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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
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