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Epithelial ovarian cancer: Pathogenesis, epidemiology, and risk factors

INTRODUCTION

The pathogenesis, incidence, epidemiology, and risk factors for epithelial ovarian cancer (EOC) will be reviewed here. Other issues, such as clinical manifestations, diagnosis, staging, treatment, and screening for ovarian cancer, and the nonepithelial primary ovarian tumors are discussed separately. (See "Epithelial ovarian cancer: Clinical manifestations, diagnostic evaluation, staging, and histopathology" and "Ovarian germ cell tumors: Pathology, clinical manifestations, and diagnosis" and "Sex cord-stromal tumors of the ovary: Granulosa-stromal cell tumors".)

PATHOGENESIS

The majority of primary ovarian tumors derive from epithelial cells on the surface of the ovary, although they can also arise from other cell types (germ cell tumors, sex cord-stromal tumors, and mixed cell type tumors).

Epithelial cancer of the ovary derives from malignant transformation of the epithelium of the ovarian surface, which is contiguous with the peritoneal mesothelium (figure 1) [1]. The molecular events leading to the development of EOC are unknown. Mutations and/or overexpression of the oncogenes HER2 c-myc and K-ras, Akt, and of the tumor suppressor gene p53 have been observed in sporadic ovarian cancer, but their contribution to pathogenesis is not well defined [2-4]. Inactivation of the tumor suppressor genes PTEN and p16 may also occur. Epigenetic phenomenon also play a role in tumorigenesis [5].

However, the molecular pathways underlying ovarian cancer progression are poorly understood. Although germline mutations in BRCA1, BRCA2, and other genes have been implicated in a small fraction of cases (see 'Genetic factors' below, epidemiologic and experimental evidence suggests that ovarian carcinogenesis is predominantly driven by factors associated with reproduction and ovulation [6,7]. In addition, mucinous and nonmucinous ovarian tumors may have different causal mechanisms related to ovulatory life [8].

Two general hypotheses have been proposed to explain the pathogenesis of EOC:
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References Top
  1. Cannistra, SA. Cancer of the ovary. N Engl J Med 2004; 351:2519.
  2. Aunoble, B, Sanches, R, Didier, E, Bignon, YJ. Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review). Int J Oncol 2000; 16:567.
  3. Havrilesky, L, Darcy, M, Hamdan, H, et al. Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2003; 21:3814.
  4. Verri, E, Guglielmini, P, Puntoni, M, et al. HER2/neu oncoprotein overexpression in epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. Clinical study. Oncology 2005; 68:154.
  5. Baylin, SB, Herman, JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16:168.
  6. Banks, E, Beral, V, Reeves, G. The epidemiology of epithelial ovarian cancer: a review. Int J Gynecol Cancer 1997; 7:425.
  7. Risch, HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998; 90:1774.
  8. Purdie, DM, Siskind, V, Bain, CJ, et al. Reproduction-related risk factors for mucinous and nonmucinous epithelial ovarian cancer. Am J Epidemiol 2001; 153:860.
  9. Casagrande, JT, Louie, EW, Pike, MC, et al. "Incessant ovulation" and ovarian cancer. Lancet 1979; 2:170.
  10. Fathalla, MF. Incessant ovulation--a factor in ovarian neoplasia?. Lancet 1971; 2:163.
  11. Cramer, DW, Welch, WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 1983; 71:717.
  12. Helzlsouer, KJ, Alberg, AJ, Gordon, GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995; 274:1926.
  13. Ness, RB, Grisso, JA, Cottreau, C, et al. Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 2000; 11:111.
  14. McSorley, MA, Alberg, AJ, Allen, DS, et al. C-reactive protein concentrations and subsequent ovarian cancer risk. Obstet Gynecol 2007; 109:933.
  15. Cramer, DW, Barbieri, RL, Fraer, AR, Harlow, BL. Determinants of early follicular phase gonadotrophin and estradiol concentrations in women of late reproductive age. Hum Reprod 2002; 17:221.
  16. Modugno, F. Ovarian cancer and high-risk women-implications for prevention, screening, and early detection. Gynecol Oncol 2003; 91:15.
  17. Casey, MJ, Bewtra, C, Hoehne, LL, et al. Histology of prophylactically removed ovaries from BRCA1 and BRCA2 mutation carriers compared with noncarriers in hereditary breast ovarian cancer syndrome kindreds. Gynecol Oncol 2000; 78:278.
  18. Barakat, RR, Federici, MG, Saigo, PE, et al. Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes. Cancer 2000; 89:383.
  19. Hartge, P, Hayes, R, Reding, D, et al. Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors: preliminary data from the prostate, lung, colon, and ovarian cancer screening trial. Am J Obstet Gynecol 2000; 183:1232.
  20. Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59:225.
  21. www.seer.cancer.gov (accessed June 5, 2007).
  22. www.cancer.gov/cancertopics/factsheet/risk/brca (accessed January 29, 2009).
  23. Memarzadeh, S, Berek, JS. Advances in the management of epithelial ovarian cancer. J Reprod Med 2001; 46:621.
  24. Kinkel, K, Lu, Y, Mehdizade, A, et al. Indeterminate Ovarian Mass at US: Incremental Value of Second Imaging Test for Characterization--Meta-Analysis and Bayesian Analysis. Radiology 2005; 236:85.
  25. Piver, MS. Hereditary ovarian cancer. Gynecol Oncol 2002; 85:9.
  26. Hartge, P, Whittemore, AS, Itnyre, J, et al. Rates and risks of ovarian cancer in subgroups of white women in the United States. The Collaborative Ovarian Cancer Group. Obstet Gynecol 1994; 84:760.
  27. Mink, PJ, Sherman, ME, Devesa, SS. Incidence patterns of invasive and borderline ovarian tumors among white women and black women in the United States. Cancer 2002; 95:2380.
  28. Whittemore, AS, R, Harris, J, Intyre. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 U.S. case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992; 136:1184.
  29. Whittemore, AS, Harris, R, Itnyre, J. 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; 136:1212.
  30. Carlson, KJ, Skates, SJ, Singer, DE. Screening for ovarian cancer. Ann Intern Med 1994; 121:124.
  31. Hemminki, K, Granstrom, C. Familial clustering of ovarian and endometrial cancers. Eur J Cancer 2004; 40:90.
  32. Negri, E, Franceschi, S, Tzonou, A, et al. Pooled analysis of 3 European case-control studies: I. Reproductive factors and risk of epithelial ovarian cancer. Int J Cancer 1991; 49:50.
  33. Shu, XO, Brinton, LA, Gao, YT, Yuan, JM. Population-based case-control study of ovarian cancer in Shanghai. Cancer Res 1989; 49:3670.
  34. Daly, M, Obrams, GI. Epidemiology and risk assessment for ovarian cancer. Semin Oncol 1998; 25:255.
  35. Mahdavi, A, Pejovic, T, Nezhat, F. Induction of ovulation and ovarian cancer: a critical review of the literature. Fertil Steril 2006; 85:819.
  36. Tworoger, SS, Fairfield, KM, Colditz, GA, et al. Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk. Am J Epidemiol 2007; 166:894.
  37. Collaborative Group, on Epidemiological Studies of Ovarian Cancer, Beral, V, Doll, R, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008; 371:303.
  38. Lurie, G, Thompson, P, McDuffie, KE, et al. Association of estrogen and progestin potency of oral contraceptives with ovarian carcinoma risk. Obstet Gynecol 2007; 109:597.
  39. Titus-Ernstoff, L, Perez, K, Cramer, DW, et al. Menstrual and reproductive factors in relation to ovarian cancer risk. Br J Cancer 2001; 84:714.
  40. Hinkula, M, Pukkala, E, Kyyronen, P, Kauppila, A. Incidence of ovarian cancer of grand multiparous women--a population-based study in Finland. Gynecol Oncol 2006; 103:207.
  41. Pike, MC, Pearce, CL, Peters, R, et al. Hormonal factors and the risk of invasive ovarian cancer: a population-based case-control study. Fertil Steril 2004; 82:186.
  42. Whiteman, DC, Siskind, V, Purdie, DM, Green, AC. Timing of pregnancy and the risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2003; 12:42.
  43. Whiteman, DC, Murphy, MF, Cook, LS, et al. Multiple births and risk of epithelial ovarian cancer. J Natl Cancer Inst 2000; 92:1172.
  44. Lambe, M, Wuu, J, Rossing, MA, Hsieh, CC. Twinning and maternal risk of ovarian cancer [letter]. Lancet 1999; 353:1941.
  45. Olsen, J, Storm, H. Pregnancy experience in women who later developed oestrogen-related cancers (Denmark). Cancer Causes Control 1998; 9:653.
  46. Akhmedkhanov, A, Toniolo, P, Zeleniuch-Jacquotte, A, et al. Luteinizing hormone, its beta-subunit variant, and epithelial ovarian cancer: the gonadotropin hypothesis revisited. Am J Epidemiol 2001; 154:43.
  47. Hankinson, SE, Hunter, DJ, Colditz, GA, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer. JAMA 1993; 270:2813.
  48. Chiaffarino, F, Parazzini, F, Decarli, A, et al. Hysterectomy with or without unilateral oophorectomy and risk of ovarian cancer. Gynecol Oncol 2005; 97:318.
  49. Narod, SA, Sun, P, Ghadirian, P, et al. Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 2001; 357:1467.
  50. Van Gorp, T, Amant, F, Neven, P, et al. Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol 2004; 18:349.
  51. Orezzoli, JP, Russell, AH, Oliva, E, et al. Prognostic implication of endometriosis in clear cell carcinoma of the ovary. Gynecol Oncol 2008; 110:336.
  52. Gertig, DM, Hunter, DJ, Cramer, DW, et al. Prospective study of talc use and ovarian cancer. J Natl Cancer Inst 2000; 92:249.
  53. Jordan, SJ, Whiteman, DC, Purdie, DM, et al. Does smoking increase risk of ovarian cancer? A systematic review. Gynecol Oncol 2006; 103:1122.
  54. Tworoger, SS, Gertig, DM, Gates, MA, et al. Caffeine, alcohol, smoking, and the risk of incident epithelial ovarian cancer. Cancer 2008; 112:1169.
  55. IARC Working Group on the Evaluation of Cancer-Preventive Strategies. IARC Handbook of Cancer Prevention: Fruit and vegetables, vol 8. Vainio, H, Bianchini, F (Eds), IARC Press, Lyon, 2003.
  56. Huncharek, M, Kupelnick, B. Dietary fat intake and risk of epithelial ovarian cancer: a meta-analysis of 6,689 subjects from 8 observational studies. Nutr Cancer 2001; 40:87.
  57. Zhang, M, Yang, ZY, Binns, CW, Lee, AH. Diet and ovarian cancer risk: a case-control study in China. Br J Cancer 2002; 86:712.
  58. McCann, SE, Moysich, KB, Mettlin, C. Intakes of selected nutrients and food groups and risk of ovarian cancer. Nutr Cancer 2001; 39:19.
  59. Bosetti, C, Negri, E, Franceschi, S, et al. Diet and ovarian cancer risk: a case-control study in Italy. Int J Cancer 2001; 93:911.
  60. Kushi, LH, Mink, PJ, Folsom, AR, et al. Prospective study of diet and ovarian cancer. Am J Epidemiol 1999; 149:21.
  61. Fairfield, KM, Hankinson, SE, Rosner, BA, et al. Risk of ovarian carcinoma and consumption of vitamins A, C, and E and specific carotenoids: a prospective analysis. Cancer 2001; 92:2318.
  62. McCann, SE, Freudenheim, JL, Marshall, JR, Graham, S. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. J Nutr 2003; 133:1937.
  63. Salazar-Martinez, E, Lazcano-Ponce, EC, Gonzalez Lira-Lira, G, et al. Nutritional determinants of epithelial ovarian cancer risk: a case-control study in Mexico. Oncology 2002; 63:151.
  64. Larsson, SC, Holmberg, L, Wolk, A. Fruit and vegetable consumption in relation to ovarian cancer incidence: the Swedish Mammography Cohort. Br J Cancer 2004; 90:2167.
  65. Bidoli, E, La Vecchia, C, Talamini, R, et al. Micronutrients and ovarian cancer: a case-control study in Italy. Ann Oncol 2001; 12:1589.
  66. Larsson, SC, Giovannucci, E, Wolk, A. Dietary folate intake and incidence of ovarian cancer: the Swedish Mammography Cohort. J Natl Cancer Inst 2004; 96:396.
  67. Tworoger, SS, Hecht, JL, Giovannucci, E, Hankinson, SE. Intake of folate and related nutrients in relation to risk of epithelial ovarian cancer. Am J Epidemiol 2006; 163:1101.
  68. Larsson, SC, Orsini, N, Wolk, A. Milk, milk products and lactose intake and ovarian cancer risk: a meta-analysis of epidemiological studies. Int J Cancer 2006; 118:431.
  69. Mommers, M, Schouten, LJ, Goldbohm, RA, van den Brandt PA. Dairy consumption and ovarian cancer risk in the Netherlands Cohort Study on Diet and Cancer. Br J Cancer 2006; 94:165.
  70. Koushik, A, Hunter, DJ, Spiegelman, D, et al. Intake of the major carotenoids and the risk of epithelial ovarian cancer in a pooled analysis of 10 cohort studies. Int J Cancer 2006; 119:2148.
  71. Chang, ET, Lee, VS, Canchola, AJ, et al. Diet and risk of ovarian cancer in the California Teachers Study cohort. Am J Epidemiol 2007; 165:802.
  72. Prentice, RL, Thomson, CA, Caan, B, et al. Low-fat dietary pattern and cancer incidence in the Women's Health Initiative Dietary Modification Randomized Controlled Trial. J Natl Cancer Inst 2007; 99:1534.
  73. Steevens, J, Schouten, LJ, Verhage, BA, et al. Tea and coffee drinking and ovarian cancer risk: results from the Netherlands Cohort Study and a meta-analysis. Br J Cancer 2007; 97:1291.
  74. Cozen, W, Peters, R, Reichardt, JK, et al. Galactose-1-phosphate uridyl transferase (GALT) genotype and phenotype, galactose consumption, and the risk of borderline and invasive ovarian cancer (United States). Cancer Causes Control 2002; 13:113.
  75. Bertone, ER, Newcomb, PA, Willett, WC, et al. Recreational physical activity and ovarian cancer in a population-based case-control study. Int J Cancer 2002; 99:431.
  76. Pan, SY, Ugnat, AM, Mao, Y. Physical activity and the risk of ovarian cancer: a case-control study in Canada. Int J Cancer 2005; 117:300.
  77. Tavani, A, Gallus, S, La Vecchia, C, et al. Physical activity and risk of ovarian cancer: an Italian case-control study. Int J Cancer 2001; 91:407.
  78. Bertone, ER, Willett, WC, Rosner, BA, et al. Prospective study of recreational physical activity and ovarian cancer. J Natl Cancer Inst 2001; 93:942.
  79. Anderson, JP, Ross, JA, Folsom, AR. Anthropometric variables, physical activity, and incidence of ovarian cancer: The Iowa Women's Health Study. Cancer 2004; 100:1515.
  80. Olsen, CM, Green, AC, Whiteman, DC, et al. Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer 2007; 43:690.
  81. Calle, EE, Rodriguez, C, Walker-Thurmond, K, Thun, MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348:1625.
  82. Boyd, J. Specific Keynote: Hereditary ovarian cancer: What we know. Gynecol Oncol 2003; 88:S8.
  83. Li, AJ, Karlan, BY. Genetic factors in ovarian carcinoma. Curr Oncol Rep 2001; 3:27.
  84. Risch, HA, McLaughlin, JR, Cole, DE, 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; 68:700.
  85. Pal, T, Permuth-Wey, J, Betts, JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005; 104:2807.
  86. Schildkraut, JM, Thompson, WD. Familial Ovarian cancer: a population-based case-control study. Am J Epidemiol 1988; 128:456.
  87. Kerlikowske, K, Brown, JS, Grady, DG. Should Women with Familial Ovarian Cancer Undergo Prophylactic Oophorectomy?. Obstet Gynecol 1992; 80:700.
  88. Bergfeldt, K, Rydh, B, Granath, F, et al. Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study. Lancet 2002; 360:891.
  89. Lynch, HT, Watson, P, Bewtra, C, et al. Hereditary ovarian cancer. Heterogeneity in age at diagnosis. Cancer 1991; 67:1460.
  90. Mecklin, JP, Jarvinen, HJ. Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer). Cancer 1991; 68:1109.
  91. Lakhani, SR, Manek, S, Penault-Llorca, F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 2004; 10:2473.
  92. Rubin, SC, Benjamin, I, Behbakht, K, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 1996; 335:1413.
  93. Boyd, J, Sonoda, Y, Federici, MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 2000; 283:2260.
  94. Chetrit, A, Hirsh-Yechezkel, G, Ben-David, Y, et al. 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; 26:20.
  95. Taniguchi, T, Tischkowitz, M, Ameziane, N, et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 2003; 9:568.
  96. Cass, I, Baldwin, RL, Varkey, T, et al. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003; 97:2187.
  97. Tan, DS, Rothermundt, C, Thomas, K, 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; 26:5530.
  98. Watson, P, Lynch, HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993; 71:677.
  99. Aarnio, M, Mecklin, J-P, Aaltonen, LA, et al. Lifetime risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64:430.
  100. Rubin, SC, Blackwood, MA, Bandera, C, et al. BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am J Obstet Gynecol 1998; 178:670.
  101. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 1996; 14:1730.
  102. Burke, W, Petersen, G, Lynch, P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. JAMA 1997; 277:915.
  103. Burke, W, Daly, M, Garber, J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. JAMA 1997; 277:997.
  104. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 1998; 339:424.
  105. Modan, B, Hartge, P, Hirsh-Yechezkel, G, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001; 345:235.
  106. Tobacman, JK, Tucker, MA, Kase, R, et al. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer prone families. Lancet 1982; 2:795.
  107. Struewing, JP, Watson, P, Easton, DF, et al. Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr 1995; :33.
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