No one doubts the deadly nature of high-grade serous ovarian cancer. This histologic subtype is responsible for most ovarian cancer deaths, representing the eighth leading cause of cancer deaths in women worldwide and the fifth in the United States. Although there has been some progress in improving the 5-year survival of those with high-grade serous ovarian cancer with poly (ADP-ribose) polymerase inhibitors, most patients’ disease is frequently found at an advanced stage, making cure rare.
Why are we interested in fallopian tubes? To answer this question, we must look at how pathogenesis has set the modern stage for care.
Closer Look at Pathogenesis
Epithelial ovarian carcinoma is not a single disease but rather consists of five different histiotypes; in order of frequency, they include high-grade serous, endometrioid, clear cell, low-grade serous, and mucinous carcinomas. Because of their common features, high-grade serous ovarian, fallopian tube, and peritoneal carcinomas are considered one clinical entity and referred to as a single entity (epithelial ovarian carcinoma or high-grade serous ovarian cancer).
Most subtypes of epithelial ovarian cancer have in common a clear origin in the ovaries and are often accompanied by preexisting benign or borderline lesions. Historically, high grade serous carcinomas appear to arise in isolation, harboring a P53 mutation, and most present at an advanced stage; in fact, the actual origin (ovaries, fallopian tubes, or peritoneum) cannot always be identified.
“Why are we interested in fallopian tubes? To answer this question, we must look at how pathogenesis has set the modern stage for care.”— Colleen M. Feltmate, MD
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Our collective experience with BRCA mutation carriers and data developed through pathologic identification of early fallopian tube precursors have revolutionized our understanding of the fallopian tubes as the primary site for serous cancers. Early investigators reported on serous tubal intraepithelial carcinomas, which developed in the distal fallopian tubes.1 The experience gained from pathologic examination of these high-risk fallopian tubes resulted in the development of the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) protocol, which is used for pathologic examination of these specimens.
This method was then used in a retrospective analysis, which examined the fallopian tubes of patients with ovarian cancer, where the predominant patient did not have BRCA-positive disease. Findings revealed that 59% to 71% were associated with serous tubal intraepithelial carcinomas after careful inspection of the fallopian tubes.2
Pathways of Metastasis of Serous Cancers
Based on the model of development of serous tubal intraepithelial carcinomas, there are several theories or pathways by which serous cancers metastasize. The first is the tumor progresses within the fallopian tubes, metastasizing to nearby tissue and then to the peritoneal cavity. In a second pathway, the serous tubal intraepithelial carcinoma metastasizes directly into the peritoneal cavity, seeding it and resulting in early dissemination of metastases. The last is certain cells escape early prior to salpingectomy and remain quiescent for a period. These cells ultimately undergo additional genetic changes to emerge as primary peritoneal high-grade serous cancer years later.
Initial studies following patients identified with serous tubal intraepithelial carcinoma lesions placed the risk of recurrence at 5% to 10%. One report with longer follow-up has estimated the 5- and 10-year risks of a follow-up “primary peritoneal” high-grade serous cancer to be higher, at 10% and 27%, respectively.3
The discovery of a serous tubal intraepithelial carcinoma imposes a later risk of high-grade serous cancer. However, it is not known whether the precursor cells from the serous tubal intraepithelial carcinoma implant on the peritoneal surface or float freely in the peritoneal fluid prior to undergoing a pivotal genomic change, resulting in tumor development.
These theories may explain why there have been no successful screening tools. Studies have tried to leverage screening using CA-125, ultrasound, or both. Although the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) indicate that either of these screening methods can be used in high-risk mutations carriers, there are currently no effective screening tests that have altered survival in screened populations (high risk or other). Thus, prevention remains an essential strategy in risk reduction and improved survival.
Who Is at Risk?
Although ovarian cancer affects about 1 in 70 women, certain mutations are associated with increased risk, especially for high-grade serous ovarian cancer. BRCA1/2 mutations are the genes most associated with the development of high-grade serous ovarian cancer, with a 15% to 40% lifetime risk. In addition to these mutations, other genes including the Lynch syndrome–associated genes MLH1, MSH2, MSH6, and PMS2/EPCAM and moderate-penetrance genes such as BRIP1, RAD51C, and RAD51D have risks ranging from 6% to 15% and warrant discussion regarding risk-reducing strategies. A strong family history may also play into elevated risk and the need for risk reduction.
Currently, recommendations for risk reduction are based on the removal of both fallopian tubes and ovaries, namely risk-reducing salpingo-oophorectomy. Unfortunately, this places many women in a position of losing hormonal function earlier than the age of nature menopause. Although options may exist for hormonal replacement for some women, many would prefer not to make this choice. The question remains what role the tubes may play in risk reduction in this population.
Studies in the general population have raised the question of opportunistic salpingectomy as a preventive strategy against high-grade serous ovarian cancer. Data from a meta-analysis of women undergoing tubal ligation demonstrated a 26% to 34% decrease in all subtypes of ovarian cancer. Retrospective cohort studies have demonstrated decreased risks of hysterectomy as well as tubal ligation. Possible mechanisms for risk reduction include the following: removing the initial site of carcinogenesis (high-grade serous carcinomas); removing the conduit for passage of endometriotic or endosalpingiotic cells (clear cell and endometrioid carcinomas); and removing the conduit for passage of carcinogens (eg, talc) or inflammation (eg, pelvic infection) to reach the ovaries. However, the role of these factors is not well established.
“Although some women may opt not to follow the recommended guidelines for oophorectomy prior to menopause, salpingectomy may offer some modicum of risk reduction.”— Colleen M. Feltmate, MD
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Although risk reduction for high-grade serous ovarian cancer in the general population undergoing opportunistic salpingectomy may be as high as 70%, inferring that the fallopian tubes may also be the origin of all high-grade serous cancers cannot be supported, yet since studies to date are retrospective, population-based cohort studies.4 A recent population-based, retrospective cohort study of all individuals in British Columbia, Canada, examined observed vs expected rates of ovarian cancer among individuals who had undergone opportunistic salpingectomy or a control surgery (hysterectomy alone or tubal ligation) between 2008 and 2017. The opportunistic salpingectomy group had no high-grade serous cancer and significantly fewer epithelial ovarian cancers than were expected when compared with the rate at which they arose in the control group.
These findings suggest that opportunistic salpingectomy is associated with a reduced risk for ovarian cancer.5 Although this is a young population of women followed for a relatively short period, it provides more data that opportunistic salpingectomy should be broadly considered.
What Surgeries Provide Opportunities for Salpingectomy?
Postpartum tubal ligation is performed in 10% of hospital deliveries. This setting represents an opportunity for bilateral salpingectomy after cesarean or vaginal delivery. Studies have evaluated the safety of this procedure, with no difference seen between complete salpingectomy and historical use of other ligation procedures.
Women who seek permanent effective sterilization often consider laparoscopic ligation, but now they should consider complete removal the fallopian tube including the fimbriated end. Other laparoscopic surgeries (such as cyst removal or oophorectomy for benign indications) provide an opportunity for opportunistic salpingectomy.
Hysterectomy for benign conditions tied with salpingectomy has now become the standard of care when possible. Given the ease with which this procedure can be performed, the idea that this could also be tied with other laparoscopic (or open) surgeries (eg, cholecystectomy, appendectomy, or colonic surgery) has been explored but has yet to be adopted widely. In general, the additional time required is likely no more than 15 minutes, depending on the surgeon’s experience.
Work on quantifying cost-effectiveness of salpingectomy vs usual care focused on a hypothetical study population is 50,000 women (aged 45) undergoing laparoscopic hysterectomy with ovarian preservation for benign indications and 300,000 women (aged 35) undergoing laparoscopic permanent contraception. In the laparoscopic hysterectomy cohort, opportunistic salpingectomy was found to be cost-saving and would yield $23.9 million in health care dollars saved. In the laparoscopic permanent contraception cohort, opportunistic salpingectomy was found to be cost-effective, with an incremental cost-effectiveness ratio of $31,432/quality-adjusted life year compared with tubal ligation, and it remains cost-effective as long as it reduces the risk for ovarian cancer by 54%.4
Concerns regarding side-effect profiles and cost have prompted studies to look at specific concerns. These studies have demonstrated safety, cost-effectiveness, and lack of effect on hormonal function in patients undergoing opportunistic salpingectomy across various clinical settings. The premise for the idea of opportunistic salpingectomy is that it represents a safe and feasible opportunity to prevent a subset of high-grade serous cancer without impacting hormonal function, the way removing both tubes and ovaries would.6-8
After evaluating the data, risks, and perceived benefits, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) have recommended that opportunistic salpingectomy in the general population, be considered for potential ovarian cancer risk reduction at the time of abdominopelvic surgery after completing childbearing.
Prophylactic salpingectomy with delayed oophorectomy for patients with BRCA-positive disease is another ovarian cancer prevention strategy that has been shown to be cost-effective.9
Currently, several prospective trials are evaluating whether these surgeries can be staged (ie, removing the fallopian tubes when childbearing is complete and then removing the ovaries later, currently within the recommended timeframe). Although some women may opt not to follow the recommended guidelines for oophorectomy prior to menopause, salpingectomy may offer some modicum of risk reduction. Larger prospective studies will be needed to better define how removing the tubes may or may not affect the overall risk for high-grade serous ovarian cancer and development of other epithelial ovarian carcinomas. These studies, however, may take another 20 years to come to fruition, given the average age of patients with ovarian cancer is between 60 and 70.
Closing Thoughts
Although opportunistic salpingectomy can be considered for all women of average risk undergoing surgery, women with high risk, greater than 5% over a lifetime, may not be able to depend on this as their only risk-reducing strategy. We are hopeful that further prospective studies may definitively show opportunistic salpingectomy is enough to decrease both high-grade serous and other ovarian cancers in these patients at least until menopause.
DISCLOSURE: Dr. Feltmate is an author for UpToDate.
REFERENCES
1. Medeiros F, Muto MG, Lee Y, et al: The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30:230-236, 2006.
2. Kindelberger DW, Lee Y, Miron A, et al: Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 31:161-169, 2007.
3. Steenbeek M, Harmsen MG, Hermens RPMG, et al: Worry and regret in the prospective multicentre TUBA study in mutation carriers. Gynecol Oncol 154:22, 2019.
4. Dilley SE, Havrilesky LJ, Bakkum-Gamez J, et al: Cost-effectiveness of opportunistic salpingectomy for ovarian cancer prevention. Gynecol Oncol 146:373-379, 2017.
5. Hanley GE, Pearce CL, Talhouk A, et al: Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Netw Open 5:e2147343, 2022.
6. Kwon JS, Tinker A, Pansegrau G, et al: Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol 121:14-24, 2013.
7. Narod SA: Salpingectomy to prevent ovarian cancer: A countercurrents series. Curr Oncol 20:145-147, 2013.
8. Madsen C, Baandrup L, Dehlendorff C, et al: Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: A nationwide case-control study. Acta Obstet Gynecol Scand 94:86-94, 2015.
9. Falconer H, Yin L, Grönberg H, et al: Ovarian cancer risk after salpingectomy: A nationwide population-based study. J Natl Cancer Inst 107:dju410, 2015.
Dr. Feltmate is Director of Minimally Invasive Surgery, Division of Gynecologic Oncology, Brigham and Women’s Hospital, and Assistant Professor, Harvard Medical School, Boston.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
