Salpingectomy to prevent ovarian cancer?

27th January 2024, A/Prof Chee L Khoo

Ovaries

The World Health Organisation classifies epithelial ovarian carcinomas into several morphological categories according to cell type: serous carcinomas (SC), mucinous carcinomas, endometrioid carcinomas, and clear-cell carcinomas, transitional-cell Brenner tumours, mixed, and undifferentiated type [1]. SC account for 75-80% of epithelial carcinomas and are subdivided into high-grade SC (HGSC) and low-grade SC (LGSC). Like any other cancers, early diagnosis would be important to improve the prognosis but often when diagnosed, ovarian cancer is in its advanced stages. Not just early detection, can we prevent ovarian cancer?

Around 1,016 women in Australia lose their life to ovarian cancer every year. 5 women will be diagnosed with ovarian cancer every day (2). In 2020, there were 944 deaths from ovarian cancer in Australia. In 2022, it is estimated that there will be 1,016 deaths. In 2022, it is estimated that a female has a 1 in 148 (or 0.68%) risk of dying from ovarian cancer by the age of 85.  In Australia the five-year survival rate for women diagnosed with ovarian cancer is 49% (1).

A systematic review looked at the role of salpingectomy in the prevention of ovarian cancer recently and I thought this was most fascinating (3). Salpingectomy to prevent ovarian cancer? What’s the pathophysiological basis of that? HGSC of the ovary traditionally has been thought to derive from the ovarian surface epithelium or from inclusion cysts within the ovary.

In 2001, Piek et al from The Netherlands found occult invasive HGSC in the fallopian tube, which closely resembled HGSC of the ovary, among women with a genetic predisposition to ovarian cancer. However, in their sample, HGSC was not present in the ovary. They hypothesised that ovarian HGSC originates from implantation of malignant or premalignant cells from the fallopian tube (5-7).

6 years later, Lee et al 12 published a sentinel study on somatic p53 suppressor gene mutations in these precursor lesions (8). Together, these findings suggest a pathogenesis characterised by DNA damage, p53 mutation, and progressive loss of cell cycle control in benign tubal mucosa that can progress to malignant cells and spread to the ovary (9-11).

Over the last 20 years, numerous studies have established that these serous tubal intraepithelial carcinomas (STICs) and small, early invasive tubal carcinomas are the precursor lesions of HGSC and can occur even among women who lack a genetic predisposition to ovarian cancer (12). These carcinomas have been most frequently detected in the fimbria of the fallopian tube, with molecular changes beginning in the secretory-type cells. These developments in the understanding of the origins of epithelial ovarian cancers have heightened interest in salpingectomy as a primary prevention strategy for ovarian cancer (13)

Many of the studies were case reports and have small samples. Kahn R, et al conducted a systematic review of the literature in 2022 to identify studies examining salpingectomy for ovarian cancer prevention (3). A total of 158 publications were reviewed and salpingectomy has been associated with ovarian cancer ~80% risk reduction. Great. Are there any downsides with salpingectomy in these well women?

Ovarian function

We have always been taught that if you interfere with the blood supply of the ovaries, like in a hysterectomy, the ovaries’ blood supply might be affected. Can salpingectomy to the same to pre-menopausal women. In 2017, Kotlyar et al performed a review of 48 articles relevant to salpingectomy published from 1946 to 2016 and concluded that salpingectomy had no significant association with ovarian reserve across most findings (14).

In a 2017 population-based observational study in Canada, Venturella et al found that the addition of bilateral salpingectomy at the time of laparoscopic hysterectomy did not alter ovarian age—as determined by follicle-stimulating hormone, anti–Müllerian hormone, antral follicle count, and ovarian vascular and flow index—in treated women up to 5 years after surgery (15).

In 2018, Asgari et al reported on a randomised clinical trial of 62 premenopausal women that compared surgical outcome and ovarian reserve after laparoscopic hysterectomy with vs without prophylactic bilateral salpingectomy (16). The authors concluded that the salpingectomy portion of the procedure did not have a negative association with ovarian reserve or increased surgical risk.

The Stop Ovarian Cancer [STOPOVCA] is a multicentre, observational, non-inferiority study looking to compare the age at menopause of women initially aged 35–45 who underwent sterilisation through opportunistic salpingectomy with a similarly aged control group who underwent sterilisation by tubal ligation or no sterilization (17). They have completed the recruitment but will not report till 2039.

Opportunistic salpingectomy?

Salpingectomy at the time of hysterectomy for benign indications, as well as caesarean delivery, has been adopted in the US and Canada. Opportunistic salpingectomy did not add to operative time, blood loss, length of hospital stay and perioperative complications. Not unexpectantly, salpingectomy uptake at the time of non-gynaecologic abdominal surgery has been slower. Gynaecologic surgeons are comfortable with pelvic anatomy and routinely perform salpingectomy. Other surgeons, however, may lack the proper training to perform it or be unaware of the benefits of opportunistic salpingectomy.

Cost-effectiveness?

Various studies have demonstrated that salpingectomy at the time of other surgical procedures is both a cost-effective and cost-saving strategy to prevent ovarian cancer in selectwomen (18-20). Most recently, Naumann et al estimated that the total savings for universal salpingectomy could be as high as $445 million annually in the US (21).

The numbers to treat

Assuming a 1.7% baseline population risk of developing ovarian cancer and a 65% reduction in risk of ovarian cancer with a salpingectomy, up to 5394 cases of epithelial ovarian cancer could be eliminated per year in the US. This represents a 39% reduction in the incidence of the disease.

Thus, studies over the last 2 decades have demonstrated that salpingectomy to prevent ovarian cancer was safe, cost-effective and was not associated with an earlier age of menopause onset. With widespread implementation, salpingectomy has the potential to reduce ovarian cancer mortality. In Australia, we don’t seem to have adopted this recommendation as they have done in the US and Canada. Should we discuss this with our patients undergoing gynaecological or non-gynaecological procedures, especially in those at high risk of ovarian cancer? Should you have a conversation with your friendly gynaecologist on behalf of our patients?

References:

  1. https://www.canceraustralia.gov.au/cancer-types/ovarian-cancer/statistics. Accessed 20th January 2024
  2. https://www.ovariancancer.net.au/. Accessed 20th January 2024
  3. Kahn RM, Gordhandas S, Godwin K, et al. Salpingectomy for the Primary Prevention of Ovarian Cancer: A Systematic Review. JAMA Surg. 2023 Nov 1;158(11):1204-1211. doi: 10.1001/jamasurg.2023.4164. Erratum in: JAMA Surg. 2023 Oct 4;: Erratum in: JAMA Surg. 2023 Oct 25;:
  4. Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195(4): 451-456. doi:10.1002/path.1000
  5. Piek JM, van Diest PJ, Zweemer RP, et al. Tubal ligation and risk of ovariancancer. Lancet. 2001;358(9284):844. doi:10.1016/S0140-6736(01)05992-X
  6. Piek JM, Verheijen RH, Kenemans P, et al. BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis. Gynecol Oncol. 2003;90(2):491. doi:10.1016/S0090-8258 (03)00365-2
  7. Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol. 2013;24(suppl 10):x16-x21. doi:10.1093/annonc/mdt463
  8. Lee Y, Miron A, Drapkin R, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007;211(1):26-35. doi:10.1002/path.2091
  9. Kurman RJ, Shih IeM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol. 2011;42 (7):918-931. doi:10.1016/j.humpath.2011.03.003
  10. Meserve EEK, Brouwer J, Crum CP. Serous tubal intraepithelial neoplasia: the concept and its application. Mod Pathol. 2017;30(5):710-721. doi:10. 1038/modpathol.2016.238
  11. Salvador S, Gilks B, Köbel M, Huntsman D, Rosen B, Miller D. The fallopian tube: primary site of most pelvic high-grade serous carcinomas. Int J Gynecol Cancer. 2009;19(1):58-64. doi:10.1111/IGC. 0b013e318199009c
  12. Przybycin CG, Kurman RJ, Ronnett BM, Shih IM, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010; 34(10):1407-1416. doi:10.1097/PAS.0b013e3181ef7b16
  13. Daly MB, Dresher CW, YatesMS, et al. Salpingectomy as a means to reduce ovarian cancer risk. Cancer Prev Res (Phila). 2015;8(5):342-348. doi:10.1158/1940-6207.CAPR-14-0293
  14. Kotlyar A, Gingold J, Shue S, Falcone T. The effect of salpingectomy on ovarian function. J Minim Invasive Gynecol. 2017
  15. Venturella R, Lico D, Borelli M, et al. 3 to 5 Years later: long-term effects of prophylactic bilateral salpingectomy on ovarian function. J Minim Invasive Gynecol. 2017;24(1):145-150. doi:10.1016/j.jmig. 2016.08.833
  16. Asgari Z, Tehranian A, Rouholamin S, et al. Comparing surgical outcome and ovarian reserve after laparoscopic hysterectomy between two methods of with and without prophylactic bilateral salpingectomy: a randomized controlled trial. J Cancer Res Ther. 2018;14(3):543-548. doi:10.4103/0973-1482.193114
  17. Gelderblom ME, IntHout J, Hermens RPMG, et al. STop OVarian CAncer (STOPOVCA) young: protocol for a multicenter follow-up study to determine the long-term effects of opportunistic salpingectomy on age at menopause. Maturitas. 2022;159:62-68. doi:10.1016/j.maturitas.2022.01. 006
  18. Venkatesh KK, Clark LH, Stamilio DM. Cost-effectiveness of opportunistic salpingectomy vs tubal ligation at the time of cesarean delivery. Am J Obstet Gynecol. 2019;220(1):106.e1-106.e10. doi:10.1016/j.ajog.2018.08.032
  19. Tai RWM, Choi SKY, Coyte PC. The cost-effectiveness of salpingectomies for family planning in the prevention of ovarian cancer. J Obstet Gynaecol Can. 2018;40(3):317-327. doi:10. 1016/j.jogc.2017.06.038
  20. Subramaniam A, Einerson BD, Blanchard CT, et al. The cost-effectiveness of opportunistic salpingectomy versus standard tubal ligation at the time of cesarean delivery for ovarian cancer risk reduction. Gynecol Oncol. 2019;152(1):127-132. doi:10.1016/j.ygyno.2018.11.009
  21. Naumann RW, Hughes BN, Brown J, et al. The impact of opportunistic salpingectomy on ovarian cancer mortality and healthcare costs: a call for universal insurance coverage. Am J Obstet Gynecol. 2021;225(4):397.e1-397.e6. doi:10.1016/j.ajog.2021.03.032