September 2012 Tubal Hypothesis of Ovarian Cancer September is Ovarian Cancer Awareness Month. In this posting, we highlight current management strategies for women at hereditary risk for ovarian cancer and an emerging possibility for future treatment based on the tubal hypothesis of ovarian cancer. Cancer Risks and Current Management: Hereditary breast and ovarian cancer (HBOC) accounts for 10-15% 1-3 of epithelial ovarian cancer, conferring lifetime risks of up to 44% for ovarian, fallopian tube and primary 4 5 peritoneal cancers. Lynch syndrome accounts for another 2% of ovarian cancers and confers lifetime risks for 6 ovarian cancer of up to 12%. Standard management recommendations for women with HBOC include risk7 reducing salpingo-oophorectomy (RRSO), ideally at age 35-40y, or upon completion of childbearing. For women with Lynch syndrome, prophylactic hysterectomy and bilateral salpingo-oophorectomy is also a risk8 reducing option upon completion of childbearing. Risk-Reducing Salpingo-Oophorectomy Technique: The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) recommend specific surgical techniques for RRSO, including removal of all tissue from the ovaries and fallopian tubes, complete visualization of the peritoneal surfaces and pelvic washings, as well as a specific approach to pathologic evaluation 9-11 comprising complete serial sectioning of the fallopian tubes and ovaries. Rigorous pathological examinations of RRSO specimens result in increased cancer detection compared to routine examination, with identification of 12 occult malignancies in up to 26% of cases. The majority of occult neoplasms involve the fallopian tubes and 13 range from epithelial atypia to carcinoma in situ to invasive carcinoma. Tubal Hypothesis: Tone et al. outline evidence supporting the distal fallopian tube as the site of origin for the most common type of epithelial ovarian cancer, high grade papillary serous carcinoma. They further describe the fallopian tube as a conduit, linking the lower genital tract to the peritoneal cavity, and allowing for 14 transmission of carcinogens, inflammatory agents, endometrial tissue and malignant cells to the ovary. Possible Future Treatment Option: The tubal hypothesis for the origin of ovarian cancer is thought-provoking and suggests the possibility of a staged approach to surgical prevention of ovarian cancer: bilateral salpingectomy with ovarian retention as a temporary risk-reducing effort for at-risk women not yet ready to 15 undergo the more definitive bilateral oophorectomy. It is important to note that the use of this procedure as a preliminary risk-reducing strategy is being evaluated in the research setting, and is currently considered an investigational procedure of unproven utility. A commentary by Collins et al. offers the following caution based 16 on a number of hypotheses regarding ovarian cancer pathogenesis: • There may be more than one route for ovarian cancer development. • It is possible that some tubal epithelium may be transferred to the ovary by endosalpingiosis; if so, it will be important to understand at what age this occurs to inform ideal timing for salpingectomy. • The border between the tubal and ovarian surface epithelium could be a site of malignant transformation, making it a high-risk zone that salpingectomy alone may not effectively address. In Summary: Ovarian cancer poses one of the gravest risks for women with HBOC or Lynch syndrome mutations. The challenge of diagnosing ovarian cancer at an early stage has led to the acceptance of prophylactic surgical intervention for risk reduction. Increasing understanding of the pathogenesis of ovarian cancer may lead to new options for prevention in the future. REFERENCES: 1. Zhang S, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):352-7. http://www.ncbi.nlm.nih.gov/pubmed/21324516 2. Alsop K, et al. BRCA Mutation Frequency and Patterns of Treatment Response in BRCA MutationPositive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. http://www.ncbi.nlm.nih.gov/pubmed/22711857 3. Pal T et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005. Dec 15;104(12)2807-16. http://www.ncbi.nlm.nih.gov/pubmed/16284991 4. Ford D, et al. Breast Cancer Linkage Consortium: Risks of cancer in BRCA1-mutation carriers. Lancet. 1994;343:692-5. http://www.ncbi.nlm.nih.gov/pubmed/7907678 5. Malander S, et al. The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol Oncol. 2006;101:238-43. http://www.ncbi.nlm.nih.gov/pubmed/16360201 6. Aarnio M, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81:214-8. http://www.ncbi.nlm.nih.gov/pubmed/10188721 7. NCCN Clinical Practice Guidelines in Oncology™. Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 1.2012. Accessed at www.nccn.org . 8. NCCN Clinical Practice Guidelines in Oncology™. Colorectal Cancer Screening Version 2.2012. Accessed at www.nccn.org. 9. ACOG. Hereditary breast and ovarian cancer syndrome. Gynecol Oncol. 2009 Apr; 113(1):6-11. http://www.ncbi.nlm.nih.gov/pubmed/19309638 10. ACOG. ACOG Practice Bulletin No. 89. Elective and Risk Reducing Salpino-oophorectomy. Obstet Gynecol. 2008 Jan; 111(1):231-41. http://www.ncbi.nlm.nih.gov/pubmed/18165419 11. Society of Gynecologic Oncologists Clinical Practice Committee Statement on Prophylactic Salpingooophorectomy. Gynecol Oncol. 2005;179-81. http://www.ncbi.nlm.nih.gov/pubmed/15979696 12. Hirst JE, et al. High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingooophorectomy. Int J Gynecol Cancer. 2009 Jul;19(5):826-9. http://www.ncbi.nlm.nih.gov/pubmed/19574767 13. Greene MH and Mai PL. What Have We Learned from Risk-Reducing Salpingo-oophorectomy? J Natl Cancer Inst. 2009 Jan 21;101(2):70-1. http://www.ncbi.nlm.nih.gov/pubmed/19141782 14. Tone AA, et al. The Role of the Fallopian Tube in Ovarian Cancer. Clin Adv Hematol Oncol. 2012 May;10(5):296-306. http://www.ncbi.nlm.nih.gov/pubmed/22706539 15. Greene MH, et al. Does Bilateral Salpingectomy with Ovarian Retention Warrant Consideration as a Temporary Bridge to Risk-Reducing Bilateral Oophorectomy in BRCA1/2 Mutation Carriers? Am J Obstet Gynecol. 2011 Jan; 204(1):19.e1-6. http://www.ncbi.nlm.nih.gov/pubmed/20619389 16. Collins IM, et al. The tubal hypothesis of ovarian cancer: caution needed. Lancet Oncol. 2011 Nov;12(12):1089-91. http://www.ncbi.nlm.nih.gov/pubmed/21868285 Do not reply to this message. If you have questions regarding information in this posting, please contact your local Regional Medical Specialist (RMS) or email medical services at firstname.lastname@example.org. If you do not know how to reach your RMS, check with your Account Executive or call 800-4-MYRIAD (800-469-7423) and ask for contact information for your local RMS.