In Korea, ovarian cancer is the tenth most prevalent cancer and the eighth leading cause of cancer-related deaths in women [1]. In 2015, 9.6 new cases of ovarian cancer and 7.2 cancer-related deaths per 100,000 women were reported. Epithelial ovarian carcinoma (EOC), which accounts for more than 85% of all ovarian cancers, is more aggressive than non-EOC, and it is responsible for 90% of ovarian cancer-related deaths. The four most common subtypes of EOC are serous (80‒85%), clear cell (5%), endometrioid (10%), and mucinous (3%) ovarian neoplasm, as categorized by their traditional histomorphologic features [2,3]. A 2-tier grading system for serous ovarian carcinoma subdivided these tumors into low-grade serous carcinoma (LGSC, type I) and high-grade serous carcinoma (HGSC, type II) [4], and HGSC is 20 times more likely than LGSC to cause death [5]. As effective screening methods for early detection of EOC are still unknown, more than 70% of ovarian cancers are diagnosed in advanced stages, with poor survival outcomes [6].

The risk factors for ovarian cancer include age, menopausal status, parity, and family history. Germline mutation in BRCA1 or BRCA2 is associated with autosomal-dominant hereditary breast and ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC), and it carries an approximately 40% lifetime risk of ovarian cancer [7,8]. Germline mutation in BRCA1 or BRCA2 is found in 12‒15% of cases of EOC, and the carcinomas that develop in patients with these mutations are commonly high-grade serous in type [9,10,11]. The lifetime risks of EOC (mainly endometrioid and clear cell types) owing to mutations in MSH2, MLH1, and MSH6, which are known as mismatch repair genes associated with HNPCC, are approximately 10%, 8%, and 7%, respectively [12]. Although HBOC and HNPCC are the most well-known conditions that predispose to EOC, mutations in BRIP1, RAD51D, and RAD51C are associated with a 10‒15% lifetime risk of cancer [13,14,15].

To prevent EOC in women at a high risk for the disease, removal of the ovaries and fallopian tubes, known as risk-reducing salpingo-oophorectomy (RRSO), is commonly recommended. The recommended age range for performing RRSO in women with BRCA1 and BRCA2 germline mutations is 35-40 years and 40-45 years, respectively, as per the National Comprehensive Cancer Network (NCCN) guideline [16]. In 2016, the Korean Society of Obstetrics and Gynecology (KSGO) recommended that women with a BRCA germline mutation should be counseled about RRSO at 35-40 years of age on an individual basis [17]. Meanwhile, as RRSO results in surgical menopause, which can affect the cardiovascular system, osteoporotic health, and quality of life [18,19], prophylactic salpingectomy and delayed oophorectomy (PSDO) is now under clinical trials as an alternative of RRSO in premenopausal women at a high risk for ovarian cancer (NCT02321228, NCT01907789). Contrary to RRSO in high-risk women, the surgical strategy to prevent EOC in women at average risk^* is controversial.

^*Women at an average risk for EOC (those who meet all criteria)

LGSC has been hypothesized to arise from a serous cystadenoma or adenofibroma, and is characterized by mutations in the KRAS, BRAF, or ERBB2 genes, in which approximately two-thirds of the tumors harbor a mutation [20,21,22]. Unlike LGSC, mutations in KRAS, BRAF, or ERBB2 rarely occur in HGSC. In contrast, TP53 mutation frequently occurs in more than 80% cases of HGSC [23,24]. TP53 mutations result in an increased nonfunctional p53; this is referred to as a “p53 signature,” which is commonly identified in HGSC [22]. The increasing RRSO in the high-risk women and improved pathologic assessments would have enabled pathologists to detect more p53 signatures derived from TP53 mutation adjacent to serous tubal intraepithelial carcinoma (STIC) lesions [25]. Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) protocol involves a meticulous examination of the fallopian tubes of high-risk women who undergo RRSO; it entails amputation of each fimbria at the infundibulum, longitudinal sectioning of the fimbria, and extensive cross-sectioning of the remainder of the tube at 2-3-mm intervals [26] (Fig. 1). STIC is now generally accepted as the earliest morphologically recognizable form of HGSC.

STIC and invasive tubal carcinoma were detected more frequently in patients who had a genetic predisposition to EOC; however, they were also detected in non-mutation carriers with HGSC, with a prevalence of 48‒75% [27,28,29,30]. According to the results of a recently published Gynecologic Oncology Group-0199 trial, occult, invasive, or serous tubal intraepithelial lesions were identified in 25 out of 966 high-risk women who underwent RRSO: 4.6%, 3.5%, and 0.5% of occult lesions were detected in women who had BRCA1 germline mutation, BRCA2 germline mutation, and were high-risk non-carriers, respectively [31]. More than 90% of these precancerous lesions were localized to the fimbrial end in both women who had BRCA germline mutations and in those who did not have the mutations [26,28,29]. The average time from STIC to HGSC was estimated as 6.5 (range, 1.4-10.7) years, and the time between the initiation of the HGSC and the development of peritoneal carcinomatosis appears to be very short in women with metastatic STIC lesions [32].

Although increasing evidences for the pathological association between STIC and HGSC are still observed, it is noteworthy that all HGSCs do not have tubal precancerous lesions. The possibility of non-tubal origin and an alternative carcinogenetic process persists, and further studies on ovarian tissue factors including hormonal milieu or ovulation are warranted.

It is known that not only sterilization but also tubal ligation confers a decreased risk of EOC. Several meta-analyses have demonstrated an approximately 26-34% decrease in the risk of EOC in women undergoing tubal ligation [33,34,35,36,37]. This effect is more pronounced in endometrioid and clear cell tumors than in serous tumors. It has been understood that the location of the ligation near the utero-tubal junction prevents the retrograde transport and ovarian seeding of endometriotic cells, which has been consistently linked to endometrioid and clear cell tumors. On the contrary, the risk of serous tumors is considerably reduced by excisional tubal sterilization rather than non-excisional tubal sterilization. Several nationwide studies have reported that salpingectomy decreases the risk of ovarian cancer by 42-77% [38,39,40]. Lessard-Anderson et al. [38] suggested that compared to other sterilization methods, excisional sterilization may more effectively reduce the risk of ovarian cancer. They compared the number of tubal sterilization cases between 194 women with serous ovarian/peritoneal cancer and matched them with 388 controls. The rate of excisional tubal sterilization was lower in the cancer group than in the controls (2.6% vs. 6.4%), and the adjusted risk of serous ovarian/peritoneal cancer was decreased by 64% after excisional tubal sterilization compared to the risk after non-excisional tubal sterilization or no sterilization (odds ratios [ORs], 0.36; 95% confidence interval [CI], 0.13-1.02). Similarly, Madsen et al. conducted a case-control study based on a nationwide registry (case group of ovarian cancer, n=13,241) [39]. They reported that tubal sterilization and bilateral salpingectomy reduce the risk of EOC by 13% and 42%, respectively (OR, 0.87; 95% CI, 0.78-0.98 and OR, 0.58; 95% CI, 0.36-0.95, respectively). Falconer et al. also revealed that salpingectomy for benign indications is associated with a reduced risk of ovarian cancer, in a national population-based cohort study [40]. Women who had previously undergone a salpingectomy (n=251,465) showed a significantly lower risk for ovarian cancer than that of women who had not undergone a salpingectomy (OR, 0.65; 95% CI, 0.52-0.81). In particular, bilateral salpingectomy was associated with a 50% decreased risk of ovarian cancer, compared to unilateral salpingectomy (OR, 0.35; 95% CI, 0.17-0.73 and OR, 0.71; 95% CI, 0.56-0.91, respectively). Although the retrospective studies cannot confirm the causal relationship for prevention of ovarian cancer, these nationwide population-based results are quite noteworthy. In 2016, Yoon et al. [41] reported the results of a meta-analysis based on these nationwide population-based studies. The risks of ovarian cancer were compared between 3,509 women who underwent bilateral salpingectomy and 5,655,702 women who did not undergo salpingectomy. Bilateral salpingectomy was revealed to reduce the risk of ovarian cancer by 49% (OR, 0.51; 95% CI, 0.35-0.75; I²=0%).

Several professional gynecologic boards have carefully stated a favorable position of prophylactic salpingectomy at the time of benign gynecologic surgery or other intraperitoneal surgery [42,43,44,45,46,47] (Table 1). In 2013, the Society of Gynecologic Oncology (SGO) stated the following: “For women at average risk of ovarian cancer, risk-reducing salpingectomy should also be discussed and considered with patients at the time of abdominal or pelvic surgery, hysterectomy or in lieu of tubal ligation” [43,44]. Subsequently, the Royal College of Obstetricians and Gynecologists (RCOG) and the American College of Obstetricians and Gynecologists also stated, in 2014 and 2015, respectively, that bilateral salpingectomy should be considered at the time of benign gynecologic surgery or other intraperitoneal surgery in women who have completed their families [45,46]. These societies supported that bilateral salpingectomy has a potential benefit to prevent ovarian cancer, with minimal procedure-related complications.

Prophylactic salpingectomy is increasingly performed in many countries. In the United States, the rate of performing prophylactic salpingectomy with hysterectomy increased by 371% in 5 years (2008-2013) [48]. However, it was revealed that 45.5% of American physicians do not routinely perform prophylactic salpingectomy in real practice, and 69.4% of them said that they actually do not believe that salpingectomy exerts a preventive effect on ovarian cancer, in a survey study [49]. Although there is a wide discrepancy in the responses of physicians from European countries, 32.7-80% of physicians routinely perform prophylactic salpingectomy during benign gynecologic surgery [50,51,52]. In Austria, 70% (269/382) of the respondents stated that they would offer or discuss prophylactic salpingectomy in average-risk women undergoing gynecological surgery for benign indications, and that salpingectomy was the preferred method for surgical sterilization at the time of cesarean delivery [51,53]. Prophylactic salpingectomy at the time of hysterectomy for benign disease was applied to women in 70-80% of institutions accredited by an academic society and in 50-65% of institutions not accredited by an academic society in Japan [54]. In China, the rate of bilateral salpingectomy increased threefold (from 22% to 60%) from 2007 to 2017 [55]. Corresponding data from Korea are unavailable.

During salpingectomy, the fallopian tubes are typically resected from the fimbrial end to the uterine cornu. In particular, the fimbrial end should be completely removed, as most STICs originate from the fimbrial end. Some authors suggested that salpingectomy does not cause functional damage to the ovary, because the ovarian blood supply is guaranteed both by infundibulopelvic vessels and the ovarian branch of the uterine artery [56]. However, the potential disadvantages to the ovarian reserve owing to diminished ovarian arterial blood flow after salpingectomy are still debatable. Therefore, resection is performed at the posterior margin of the fallopian tubes, while conserving the mesosalpinx (Figs. 2 and 3).

Current evidences support that the fallopian tube plays a major role in the carcinogenesis of ovarian/fallopian/peritoneal cancer, and that bilateral salpingectomy seems to be an effective risk-reducing option. With the increasing adoption of prophylactic salpingectomy, the rate of ovarian/fallopian/peritoneal cancer in the general population is expected to gradually decrease over time. Women not at a high risk for EOC who have completed their families should be carefully considered for prophylactic salpingectomy at the time of their scheduled gynecologic surgery. Further prospective trials for prophylactic salpingectomy in various clinical settings, including non-gynecologic surgery, are warranted.