surg Pathol 2010; 34(3):433-43. doi: 10.1097/PAS.0b013e3181 cf3d79.

7. Senturk E, Cohen S, Dottino PR, Martignetti JA. A critical re-appraisal of BRCA1 methylation studies in ovarian cancer. Gynecol Oncol 2010; 119(2):376-83. doi: 10.1016/j.ygyno.2010.07.026.

8. Martin DC. Cancer and endometriosis: do we need to be concerned? Semin Reprod Endocrinol 1997; 15(3):319-24.

9. Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C,Medeiros F. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol 2007; 31(2):161-9.

10. Przybycin CG, Kurman RJ, Ronnett BM, Shih IeM, Vang R.Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol 2010; 34(10):1407-16. doi:10.1097/PAS.0b013e3181ef7b16.

11. Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 2007; 25(25):3985-90.

12. Sehdev AS, Kurman RJ, Kuhn E, Shih IeM. Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP),cyclin E and fatty acid synthase. Mod Pathol 2010; 23(6):844-55. doi: 10.1038/modpathol.2010.60.

13. Kuhn E, Meeker A, Wang TL, Sehdev AS, Kurman RJ, Shih IeM. Shortened telomeres in serous tubal intraepithelial carcinoma: an early event in ovarian high-grade serous carcinogenesis. Am J Surg Pathol 2010; 34(6):829-36.doi: 10.1097/PAS.0b013e3181dcede7.

14. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006; 30(2):230-6.

15. Kim J, Coffey DM, Creighton CJ, Yu Z, Hawkins SM,Matzuk MM. High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc Natl Acad Sci USA 2012; 109(10):3921-6. doi: 10.1073/pnas.1117135109.

16. Lessard-Anderson CR, Handlogten KS, Molitor RJ, Dowdy SC, Cliby WA, Weaver AL. Effect of tubal sterilization technique on risk of serous epithelial ovarian and primary peritoneal carcinoma. Gynecol Oncol 2014; 135(3):423-7.doi: 10.1016/j.ygyno.2014.10.005.

17. Madsen C, Baandrup L, Dehlendorff C, Kjaer SK. Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case–control study. Acta Obstet Gynecol Scand 2015; 94(1):86-94. doi: 10.1111/aogs.12516.

18. Falconer H, Yin L, Gronberg H, Altman D. Ovarian cancer risk after salpingectomy: a nationwide population-based study. J Nat Cancer Inst 2015; 27:107(2). pii: dju410. doi:10.1093/jnci/dju410.

19. Kwon JS, Mc Alpine JN, Hanley GE, Finlayson SJ, Cohen T,Miller DM. Costs and benefits of opportunistic salpingectomy as an ovarian cancer prevention strategy. Obstet Gynecol 2015; 125(2): 338-45. doi: 10.1097/AOG.0000 000000000630.

20. Vorwergk J, Radosa MP, Nicolaus K, Baus N, Jimenez Cruz,Rengsberger M. Prophylactic bilateral salpingectomy (PBS)to reduce ovarian cancer risk incorporated in standard premenopausal hysterectomy: complications and re-operation rate. J Cancer Res Clin Oncol 2014; 140(5):859-65. doi: 10.1007/s00432-014-1622-6.

21. Nagle CM, Oslen CM, Webb PM, Jordan SJ, Whiteman DC,Green AC. Endometrioid and clear cell ovarian cancers—a comparative analysis of risk factors. Euro J Cancer 2008;44(16):2477-84. doi: 10.1016/j.ejca.2008.07.009.

22. Cibula D, Widschwendter M, Majek O, Dusek L. Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update 2011; 17(1):55-67. doi: 10.1093/humupd/dmq030.

23. Rice MS, Hankinson SE, Tworoger SS. Tubal ligation, hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the nurse’s health studies. Fertil Steril 2014;102(1):192-8.e3. doi: 10.1016/j.fertnstert.2014.03.041.

24. Danis RB, Della Badia CR, Richard SD. Postpartum permanent sterilization: Could bilateral salpingectomy replace bilateral tubal ligation? J Minim Invasive Gynecol 2016; 23(6):928-32. doi: 10.1016/j.jmig.2016.05.006.

25. Parker WH, Feskanich D, Broder MS, Chang E, Shoupe D,Farquhar CM. Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses’ health study. Obstet Gynecol 2013; 121(4):709-16. doi: 10.1097/AOG.0b013e3182864350.

26. Rocca WA, Bower JH, Maraganore DM, Ahlskog JE,Grossardt BR, de Andrade M. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007; 69(11):1074-83.

27. Rocca WA, Bower JH, Maraganore DM, Ahlskog JE,Grossardt BR, de Andrade M. Increased risk of Parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008; 70(3):200-9.

28. Rocca WA, Grossardt BR, Maraganore DM. The long-term effects of oophorectomy on cognitive and motor aging are age dependent. Neurodegener Dis 2008; 5(3-4):257-60.

29. Kwon JS, Tinker A, Pansegrau G, McAlpine J, Housty M,McCullum M. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers.Obstet Gynecol 2013; 121(1):14-24. doi: http://10.1097/AOG.0b013e3182783c2f.

30. Zhao JR, Wing R, Hulka JF. Ovarian function in monkeys after bilateral salpingectomy. Int J Fertil 1984; 29(2):118-21.

31. Halme J, Rong ZJ, Wing R, Raj MH, Raj S. The removal of fallopian tubes has no adverse effect of subsequent ovarian function in rabbits. Fertil Steril 1982; 38(5):621-4.

32. Morelli M, Venturella R, Mocciaro R, Di Cello A, Rania E,Lico D. Prophylactic salpingectomy in premenopausal lowrisk women for ovarian cancer: primum non nocere. Gynecol Oncol 2013; 129(3):448-51. doi: 10.1016/j.ygyno.2013.03.023.

33. Findley AD, Siedhoff MT, Hobbs KA, Steege JF, Carey ET,McCall CA. Short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial. Fertil Steril 2013; 100(6):1704-8. doi: 10.1016/j.fertnstert.2013.07.1997.

34. Atalay MA, Cetinkaya Demir B, Ozerkan K. Change in the ovarian environment after hysterectomy with bilateral salpingectomy: is it the technique or surgery itself? Eur J Obstet Gynecol Reprod Biol 2016; 204:57-61. doi: 10.1016/j.ejogrb.2016.07.483.

35. Dar P, Sachs GS, Strassburger D, Bukovsky I, Arieli S.Ovarian function before and after surgery in artificial reproductive technology patients. Hum Reprod 2000;15(1):142-4.

36. Qin F, Du DF, Li XL. The effect of salpingectomy on ovarian reserve and ovarian function. Obstet Gynecol Surv 2016;71(6): 369-76. doi: 10.1097/OGX.0000000000000323.

37. Kang JH, Nam SH, Song T, Kim WY, Lee KW, Kim KH. Public perception of risk-reducing salpingectomy for preventing ovarian cancer. Obstet Gynecol Sci 2015; 58(4):284-8. doi: 10.5468/ogs.2015.58.4.284.

38. The Society of Gynecologic Oncology of Canada. GOC statement regarding salpingectomy and ovarian cancer prevention. 2011 [cited 2017 May 9]. Available from:https://www.g-o-c.org/uploads/11sept15_gocevidentiary statement_final_en.pdf.

39. Committee on Gynecologic Practice. Committee Opinion No. 620: Salpingectomy for Ovarian Cancer Prevention.Obstet Gynecol 2015; 125(1):279-81. doi: 10.1097/01.AOG.0000459871.88564.09.

40. Gill Se, Mills BB. Physician opinions regarding elective bilateral salpingectomy with hysterectomy and for sterilization. J Minim Invasive Gynecol 2013; 20(4):517-21. doi:10.1016/j.jmig.2013.02.010.

41. Reade CJ, Finlayson S, McAlpine J, Tone AA, Fung-Kee-Fung, Ferguson SE. Risk-reducing salpingectomy in Canada: a survey of obstetrician-gynecologists. J Obstet Gynaecol Can 2013; 35(7):627-34. doi: 10.1016/S1701-2163(15)30894-X.

42. Kapurubandara S, Qin V, Gurram D, Anpalagan A, Merkur H, Hogg R. Opportunistic bilateral salpingectomy during gynecological surgery for benign disease: a survey of current Australian practice. Aust N Z J Obstet Gynaecol 2015;55(6):606-11. doi: 10.3802/jgo.2017.28.e52.

43. Venturella R, Rocca M, Lico D, Trapasso S, Di Cello A,Gizzo S. Prophylactic bilateral salpingectomy for the prevention of ovarian cancers: What is happening in Italy?Eur J Cancer Prev 2016; 25(5):410-5. doi: 10.1097/CEJ.0000000000000191.

44. Garcia C, Martin M, Tucker LY, Lyon L, Armstrong MA,McBride-Allen S. Experience with opportunistic salpingectomy in a large, community based health system in United States. Obstet Gynecol 2016; 128(2):277-83. doi:10.1097/AOG.0000000000001531.

45. Mikhail E, Salemi JL, Wyman A, Salihu HM, Imudia AN, Hart S. Trends of bilateral salpingectomy during vaginal hysterectomy with and without laparoscopic assistance performed for benign indications in United States. J Minim Invasive Gynecol 2016; 23(7):1063-9.e1. doi: 10.1016/j.jmig.2016.07.009.

10.24920/J1001-9294.2017.022

for publication November 24, 2016.

＊Corresponding author Tel: 86-21-63455050-8426, Fax: 86-21-63455090, E-mail: yix@fudan.edu.cn