The Fallopian Tube Origin of Ovarian Cancer: How a New Origin Story Changed Prevention

Key Takeaways:

• In a pathology series that examined the fallopian tubes in full, 71% of pelvic serous carcinomas classified as ovarian involved the lining of the fallopian tube and 48% had a coexisting tubal intraepithelial carcinoma; 93% of those early tubal cancers sat in the fimbriae, the fringed end of the tube beside the ovary.
• In the UK Collaborative Trial of Ovarian Cancer Screening, which randomized 202,562 women aged 50 to 74 and followed them for a median of 16.3 years, annual screening with a CA-125-based strategy or with transvaginal ultrasound did not significantly reduce deaths from ovarian or tubal cancer.
• In a Swedish nationwide cohort, women who had had a salpingectomy for a benign reason had a lower risk of ovarian cancer than the general population (hazard ratio 0.65), and removal of both tubes was associated with a larger reduction than removal of one (hazard ratio 0.35 versus 0.71).

High-grade serous carcinoma is the most common and most lethal form of what we call ovarian cancer, and the majority of women with it are diagnosed only after it has spread through the abdomen. For most of the twentieth century, the assumption was that it began on the surface of the ovary. That story has been substantially rewritten, and the relationship between the fallopian tube and ovarian cancer is now at the center of how physicians think about prevention. The first clue came from an unexpected place. When women carrying BRCA mutations had their tubes and ovaries removed to lower their risk, pathologists who examined the tissue closely kept finding tiny, early cancers not in the ovary but in the fimbria, the fringed, finger-like end of the fallopian tube that drapes over the ovary. Researchers then applied the same meticulous sectioning protocol to consecutive cases of advanced pelvic serous cancer. Among cases classified as ovarian, 71 percent involved the lining of the tube and 48 percent carried a small focus of what is now called serous tubal intraepithelial carcinoma, or STIC. Ninety-three percent of those lesions sat in the fimbriae, and in every case tested, the tubal lesion and the ovarian tumor shared an identical p53 mutation.

Shared mutations suggest kinship, but they do not by themselves establish which lesion came first. That question was addressed with whole-exome sequencing. In nine patients, researchers laser-dissected precursor lesions from the fallopian tube, including early p53 signatures and STICs, along with the ovarian tumors and metastases, and reconstructed their evolutionary family tree. Most of the tumor-specific alterations found in the ovarian cancers, including changes in TP53, BRCA1, BRCA2, and PTEN, were already present in the tubal lesions, and the analysis placed the tubal lesions upstream as precursors. It also estimated a window of about seven years between the development of a STIC and the start of the ovarian carcinoma, with metastases following rapidly after that. The sample was small, and not every high-grade serous cancer is thought to arise this way, but the picture fits a large body of pathology: in many women, the cancer begins in the tube and seeds the ovary and the peritoneum, so the disease is already spreading by the time anything in the ovary could be seen on a scan.

What does the fallopian tube and ovarian cancer link mean for prevention?

It explains two findings that once seemed puzzling. The first is why screening has disappointed. In the largest trial ever done, more than 200,000 postmenopausal women were randomized to annual screening built around the blood marker CA-125, annual transvaginal ultrasound, or no screening, and followed for a median of more than sixteen years. The CA-125-based strategy found more cancers at stage I and fewer at stage IV, yet deaths from ovarian and tubal cancer were not significantly reduced, and the investigators concluded that general population screening cannot be recommended. A cancer that starts microscopically in the tube and spreads early is a poor target for a test aimed at the ovary. The second finding is why removing the tubes appears protective. In a Swedish national cohort, women who had had a salpingectomy for a benign reason had a 35 percent lower risk of ovarian cancer, with a greater reduction when both tubes were removed, and in British Columbia, among nearly 26,000 women who had their tubes removed during a hysterectomy or instead of a tubal ligation, no serous ovarian cancers were observed where about five would have been expected. This is called opportunistic salpingectomy: when a woman is already having pelvic surgery and has finished childbearing, the tubes can be removed while the ovaries, and their hormones, are left in place. These data are observational and follow-up is still short, so it is not a reason to have surgery on its own, and women at inherited high risk follow separate specialist guidance. For everyone, the practical steps are to share any family history of ovarian or breast cancer with a physician, to ask about opportunistic salpingectomy before a planned pelvic surgery, and to have persistent new bloating, pelvic pain, or early fullness checked promptly.

References:

1. Kindelberger, D. W., Lee, Y., Miron, A., Hirsch, M. S., Feltmate, C., Medeiros, F., et al. (2007). Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. American Journal of Surgical Pathology, 31(2), 161-169.
2. Labidi-Galy, S. I., Papp, E., Hallberg, D., Niknafs, N., Adleff, V., Noe, M., et al. (2017). High grade serous ovarian carcinomas originate in the fallopian tube. Nature Communications, 8(1), 1093.
3. Menon, U., Gentry-Maharaj, A., Burnell, M., Singh, N., Ryan, A., Karpinskyj, C., et al. (2021). 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, 397(10290), 2182-2193.
4. Falconer, H., Yin, L., Grönberg, H., & Altman, D. (2015). Ovarian cancer risk after salpingectomy: A nationwide population-based study. Journal of the National Cancer Institute, 107(2), dju410.
5. Hanley, G. E., Pearce, C. L., Talhouk, A., Kwon, J. S., Finlayson, S. J., McAlpine, J. N., et al. (2022). Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Network Open, 5(2), e2147343.