Updated June 7, 2024
Ovarian cancer is the 7th most common malignancy in British Columbia women with a crude incidence rate of 12.2 per 100,000 reported in 2021. The incidence rate has slowly decreased over the last 40 years. The 5-year survival for ovarian cancer is approximately 40-50 %. Epithelial ovarian carcinomas (EOC) account for ~90% of all ovarian malignancies. EOC encompasses 5 distinct diseases, with different presentations (e.g., average age of diagnosis and stage), response to chemotherapy, prognosis, molecular features, and site of origin [1, 2]. While these carcinomas share a common site of tumor growth in the ovary, they are increasingly considered as different diseases in need of disease specific management.
High-grade serous carcinoma (HGSC) is the most common histological subtype (60% of EOC) usually presenting at advanced stage and accounting for most deaths from ovarian cancer. It now recognized that almost all HGSC originate in the distal fallopian tube epithelium and that this histotype is most closely associated with hereditary breast and ovarian cancer syndrome (e.g., BRCA1 or BRCA2 mutations). Fallopian tube carcinoma was previously considered a separate disease site, but the understanding that HGSC of fallopian origin often appear as a dominant mass on the ovary, there is a move to label these tumours “tubo-ovarian”, “pelvic serous”, or “Mullerian serous” (non-uterine) carcinomas [3, 4]. The two next most common types of EOC, clear cell (10%) and endometrioid (10%), are often associate with endometriosis that has implanted on the ovaries or in the peritoneal cavity and undergone malignant transformation. Low grade serous carcinoma (LGSC) and mucinous carcinoma comprise the remaining 2 types of EOC and are very rare (<5% each). LGSC may arise from borderline serous carcinomas (tumours of low malignant potential) or from cells in the fallopian tube. The precursor cell of mucinous of the ovary are not defined.
Higher risk of ovarian cancer has been observed in women with no children or with low numbers of live births. Risk factors that can promote changes at the fallopian tube epithelium include ascending infections (e.g., pelvic inflammatory disease) and retrograde menstruation. Endometriosis is also a well-known risk factor for ovarian cancers, but most strongly associated with clear cell and endometrioid subtypes. Interventions that prevent passage from the lower genital tract or uterus via the fallopian tube to the ovary and peritoneal cavity (e.g., tubal ligation) have shown substantial risk reduction, most notably in clear cell and endometrioid histotypes. These findings support the important role the fallopian tube plays in the development of ovarian cancer, not only as the site of origin for most high-grade serous carcinomas but also as a conduit for inflammatory stimuli including endometriosis and infection.
Family history of breast and ovarian cancer has long known to be associated with risk of disease and plays a much more profound role in ovarian HGSC with an estimated 1 in 5 women with HGSC harbouring germline BRCA1 or BRCA2 mutations. Clear cell and endometrioid tumors can be associated with Lynch syndrome (previously referred to as Hereditary Non-Polyposis Colorectal Carcinoma [HNPCC]), which is associated with increased lifetime risks of developing colorectal carcinoma, endometrial carcinoma, ovarian cancer and other primary tumors.
Key Message: There are no effective screening/early detection strategies for ovarian cancer.
There are no screening tests proven to detect EOC at an early stage and reduce the number of women who die from this disease. Modalities such as pelvic examination, CA125 measurements and pelvic ultrasound have been tested as screening methods in well executed international clinical trials and have failed to demonstrate a benefit in survival [5, 6] The trials had unacceptably high rate of false positive tests leading to unnecessary surgery. Therefore, ovarian cancer screening is currently not recommended by any jurisdiction, including the Society of Gynecologic Oncology of Canada and the American College of Obstetrics and Gynecology.
- UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) This large-scale trial involved over 200,000 postmenopausal women and evaluated multimodal screening with CA125 and transvaginal ultrasound.
- Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial This US-based trial included over 78,000 women and assessed annual screening with CA125 and transvaginal ultrasound.
1) Opportunistic salpingectomy for average-risk women: For women who are undergoing any pelvic surgery and who have met their reproductive needs, consideration should be given to removal of the fallopian tubes.
Rationale: Given the lack of effective screening strategies, opportunities for prevention should be considered. Given that the fallopian tube plays a key role in cancer development, both as a site of origin (e.g., HGSCs) and as a conduit for endometriosis (which is associated with clear cell and endometrioid cancers), the fallopian tubes can be removed in women who are undergoing pelvic surgery and no longer need their tubes for reproductive purposes. Titled “opportunistic salpingectomy” this option is directed at women at ‘low risk’ for developing ovarian cancer (i.e., the general population, women not known to have an inherited mutation) and to be performed at the time of hysterectomy for benign conditions or when permanent sterilization is being done (e.g., salpingectomy in lieu of tubal ligation).
Emerging data demonstrate that opportunistic salpingectomy appears to be very safe. There is no noted increased risk of adverse perioperative outcomes or minor complications [7, 8, 9] In addition, there is no apparent impact on the timing of menopause onset, although longer-term hormonal outcomes are still unknown needed [10-14]. A population-based, retrospective cohort study examining OS done for the purpose of ovarian cancer prevention in BC (n=25,88) and comparing to individuals who underwent hysterectomy alone or tubal ligation (n=32,080) reported 0 serous ovarian cancers in the OS group. The age-adjusted expected number, had serous cancers been arising at the same rate in the OS group as in the control group, was 5.27 (95%CI, 1.78-19.29). There were no differences in observed and expected rates of breast or colorectal cancer and the difference in serous cancers could not be explained by differences in known risk and protective factors for ovarian cancer between the groups [15].
2) Risk-reducing surgery in high-risk women: Bilateral removal of ovaries and fallopian tubes by age 40 or when childbearing is complete. Salpingectomy with delayed oopherectomy in this population is unproven but can be considered in well-informed individuals or as part of a clinical trial.
Bilateral removal of the fallopian tubes (salpingectomy) and ovaries (oophorectomy) (BSO) is the standard of care for BRCA1/BRCA2 mutation carriers who have completed childbearing and wish to reduce their future risk of ovarian and fallopian tube cancers. Surgery is typically offered between the ages of 35-40 for BRCA1, and 40-45 for BRCA2.
Those with other lower penetrance hereditary predisposition (e.g., RAD51C/D, BRIP1) or Lynch Syndrome (see section 15.4 Lynch Syndrome (LS) and DNA Mismatch Repair Proteins) have about a 10% risk of ovarian cancer and should be referred to discuss surgical removal of their tubes and ovaries [16].
Because most BRCA-associated cancers appear to arise in the fallopian tubes, it would seem reasonable to offer salpingectomy as a risk-reducing procedure to these high-risk women, with consideration for delayed removal of the ovaries at the time of expected menopause. Modeling studies suggest this approach may be both clinically effective and cost-effective [17, 18]. However, the true effectiveness of this 2-step risk reducing procedure is not yet known. Patients considering the 2-step procedure are strongly encouraged to participate in a clinical trial addressing this strategy (e.g., SOROCk through NRG Oncology: https://www.nrgoncology.org/SOROCk; TUBA-WISP II study through the Dutch Cancer Society:
https://www.tuba-wisp.org/).
There are 2 compelling reasons to remove the ovaries: (1) a small proportion of BRCA-associated cancers may arise primarily in the ovaries, and (2) premenopausal oophorectomy reduces breast cancer risk by approximately 50%. Salpingectomy alone in this population should be reserved only for individuals who decline standard of care.
3) Chemoprevention such as oral contraceptive pills may also be considered and are believed to be effective in reducing ovarian/fallopian tube cancer risk by about 50% if used for 5 years by both low-risk and high-risk women [19, 20]. The caveat is that there may be an increased risk of breast cancer associated with oral contraceptives in BRCA1 mutation carriers [19].
1. Gilks, C.B., et al., Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol, 2008. 39(8): p. 1239-51.
2. Kobel, M., et al., Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med, 2008. 5(12): p. e232.
3. Singh, N., et al., Primary site assignment in tubo-ovarian high-grade serous carcinoma: Consensus statement on unifying practice worldwide. Gynecol Oncol, 2016. 141(2): p. 195-198.
4. Singh, N., et al., Adopting a Uniform Approach to Site Assignment in Tubo-Ovarian High-Grade Serous Carcinoma: The Time has Come. Int J Gynecol Pathol, 2016. 35(3): p. 230-7.
5. Menon U et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2021 Jun 5;397(10290):2182-2193. doi: 10.1016/S0140-6736(21)00731-5. Epub 2021 May 12. PMID: 33991479; PMCID: PMC8192829.
6. Buys SS et al.,; PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8;305(22):2295-303. doi: 10.1001/jama.2011.766. PMID: 21642681.
7. McAlpine JN, Hanley GE, Woo MM, Tone AA, Rozenberg N, Swenerton KD, et al. Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. American journal of obstetrics and gynecology. 2014;210(5):471 e1-11.
8. Hanley GE, McAlpine JN, Pearce CL, Miller D. The performance and safety of bilateral salpingectomy for ovarian cancer prevention in the United States. American journal of obstetrics and gynecology. 2017;216(3):270 e1- e9.
9. Hanley GE, Kwon JS, Finlayson SJ, Huntsman DG, Miller D, McAlpine JN. Extending the safety evidence for opportunistic salpingectomy in prevention of ovarian cancer: a cohort study from British Columbia, Canada. American journal of obstetrics and gynecology. 2018;219(2):172 e1- e8.
10. Hanley GE, Kwon JS, McAlpine JN, Huntsman DG, Finlayson SJ, Miller D. Examining indicators of early menopause following opportunistic salpingectomy: a cohort study from British Columbia, Canada. American journal of obstetrics and gynecology. 2020;223(2):221 e1- e11.
11. Morelli M, Venturella R, Mocciaro R, Di Cello A, Rania E, Lico D, et al. Prophylactic salpingectomy in premenopausal low-risk women for ovarian cancer: primum non nocere. Gynecologic oncology. 2013;129(3):448-51.
12. Venturella R, Lico D, Borelli M, Imbrogno MG, Cevenini G, Zupi E, et al. 3 to 5 Years Later: Long-term Effects of Prophylactic Bilateral Salpingectomy on Ovarian Function. Journal of minimally invasive gynecology. 2017;24(1):145-50.
13. Findley AD, Siedhoff MT, Hobbs KA, Steege JF, Carey ET, McCall CA, et al. Short-term effects of salpingectomy during lapa roscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial. Fertility & Sterility. 2013;100(6):1704-8.
14. van Lieshout LAM, Steenbeek MP, De Hullu JA, Vos MC, Houterman S, Wilkinson J, et al. Hysterectomy with opportunistic salpingectomy versus hysterectomy alone. Cochrane Database of Systematic Reviews. 2019;8:CD012858.
15. Hanley GE, Pearce CL, Talhouk A, Kwon JS, Finlayson SJ, McAlpine JN, Huntsman DG, Miller D. Outcomes From Opportunistic Salpingectomy for Ovarian Cancer Prevention. JAMA Netw Open. 2022 Feb 1;5(2):e2147343. Doi: 10.1001/jamanetworkopen.2021.47343
16. Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, Bernards SS, casadei S, Yi Q, Burger RA Chan JK, Davidson SA, Mannel RS, DiSilvestro PA, Lankes HA, Ramirez NC, King MC, Swisher EM, Birrer MJ. Inherited Mutations in Women with Ovarian Carcinoma. JAMA Oncol . 2016 Apr;2(4):482-90. doi: 10.1001/jamaoncol.2015.5495)
17. Kwon JS, Tinker A, Pansegrau G, McAlpine J, Housty M, McCullum M, Gilks CB. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol 2013 Jan;121(1):14-24 doi: 10.1097/aog.0b013e3182783c2f
18. Harmsen MG, et al. Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study. BMC Cancer 2015 Aug 19:15:593. doi: 10.1186/s12885-015-1597-y
19. Narod, S.A., et al., Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med, 1998. 339(7): p. 424-8.
20. Whittemore, A.S., R. Harris, and J. Itnyre, Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol, 1992. 136(10): p. 1212-20.
