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Paradigm shift: Prophylactic salpingectomy for ovarian cancer risk reduction

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Gaining momentum: 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.


 

EXPERT ANALYSIS FROM MINIMALLY INVASIVE SURGERY WEEK

References

LAS VEGAS – Removing the fallopian tubes at the time of pelvic surgeries as a potential means of reducing ovarian cancer risk appears to be a movement that’s picking up steam in clinical practice.

A recent survey of 234 U.S. gynecologists showed prophylactic bilateral salpingectomy is catching on when performed in conjunction with hysterectomy, but far less so for tubal sterilization, Dr. Austin Findley observed at the annual Minimally Invasive Surgery Week.

A total of 54% of respondents indicated they routinely perform salpingectomy at the time of hysterectomy in an effort to reduce the risk of ovarian cancer as well as to avoid the need for reoperations. However, only 7% of the gynecologic surgeons said they perform salpingectomy for tubal sterilization, even though 58% of respondents stated they believe the procedure is the most effective form of tubal sterilization (J. Minim. Invasive Gynecol. 2013;20:517-21).

Dr. Austin Findley

Dr. Austin Findley

“In my experience at various hospitals, I think these numbers are a pretty accurate reflection of what folks are doing,” commented Dr. Findley of Wright State University in Dayton, Ohio.

The prophylactic salpingectomy movement is an outgrowth of the tubal hypothesis of ovarian cancer.

“There is now increasing and dramatic evidence to suggest that most ovarian cancers actually originate in the distal fallopian tubes. I think this is a concept most people are unaware of or are just becoming accustomed to. The tubal hypothesis represents a major paradigm shift in the way we think about ovarian cancers. The previous belief that excessive ovulation is a cause of ovarian cancer is no longer regarded as accurate,” he explained at the meeting presented by the Society of Laparoscopic Surgeons and affiliated societies.

Ovarian cancer is the No. 1 cause of mortality from gynecologic malignancy, accounting for more than 14,000 deaths per year, according to National Cancer Institute data. The lifetime risk of the malignancy is 1.3%, with the average age at diagnosis being 63 years.

Only 10%-15% of ovarian cancers occur in women at high risk for the malignancy because they carry a BRCA mutation or other predisposing gene. The vast majority of ovarian cancer deaths are caused by high-grade serous tumors that have been shown to be strongly associated with precursor lesions in the distal fallopian tubes of women at low risk for the malignancy.

There is no proven-effective screening program or risk-reduction method for these low-risk women. However, with 600,000 hysterectomies and 700,000 tubal sterilizations being performed annually in the United States, prophylactic salpingectomy has been advocated as an attractive opportunity to potentially reduce ovarian cancer risk. Other common pelvic surgeries in which it might be used for this purpose include excision of endometriosis and laparoscopy for pelvic pain. It also has recently been shown to be feasible and safe post partum at cesarean or vaginal delivery (Obstet. Gynecol. 2014 [doi: 10.1097/01.AOG.0000447427.80479.ae]).

But the key word here is “potentially.” It must be emphasized that at present the ovarian cancer prevention benefit of prophylactic salpingectomy remains hypothetical; in theory, the procedure should reduce ovarian cancer risk, but there is not yet persuasive evidence that it actually does, Dr. Findley emphasized at the meeting, presented by the Society of Laparoendoscopic Surgeons and affiliated societies.

In contrast, one well-established ancillary benefit of prophylactic salpingectomy is that it eliminates the need for future reoperation for salpingectomy. This was demonstrated in a large Danish cohort study including close to 10,000 women undergoing hysterectomy and a similar number undergoing sterilization procedures. Among the nearly two-thirds of hysterectomy patients who had both fallopian tubes retained, there was a 2.13-fold increased likelihood of subsequent salpingectomy, compared with nonhysterectomized women.

Similarly, Danish women who underwent a sterilization procedure with retention of the fallopian tubes – typically tubal ligation with clips – were 2.42 times more likely to undergo subsequent salpingectomy, most often because of the development of hydrosalpinx, infection, ectopic pregnancy, or other complications (BMJ Open 2013;3 [doi:10.1136/bmjopen-2013-002845]).

The most commonly cited potential risk of prophylactic salpingectomy – decreased ovarian function – now appears to be a nonissue. This was demonstrated in a recent retrospective Italian study (Gynecol. Oncol. 2013;129:448-51) as well as in a pilot randomized controlled trial conducted by Dr. Findley and his coworkers (Fertil. Steril. 2013;100:1704-8), which appears to have answered many skeptics’ concerns. Indeed, Dr. Findley’s coinvestigator Dr. Matthew Siedhoff said he has recently been approached by researchers interested in collaborating in a larger confirmatory randomized trial, but all parties eventually agreed it was a no-go.

Dr. Matthew Siedhoff

Dr. Matthew Siedhoff

“It’s a little hard to demonstrate equipoise for a larger randomized controlled trial. We’re beyond that now, given that prophylactic salpingectomy really doesn’t seem to make a difference as far as ovarian function,” according to Dr. Siedhoff, director of the division of advanced laparoscopy and pelvic pain at the University of North Carolina, Chapel Hill.

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