Paradigm shift: Prophylactic salpingectomy for ovarian cancer risk reduction

The practice of salpingectomy for ovarian cancer risk reduction has quietly gained momentum in the gynecology world, however, it has not been well advertised in the patient community, despite steadily increasing amounts of data to support its plausibility as a risk-reducing strategy. Recent surveys reveal that physicians are slowly changing practices and including “prophylactic” salpingectomy during benign gynecologic surgeries, including at the time of hysterectomy, tubal sterilization (including at the time of cesarean section), and at the time of surgery for other benign gynecologic conditions, such as laparoscopy for endometriosis.

While the change in practice is encouraging, the supporting hypothesis is still in its infancy. The historical theory of the etiology of ovarian cancer states that ovulation events led to an increased risk of ovarian cancer. The theory of “incessant ovulation” suggested that the epithelium of the ovary is sensitive to the number of events of ovulation, which may in turn act as a promoting factor in the carcinogenic process (Clinical Gynecologic Oncology, 8th ed.; Epithelial Ovarian Cancer (Chapter 11) [Maryland Heights, Mo.: Mosby, 2012]). This was supported by epidemiologic data that noted that women who used oral contraceptives, had multiple pregnancies, breastfed, and underwent late menarche and early menopause were at decreased risk of developing ovarian cancer (Cancer Causes Control 2007;18:517 ; Am. J. Epidemiol. 1992;136:1184-203; Int. J. Epidemiol. 2000;29:799-802). The hypothesis was adopted, as the epidemiology of ovulation was supportive.

The weakness of the incessant ovulation theory has been our inability to identify precursor lesions. In almost all other gynecologic malignancies, a precursor lesion has been identified and supports a theory of carcinogenesis. In patients with ovarian cancer, over 80% are diagnosed with advanced stage, and this is where the new theory of the pathogenesis of ovarian cancer originating in the fimbriated end of the fallopian tube begins to have credibility. Serous tubal intraepithelial carcinoma (STIC) lesions are the proposed precursor lesions to high-grade serous carcinomas. STIC lesions exhibit histologic features of morphologic atypia (increased nuclear/cytoplasmic ratio, prominent nucleoli, increased proliferation with an intact basement membrane, variably stratified fallopian tube epithelium with nuclear pleomorphism) and have evidence of TP53 mutations (J. Pathol. 2012;226:421-6 ). STIC lesions were first described as a potential precursor to fallopian tube serous carcinoma in the 1950s, however, it was not proposed as a precursor to extra-fallopian tube serous pelvic cancers until the 2000s (Am. J. Obstet. Gynecol. 1950;59:58-67). One of the suggested pathogeneses of this evolving hypothesis stipulates that TP53 mutations are associated with telomere shortening, one of the main genetic manifestations in cancer development, leading to chromosomal instability, gene expression reprogramming, and tumor progression (Am. J. Surg. Pathol. 2010;34:829-3). The finding of TP-53 mutations in STIC further supports the STIC precursor hypothesis, as identical mutations have been reported in concurrent high-grade serous carcinomas, providing evidence that supports the clonal relationship of the two lesions (J. Pathol. 2012;226:421-6 ). The theory further stipulates that STIC cells can exfoliate and disseminate to the ovary and peritoneal surfaces prior to becoming invasive, and subsequently demonstrating invasion at the distant sites. In addition, this theory can explain the development of primary peritoneal high-grade serous cancer, a disease essentially identical to high-grade serous ovarian cancer, although the etiology of this disease is largely unknown.

Interest in the STIC to extra–fallopian tube serous cancers hypothesis was enhanced by the histopathologic evaluation of the ovaries and fallopian tubes of BRCA-positive women undergoing prophylactic bilateral salpingo-oophorectomy. In this population, women were diagnosed with a serous cancer (up to 17%), and roughly 80% occurred in the fallopian tube (Gynecol. Oncol. 2002;87:52-6 ). STIC was subsequently described to occur not only in BRCA-positive women, but in sporadic cases of serous cancer as well (Am. J. Surg. Pathol. 2007;31:161-9).Additionally, up to 60%-70% of sporadic high-grade serous cancers (ovarian, primary peritoneal) have been reported to have STIC lesions on final pathology (Int. J. Gynecol. Cancer 2009;19:58-64 ). The finding of a STIC lesion is not routinely noted in pathology reports however, possibly due to the lack of serial sectioning of tubes and ovaries in the general population, when no germline mutation is present.

While the majority of the data supporting STIC as a potential precursor lesion to ovarian cancer is from the BRCA literature, the application of the theory can be and has been extrapolated to women at baseline ovarian cancer risk. As described in the article presented, there appears to be a paradigm shift in benign gynecology practice towards prophylactic salpingectomy for ovarian cancer risk reduction. The appropriate application of the prophylactic salpingectomy should be as described – at the time of benign hysterectomies, tubal sterilizations, and can be performed at the time of surgeries for other benign conditions (endometriosis, pelvic masses, diagnostic laparoscopies).

The data from this paradigm shift in practice will contribute significantly to answering some of the many questions surrounding this hypothesis, including the incidence of STIC in the baseline risk population, as well as answer the question of whether this practice will actually reduce the ovarian cancer incidence in the years to come. Additionally, investigation into the efficacy of ovarian cancer risk reduction of prophylactic salpingectomy in the high-risk patients (those with germline mutations) who undergo ovarian conservation at the time of salpingectomy is imperative. These women are currently counseled to undergo prophylactic bilateral salpingo-oophorectomy at the age of 35 or at the time of childbearing completion. As data support that oophorectomy for benign disease in women under the age of 50 increases all-cause mortality (Obstet. Gynecol. 2009;113:1027-37), the impact that prophylactic salpingectomy with ovarian conservation has in this population could be monumental, as this represents a group of women subjected to the sequelae of early surgical menopause. Furthermore, given the current economic climate of modern medicine, additional investigation into the cost-effectiveness of salpingectomy as a risk-reducing option in both women with increased risk (germline mutation) and in the general population, is indicated.

In conclusion, the practice of prophylactic salpingectomy is still in its infancy. The early paradigm shift will certainly contribute to the existing literature and potentially improve our ability to reduce risk of ovarian cancer, without compromising the overall health of our patients through surgical castration. The current hypothesis of STIC as the primary site for ovarian cancer carcinogenesis is certainly plausible and may allow for improved screening modalities and targeted therapies, which may lead to improved outcomes for our patients.

Caroline C. Billingsley, M.D., and Larry J. Copeland, M.D., who are gynecologic oncologists at Ohio State University, Columbus, wrote this commentary.