Familial Gynecologic Cancers: Whom to Screen and How to Manage?

  • Kari L. Ring
  • Rachel Michaelson-Cohen
  • Karen H. Lu
  • Uziel Beller


Gynecologic cancers are important components of several hereditary cancer syndromes. Identification of individuals who harbor germline mutations in cancer susceptibility genes is important not only for prevention in unaffected family members but also for the cancer patient, in terms of therapeutic implications and prevention of second cancers. While significant strides have been made in the identification of women with Hereditary Breast/Ovarian Cancer and Lynch syndrome, several questions remain in terms of whom to offer genetic testing, how to screen for cancers, and the best way to reduce cancer risk. This chapter addresses these issues from different viewpoints. Screening all patients with high-grade serous ovarian cancer for BRCA1/2 germline mutations is one strategy that could improve counseling for patients regarding disease course, treatment options, prevention of second cancers, and prevention of cancers in family members who may also harbor BRCA mutations. However, given the current cost of genetic testing, this strategy may not be cost-effective in the healthcare system. Reflex tumor testing for Lynch syndrome, with immunohistochemistry or microsatellite instability analysis, can increase the detection of Lynch-associated endometrial cancers and prevention of secondary cancers, most notably colorectal cancer. However, several questions remain regarding the optimal strategy and implementation of reflex testing in all endometrial cancer patients. Based on the current understanding of the tubal origin of BRCA-associated ovarian cancers, risk-reducing salpingectomy is an attractive option for younger patients with BRCA1/2 mutations in whom fertility is a concern. Unfortunately, there is no objective evidence that the substantial risk reduction seen with risk-reducing salpingo-oophorectomy would be translated to risk-reducing salpingectomy. Many questions remain regarding screening BRCA1/2 mutation carriers with CA-125 and ultrasound every 6 months. Ongoing, large prospective trials will likely help to answer some of these questions. Until then, patients do need to understand the drawbacks of our current screening methods, especially when considering risk-reducing salpingo-oophorectomy. There is a paucity of evidence when considering endometrial cancer screening in patients with Lynch syndrome; however, annual endometrial biopsy remains one option. As we understand more about familial gynecologic cancers, including Hereditary Breast/Ovarian Cancer and Lynch syndrome, large prospective studies are needed to help address current screening guidelines and management recommendations for these patients.


Ovarian Cancer Endometrial Cancer Mutation Carrier Germline Mutation Lynch Syndrome 


  1. 1.
    King M-C, Marks JH, Mandell JB, TNYBCS Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Antoniou A, Pharoah PDP, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117–30.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998;62(3):676–89.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81(2):214–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 1997;6(1):105–10.PubMedCrossRefGoogle Scholar
  6. 6.
    Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, Bandipalliam P, Chen LM, Allen B, Conrad P, Terdiman J, Sun C, Daniels M, Burke T, Gersheson DM, Lynch H, Lynch P, Broaddus RR. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol. 2005;105(3):569–74.PubMedCrossRefGoogle Scholar
  7. 7.
    McDermott U, Downing JR, Stratton MR. Genomics and the continuum of cancer care. N Engl J Med. 2011;364(4):340–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Screening for Ovarian Cancer: Clinical Summary of U.S. Preventive Services Task Force Reaffirmation Recommendation. AHRQ Publication No. 12-05165-EF-5, September 2012. http://www.uspreventiveservicestaskforce.org/uspstf12/ovarian/ovarcancersum.htm.
  9. 9.
    Vencken PM, Kriege M, Hoogwerf D, Beugelink S, van der Burg MEL, Hooning MJ, et al. Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol. 2011;22(6):1346–52.PubMedCrossRefGoogle Scholar
  10. 10.
    Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, et al. Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol. 2002;20(2):463–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: The National Israeli Study of Ovarian Cancer. J Clin Oncol. 2008;26(1):20–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Tan DSP, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA, LiVolsi VA, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med. 1996;335(19):1413–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654–63.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle. 2005;4(9):1176–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.PubMedCrossRefGoogle Scholar
  19. 19.
    McCabe N, Turner NC, Lord CJ, Kluzek K, Białkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. The Lancet. 2010;376(9737):245–51.CrossRefGoogle Scholar
  21. 21.
    Iglehart JD, Silver DP. Synthetic lethality—a new direction in cancer-drug development. N Engl J Med. 2009;361(2):189–91.PubMedCrossRefGoogle Scholar
  22. 22.
    Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807–16.PubMedCrossRefGoogle Scholar
  23. 23.
    Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci. 2011;108(44):18032–7.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Wickramanyake A, Bernier G, Pennil C, Casadei S, Agnew KJ, Stray SM, et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012;127(3):552–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Schrader KA, Hurlburt J, Kalloger SE, Hansford S, Young S, Huntsman DG, Gilks CB, McAlpine JN. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol. 2012;120(2):235–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in brca1 or brca2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–75.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, Lishinsky E, Shohat M, Weber BL, Beller U, Lahad A, Halle D. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet. 1997;60(5):1059–67.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Karchin RAM, Agarwal M, Sali A, Couch F, Beattie MS. Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios. Cancer Inform. 2008;6:203–16.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Ready KJ, Gutierrez-Barrera AM, Atchley D, Solomon KK, Amos C, Meric-Bernstam F, Lu KH, Hortobagyi GN, Arun B. Cancer risk management decisions of women with BRCA variants of uncertain significance. J Clin Oncol. 2008;26:Abstract #22021.Google Scholar
  30. 30.
    Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121(2):353–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Risch HA, McLaughlin JR, Cole DEC, Rosen B, Bradley L, Kwan E, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700–10.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Malander S, Ridderheim M, Måsbäck A, Loman N, Kristoffersson U, Olsson H, et al. One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden. Eur J Cancer. 2004;40(3):422–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Kwon JS, Daniels MS, Sun CC, Lu KH. Preventing future cancers by testing women with ovarian cancer for BRCA mutations. J Clin Oncol. 2010;28(4):675–82.PubMedCrossRefGoogle Scholar
  34. 34.
    Kwon JS, Gutierrez-Barrera AM, Young D, Sun CC, Daniels MS, Lu KH, et al. Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol. 2010;28(27):4214–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 2000;283(17):2260–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Lancaster JM, Powell CB, Kauff ND, Cass I, Chen L-M, Lu KH, et al. Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2007;107(2):159–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66(15):7810–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Schneider R, Schneider C, Kloor M, Fürst A, Möslein G. Lynch syndrome: clinical, pathological, and genetic insights. Langenbecks Arch Surg. 2012;397(4):513–25.PubMedCrossRefGoogle Scholar
  39. 39.
    Schmeler K, Lu K. Gynecologic cancers associated with Lynch syndrome/HNPCC. Clin Transl Oncol. 2008;10(6):313–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Vasen HFA, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology. 1999;116(6):1453–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Umar A, Boland CR, Terdiman JP, Syngal S, Chapelle A, Rüschoff J, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261–8.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Backes FJ, Leon ME, Ivanov I, Suarez A, Frankel WL, Hampel H, et al. Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer. Gynecol Oncol. 2009;114(3):486–90.PubMedCrossRefGoogle Scholar
  43. 43.
    Leenen CHM, van Lier MGF, van Doorn HC, van Leerdam ME, Kooi SG, de Waard J, et al. Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤70 years. Gynecol Oncol. 2012;125(2):414–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Garg K, Soslow RA. Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. J Clin Pathol. 2009;62(8):679–84.PubMedCrossRefGoogle Scholar
  45. 45.
    Westin SN, Lacour RA, Urbauer DL, Luthra R, Bodurka DC, Lu KH, et al. Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol. 2008;26(36):5965–71.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Ryan P, Mulligan AM, Aronson M, Ferguson SE, Bapat B, Semotiuk K, et al. Comparison of clinical schemas and morphologic features in predicting Lynch syndrome in mutation-positive patients with endometrial cancer encountered in the context of familial gastrointestinal cancer registries. Cancer. 2012;118(3):681–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Clarke BA, Cooper K. Identifying Lynch syndrome in patients with endometrial carcinoma: shortcomings of morphologic and clinical schemas. Adv Anat Pathol. 2012;19(4):231–8. doi: 10.1097/PAP.0b013e31825c6b76.PubMedCrossRefGoogle Scholar
  48. 48.
    Hampel H. Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer. J Natl Compr Canc Netw. 2010;8(5):597–601.PubMedGoogle Scholar
  49. 49.
    Mvundura M, Grosse SD, Hampel H, Palomaki GE. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med. 2010;12(2):93–104.PubMedCrossRefGoogle Scholar
  50. 50.
    Modica I, Soslow RA, Black D, Tornos C, Kauff N, Shia J. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol. 2007;31(5):744–51. doi: 10.1097/01.pas.0000213428.61374.06.PubMedCrossRefGoogle Scholar
  51. 51.
    Kwon JS, Scott JL, Gilks CB, Daniels MS, Sun CC, Lu KH. Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol. 2011;29(16):2247–52.PubMedCrossRefGoogle Scholar
  52. 52.
    Kalloger SE, Allo G, Mulligan AM, Pollett A, Aronson M, Gallinger S, et al. Use of mismatch repair immunohistochemistry and microsatellite instability testing: exploring Canadian practices. Am J Surg Pathol. 2012;36(4):560–9. doi: 10.1097/PAS.0b013e31823f3b28.PubMedCrossRefGoogle Scholar
  53. 53.
    Boland CR, Shike M. Report from the Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer. Gastroenterology. 2010;138(7):2197.e1–e7.CrossRefGoogle Scholar
  54. 54.
    Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193–201.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Carcangiu ML, Radice P, Casalini P, Bertario L, Merola M, Sala P. Lynch syndrome—related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. Int J Surg Pathol. 2010;18(1):21–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Garg K, Leitao MMJ, Kauff ND, Hansen J, Kosarin K, Shia J, et al. Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol. 2009;33(6):925–33. doi: 10.1097/PAS.0b013e318197a046.PubMedCrossRefGoogle Scholar
  57. 57.
    Honore LH, Hanson J, Andrew SE. Microsatellite instability in endometrioid endometrial carcinoma: correlation with clinically relevant pathologic variables. Int J Gynecol Cancer. 2006;16(3):1386–92.PubMedCrossRefGoogle Scholar
  58. 58.
    Mercado RC, Hampel H, Kastrinos F, Steyerberg E, Balmana J, Stoffel E, et al. Performance of PREMM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases. Genet Med. 2012;14(7):670–80.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009;11(1):42–65.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Lu KH, Schorge JO, Rodabaugh KJ, Daniels MS, Sun CC, Soliman PT, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25(33):5158–64.PubMedCrossRefGoogle Scholar
  61. 61.
    Bartley AN, Luthra R, Saraiya DS, Urbauer DL, Broaddus RR. Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing. Cancer Prev Res. 2012;5(2):320–7.CrossRefGoogle Scholar
  62. 62.
    Chubak B, Heald B, Sharp RR. Informed consent to microsatellite instability and immunohistochemistry screening for Lynch syndrome. Genet Med. 2011;13(4):356–60.PubMedCrossRefGoogle Scholar
  63. 63.
    Berg AO, Armstrong K, Botkin J et al. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11(1):35–41.Google Scholar
  64. 64.
    van der Velde NM, Mourits MJE, Arts HJG, de Vries J, Leegte BK, Dijkhuis G, et al. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers? Int J Cancer. 2009;124(4):919–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Woodward ER, Sleightholme HV, Considine AM, Williamson S, McHugo JM, Cruger DG. Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective. BJOG. 2007;114(12):1500–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, van’t Veer L, Garber JE, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616–22.PubMedCrossRefGoogle Scholar
  67. 67.
    Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a brca1 or brca2 mutation. JAMA. 2006;296(2):185–92.PubMedCrossRefGoogle Scholar
  68. 68.
    NCCN Guidelines Version 1. Hereditary breast and/or ovarian cancer syndrome. 2012. Available from: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.
  69. 69.
    Yates MS, Meyer LA, Deavers MT, Daniels MS, Keeler ER, Mok SC, et al. Microscopic and early-stage ovarian cancers in BRCA1/2 mutation carriers: building a model for early BRCA-associated tumorigenesis. Cancer Prev Res. 2011;4(3):463–70.CrossRefGoogle Scholar
  70. 70.
    Lu KH, Garber JE, Cramer DW, Welch WR, Niloff J, Schrag D, et al. Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy. J Clin Oncol. 2000;18(14):2728–32.PubMedGoogle Scholar
  71. 71.
    Domchek S, Friebel T, Garber J, Isaacs C, Matloff E, Eeles R, et al. Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers. Breast Cancer Res Treat. 2010;124(1):195–203.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Hirst JE, Gard GB, McIllroy K, Nevell D, Field M. High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingo-oophorectomy. Int J Gynecol Cancer. 2009;19(5):826–9. doi: 10.1111/IGC.0b013e3181a1b5dc.PubMedCrossRefGoogle Scholar
  73. 73.
    Powell CB, Kenley E, Chen LM, Crawford B, McLennan J, Zaloudek C, et al. Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol. 2005;23(1):127–32.PubMedCrossRefGoogle Scholar
  74. 74.
    Finch A, Shaw P, Rosen B, Murphy J, Narod SA, Colgan TJ. Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol. 2006;100(1):58–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Crum CP, Drapkin R, Kindelberger D, Medeiros F, Miron A, Lee Y. Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res. 2007;5(1):35–44.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, et al. The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol. 2007;19(1):3–9. doi: 10.1097/GCO.0b013e328011a21f.PubMedCrossRefGoogle Scholar
  77. 77.
    Finch A, Evans G, Narod SA. BRCA carriers, prophylactic salpingo-oophorectomy and menopause: clinical management considerations and recommendations. Womens Health. 2012;8(5):543–55.Google Scholar
  78. 78.
    Kurman RJ, Shih I-M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol. 2011;42(7):918–31.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med. 1987;316(18):1105–10.PubMedCrossRefGoogle Scholar
  80. 80.
    Rivera CM, Grossardt BR, Rhodes DJ, Brown RDJ, Roger VL, Melton LJI, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16(1):15–23. doi: 10.1097/gme.0b013e31818888f7.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Rivera CM, Grossardt BR, Rhodes DJ, Rocca WA. Increased mortality for neurological and mental diseases following early bilateral oophorectomy. Neuroepidemiology. 2009;33(1):32–40.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Lobo RA. Surgical menopause and cardiovascular risks. Menopause. 2007;14(3):562–6. doi: 10.1097/gme.0b013e318038d333.PubMedCrossRefGoogle Scholar
  83. 83.
    Challberg J, Ashcroft L, Lalloo F, Eckersley B, Clayton R, Hopwood P, et al. Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT. Br J Cancer. 2011;105(1):22–7.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet Gynecol. 2009;113(5):1027–37.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Rocca WA, Grossardt BR, Miller VM, Shuster LT, Brown RDJ. Premature menopause or early menopause and risk of ischemic stroke. Menopause. 2012;19(3):272–7. doi: 10.1097/gme.0b013e31822a9937.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Rocca WA, Bower J, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69(11):1074–83.PubMedCrossRefGoogle Scholar
  87. 87.
    Karst AM, Levanon K, Drapkin R. Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc Natl Acad Sci. 2011;108:7547–52.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Greene MH, Mai PL, Schwartz PE. 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;204(1):19.e1–e6.Google Scholar
  89. 89.
    Kramer JL, Velazquez IA, Chen BE, Rosenberg PS, Struewing JP, Greene MH. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol. 2005;23(34):8629–35.PubMedCrossRefGoogle Scholar
  90. 90.
    Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case–control study. J Clin Oncol. 2005;23(30):7491–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Partridge E, Kreimer AR, Greelee RT, Williams C, Xu JL, Church TR, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009;113:775–82.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Fishman DA, Cohen L, Blank SV, Shulman L, Singh D, Bozorgi K, et al. The role of ultrasound evaluation in the detection of early-stage epithelial ovarian cancer. Am J Obstet Gynecol. 2005;192(4):1214–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Johnson CC, Kessel B, Riley TL, Ragard LR, Williams CR, Xu J-L, et al. The epidemiology of CA-125 in women without evidence of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Gynecol Oncol. 2008;110(3):383–9.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Meden H. F-MA. CA 125 in benign gynecological conditions. Int J Biol Markers. 1998;13(4):231–7.PubMedGoogle Scholar
  95. 95.
    Hermsen BBJ, Olivier RI, Verheijen RHM, van Beurden M, de Hullu JA, Massuger LF, et al. No efficacy of annual gynaecological screening in BRCA1//2 mutation carriers; an observational follow-up study. Br J Cancer. 2007;96(9):1335–42.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Bosse K, Rhiem K, Wappenschmidt B, Hellmich M, Madeja M, Ortmann M, et al. Screening for ovarian cancer by transvaginal ultrasound and serum CA125 measurement in women with a familial predisposition: a prospective cohort study. Gynecol Oncol. 2006;103(3):1077–82.PubMedCrossRefGoogle Scholar
  97. 97.
    Stirling D, Evans DGR, Pichert G, Shenton A, Kirk EN, Rimmer S, et al. Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international federation of gynecology and obstetrics system. J Clin Oncol. 2005;23(24):5588–96.PubMedCrossRefGoogle Scholar
  98. 98.
    Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. Ovarian cancer screening in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol. 2005;193(5):1630–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Greene MH, Piedmonte M, Alberts D, Gail M, Hensley M, Miner Z, et al. A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group Study. Cancer Epidemiol Biomarkers Prev. 2008;17(3):594–604.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Skates SJ, Menon U, MacDonald N, Rosenthal AN, Oram DH, Knapp RC, et al. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women. J Clin Oncol. 2003;21(10 Suppl):206–10.CrossRefGoogle Scholar
  101. 101.
    Menon U, Skates SJ, Lewis S, Rosenthal AN, Rufford B, Sibley K, et al. Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol. 2005;23(31):7919–26.PubMedCrossRefGoogle Scholar
  102. 102.
    Moore RG, Miller MC, Steinhoff MM, Skates SJ, Lu KH, Lambert-Messerlian G, et al. Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders. Am J Obstet Gynecol. 2012;206(4):351.e1–e8.Google Scholar
  103. 103.
    Rosenthal AN, Fraser L, Manchanda R, Badman P, Philpott S, Mozersky J, et al. Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule. J Clin Oncol. 2013;31(1):49–57.PubMedCrossRefGoogle Scholar
  104. 104.
    Stupart DA, Goldberg PA, Algar U, Ramesar R. Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis. 2009;11(2):126–30.PubMedCrossRefGoogle Scholar
  105. 105.
    Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to lynch syndrome: a systematic review. JAMA. 2006;296(12):1507–17.PubMedCrossRefGoogle Scholar
  106. 106.
  107. 107.
    Huang M, Sun S, Boyd-Rogers S, Burwaza J, Milbourne A, Keeler E, Yzquierdo R, Lynch P, Peterson SK, Lu K. Prospective study of combined colon and endometrial cancer screening in women with lynch syndrome: a patient-centered approach. J Oncol Pract. 2011;7(1):43–7.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Dijkhuizen FP, Brölmann HA, Potters AE, Bongers MY, Heinz AP. The accuracy of transvaginal ultrasonography in the diagnosis of endometrial abnormalities. Obstet Gynecol. 1996;87(3):345–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Gerritzen LM, Hoogerbrugge N, Oei AM, Nagengast F, Ham MPC, Massuger LAG, et al. Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome. Fam Cancer. 2009;8(4):391–7.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Renkonen-Sinisalo L, Bützow R, Leminen A, Lehtovirta P, Mecklin J-P, Järvinen HJ. Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer. 2007;120(4):821–4.PubMedCrossRefGoogle Scholar
  111. 111.
    Dove-Edwin I, Boks D, Goff S, Kenter GG, Carpenter R, Vasen HFA, et al. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer. 2002;94(6):1708–12.PubMedCrossRefGoogle Scholar
  112. 112.
    Rijcken FEM, Mourits MJE, Kleibeuker JH, Hollema H, van der Zee AGJ. Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol. 2003;91(1):74–80.PubMedCrossRefGoogle Scholar
  113. 113.
    Dijkhuizen FP, Mol B, Brolmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer. 2000;89(8):1765–72.PubMedCrossRefGoogle Scholar
  114. 114.
    Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354(3):261–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, Peltomäki P, Aaltonen LA, Mecklin J-P. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol. 2009;27(28):4793–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Manchanda R, Saridogan E, Abdelraheim A, Johnson M, Rosenthal A, Benjamin E, et al. Annual outpatient hysteroscopy and endometrial sampling (OHES) in HNPCC/Lynch syndrome (LS). Arch Gynecol Obstet. 2012;286(6):1555–62.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Kari L. Ring
    • 1
  • Rachel Michaelson-Cohen
    • 2
  • Karen H. Lu
    • 1
    • 3
  • Uziel Beller
    • 4
  1. 1.Gynecologic Oncology and Reproductive MedicineThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Obstetrics and Gynecology, Medical Genetics Institute, Shaare Zedek Medical CenterThe Hebrew University of JerusalemJerusalemIsrael
  3. 3.Department of Gynecologic OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  4. 4.Department of Obstetrics and GynecologyHebrew University, Shaare Zedek Medical CenterJerusalemIsrael

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