Ovarian, Fallopian Tube, & Primary Peritoneal Cancer Prevention (PDQ®)—Health Professional Version - National Cancer Institute

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention (PDQ®)–Health Professional Version

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Who Is at Risk?

Ovarian cancer is a rare disease, with carcinomas comprising approximately 90% of tumors and germ cell and stromal tumors accounting for the remainder. Ovarian carcinoma is a disease that predominantly affects postmenopausal women. Ovarian carcinomas consist of several histopathologic types, with high-grade serous being both the most common and most lethal. The category of ovarian borderline tumor or tumor of low-malignant potential, which historically had been considered in the context of ovarian cancer, is now generally considered a nonmalignant entity, although it has a postulated relationship with the development of some histologic subtypes of low-grade ovarian carcinomas.[1]

Risk factors for ovarian cancer include a family history of breast and/or ovarian cancer and inheritance of deleterious mutations in BRCA1, BRCA2, and selected other high-penetrance genes.[2-6] (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.) Other risk factors for ovarian cancer include obesity, tall height, endometriosis, and the use of postmenopausal hormone therapy.[7-9]

Associations of some risk factors with ovarian cancer vary by histopathologic subtype. The association of endometriosis with ovarian cancer is stronger for nonserous subtypes, especially clear cell carcinoma and endometrioid subtypes.[10] Further, among carriers of deleterious mutations in BRCA1 or BRCA2, increasing evidence suggests that many tumors previously classified as ovarian high-grade serous carcinoma may develop from malignant cells arising in the tubal epithelium (serous tubal intraepithelial carcinoma [STIC]), although these tumors continue to be referred to as ovarian cancers in most writings. It is hypothesized that high-grade serous carcinomas among individuals who are not carriers of mutations in BRCA1 or BRCA2 may also develop in the fallopian tube, but few STICs have been identified among these women in the absence of concurrent high-stage disease. Further, data suggest that the distinction of high-grade serous carcinomas from other histologic types of high-grade carcinomas, particularly endometrioid carcinomas, is not reliable. Reported rates of mucinous carcinoma diagnoses have declined dramatically, but expert pathology reviews suggest that this reflects increased recognition of metastases from occult gastrointestinal primary tumors to the ovary, rather than a true decline in rates of ovarian primary tumors.[11]

Factors associated with a decreased risk of ovarian cancer include multiparity, use of oral contraceptives, multiple pregnancies, breastfeeding, tubal ligation, and salpingectomy.[12-15] Compared with nulliparous women, the risk of ovarian cancer is reduced by 30% to 60% among parous women, with additive protection for each additional birth.[16,17]

References

Kurman RJ, Carcangiu ML, Young RH, eds.: WHO Classification of Tumours of Female Reproductive Organs. 4th ed. Lyon, France: International Agency for Research on Cancer, 2014.
Bolton KL, Ganda C, Berchuck A, et al.: Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the Ovarian Cancer Association Consortium (OCAC). J Intern Med 271 (4): 366-78, 2012. [PUBMED Abstract]
Weissman SM, Weiss SM, Newlin AC: Genetic testing by cancer site: ovary. Cancer J 18 (4): 320-7, 2012 Jul-Aug. [PUBMED Abstract]
Hunn J, Rodriguez GC: Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol 55 (1): 3-23, 2012. [PUBMED Abstract]
Pal T, Akbari MR, Sun P, et al.: Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer 107 (10): 1783-90, 2012. [PUBMED Abstract]
Gayther SA, Pharoah PD: The inherited genetics of ovarian and endometrial cancer. Curr Opin Genet Dev 20 (3): 231-8, 2010. [PUBMED Abstract]
Lacey JV Jr, Brinton LA, Leitzmann MF, et al.: Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and Health Study Cohort. J Natl Cancer Inst 98 (19): 1397-405, 2006. [PUBMED Abstract]
Trabert B, Wentzensen N, Yang HP, et al.: Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study. Br J Cancer 107 (7): 1181-7, 2012. [PUBMED Abstract]
Lahmann PH, Cust AE, Friedenreich CM, et al.: Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 126 (10): 2404-15, 2010. [PUBMED Abstract]
Poole EM, Lin WT, Kvaskoff M, et al.: Endometriosis and risk of ovarian and endometrial cancers in a large prospective cohort of U.S. nurses. Cancer Causes Control 28 (5): 437-445, 2017. [PUBMED Abstract]
Seidman JD, Kurman RJ, Ronnett BM: Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol 27 (7): 985-93, 2003. [PUBMED Abstract]
Garg PP, Kerlikowske K, Subak L, et al.: Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol 92 (3): 472-9, 1998. [PUBMED Abstract]
Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002. [PUBMED Abstract]
Mills PK, Riordan DG, Cress RD, et al.: Hormone replacement therapy and invasive and borderline epithelial ovarian cancer risk. Cancer Detect Prev 29 (2): 124-32, 2005. [PUBMED Abstract]
Calle EE, Rodriguez C, Walker-Thurmond K, et al.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348 (17): 1625-38, 2003. [PUBMED Abstract]
Permuth-Wey J, Sellers TA: Epidemiology of ovarian cancer. Methods Mol Biol 472: 413-37, 2009. [PUBMED Abstract]
Wentzensen N, Poole EM, Trabert B, et al.: Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium. J Clin Oncol 34 (24): 2888-98, 2016. [PUBMED Abstract]

Overview

Note: Separate PDQ summaries on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening and Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatmentare also available.

Factors With Adequate Evidence of an Increased Risk of Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Family history and inherited susceptibility to ovarian, fallopian tube, and primary peritoneal cancer

Based on solid evidence, women with a family history of ovarian cancer, especially in a first-degree relative, and those with an inherited predisposition to ovarian cancer, such as a BRCA1 or BRCA2 mutation, have an increased risk of developing ovarian cancer. (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Endometriosis

Based on fair evidence, self-reported and laparoscopically confirmed endometriosis is associated with an increased risk of ovarian cancer.[1,2] The association is stronger with nonserous histologic subtypes, specifically endometrioid and clear cell carcinomas.[2,3]

Magnitude of Effect: Modest with observed relative risks (RRs) of 1.8 to 2.4.

Study Design: Cohort and case-control studies.
Internal Validity: Good.
Consistency: Fair.
External Validity: Good.

Hormone replacement therapy

Based on fair evidence, current or recent hormone therapy is associated with a small increased risk of ovarian cancer. Risks attenuate after hormone therapy is discontinued. Risks did not differ by preparation type (estrogen only vs. combined estrogen/progestin).[4,5]

Magnitude of Effect: Modest with observed RRs of 1.20 to 1.8.

Study Design: One randomized clinical trial, cohort and case-control studies.
Internal Validity: Good.
Consistency: Fair.
External Validity: Good.

Obesity and height

Based on fair evidence, increases in height and body mass index (BMI) are associated with a modest increased risk of ovarian cancer.

Magnitude of Effect: Based on an overview analysis of 25,157 women with ovarian cancer and 81,211 women without ovarian cancer from 47 epidemiological studies, the RR of ovarian cancer per 5 cm increase in height is 1.07 (95% confidence interval [CI], 1.05–1.09). The RR of ovarian cancer per 5 kg/m2 increase in BMI is 1.10 (95% CI, 1.07–1.13) among never-users of hormone therapy and 0.95 (95% CI, 0.92–0.99) among ever-users of hormone therapy.[6]

Study Design: Cohort and case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Factors With Adequate Evidence of a Decreased Risk of Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Oral contraceptives: benefits

Based on solid evidence, oral contraceptive use is associated with a decreased risk of developing ovarian cancer.

Magnitude of Effect: The degree of risk reduction varies by duration of oral contraceptive use and time since last use. For 1 to 4 years of oral contraceptive use, the RR reduction is 22%, and for 15 or more years of use, the RR reduction is 56%. The reduction in risk persisted for more than 30 years after use was discontinued, but the degree of reduction attenuated over time. The risk reduction per 5 years of oral contraceptive use was 29% for women who discontinued use less than 10 years ago and decreased to 15% for women who discontinued use 20 to 29 years ago. Ten years of use reduced cancer incidence before age 75 years from 1.2 to 0.8 per 100 users and reduced mortality from 0.7 to 0.5 per 100 users. The number needed-to-treat for 5 years was estimated to be about 185 women.

Study Design: Multiple case-control and cohort studies; meta-analyses.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Oral contraceptives: harms

Based on solid evidence, combined current use of estrogen-progestin oral contraceptive use is associated with an increased risk of venous thromboembolism, particularly among smokers, for whom use is contraindicated. Oral contraceptives are not associated with a long-term increased risk of breast cancer but may be associated with a short-term increased risk while a woman is taking oral contraceptives. The risk of breast cancer declines with time since last use.

Magnitude of Effect: The risks may vary by preparation. Overall, the absolute risk of venous thromboembolism is about three events per 10,000 women per year while taking oral contraceptives. The risk is modified by smoking. Breast cancer risk among long-term (>10 years) current users is estimated at one extra case per year per 100,000 women. The risk dissipates with time since last use.

Study Design: Observational studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Tubal ligation: benefits

Based on solid evidence, tubal ligation is associated with a decreased risk of ovarian cancer.

Magnitude of Effect: Adjusting for other forms of contraception, tubal ligation provides a relative reduction in the odds of developing ovarian cancer of about 30%.

Study Design: Multiple case-control studies and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Tubal ligation: harms

Based on fair evidence, harms include surgical risks, including the following:[7]

Major morbidity including blood transfusion, reoperation, or hospital readmission (rate of 1.0 per 100 procedures).
Minor morbidity including postoperative fever, urinary tract infections, or wound infections (rate of 6.0 per 100 procedures).

Multiparity

Based on good evidence, multiparity is associated with a decreased risk of ovarian cancer.

Magnitude of Effect: Based on good evidence from multiple observational epidemiological studies, parous women have an approximately 30% lower ovarian cancer risk than nulliparous women.[6,8,9]

Study Design: Observational epidemiologic studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Salpingectomy

Based on limited data, salpingectomy is associated with a decrease in risk of ovarian cancer.

Magnitude of Effect: Approximately 50% decrease for bilateral salpingectomy, less protection for unilateral salpingectomy.

Study Design: Observational epidemiologic studies from several different countries.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Breastfeeding

Based on solid evidence, breastfeeding is associated with a decreased risk of ovarian cancer.

Magnitude of Effect: 2% decrease with every month of breastfeeding.[10]

Study Design: Multiple case-control and cohort studies; meta-analysis.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Risk-reducing bilateral salpingo-oophorectomy: benefits

Based on solid evidence, risk-reducing bilateral salpingo-oophorectomy is associated with a decreased risk of ovarian cancer. Peritoneal carcinomatosis has been reported rarely following surgery. Risk-reducing surgery is generally reserved for women at high risk of developing ovarian cancer, such as women who have an inherited susceptibility to ovarian cancer.

Magnitude of Effect: 90% reduction in risk of ovarian cancer observed among women with a BRCA1 or BRCA2 mutation.

Study Design: Multiple case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Risk-reducing bilateral salpingo-oophorectomy: harms

Based on solid evidence, prophylactic oophorectomy among women who are still menstruating at the time of surgery is associated with infertility, vasomotor symptoms, decreased sexual interest, vaginal dryness, urinary frequency, decreased bone-mineral density, and increased cardiovascular disease.

Magnitude of Effect: Reported prevalence of vasomotor symptoms varies from 41% to 61.4% among women who underwent oophorectomy before natural menopause. Women with bilateral oophorectomy who did not take hormone therapy were twice as likely to have moderate or severe hot flashes compared with women who underwent natural menopause. The RR of cardiovascular disease among women with bilateral oophorectomy and early menopause was 4.55 (95% CI, 2.56–9.01).

Study Design: Cohort and case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Areas of Uncertainty

Ovarian hyperstimulation for infertility treatment

Evidence is poor to determine the association between ovarian hyperstimulation and the risk of ovarian cancer. Risk of ovarian cancer may be increased among women who remain nulligravid after being treated with ovarian stimulating medications.

Magnitude of Effect: Uncertain—risk of invasive ovarian cancer may be increased among women who remain nulligravid after treatment; risk of borderline ovarian tumors may be increased among women treated with infertility drugs.

Study Design: Cohort and case-control studies; systematic review.
Internal Validity: Fair.
Consistency: Poor.
External Validity: Fair.

References

Poole EM, Lin WT, Kvaskoff M, et al.: Endometriosis and risk of ovarian and endometrial cancers in a large prospective cohort of U.S. nurses. Cancer Causes Control 28 (5): 437-445, 2017. [PUBMED Abstract]
Pearce CL, Templeman C, Rossing MA, et al.: Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 13 (4): 385-94, 2012. [PUBMED Abstract]
Mogensen JB, Kjær SK, Mellemkjær L, et al.: Endometriosis and risks for ovarian, endometrial and breast cancers: A nationwide cohort study. Gynecol Oncol 143 (1): 87-92, 2016. [PUBMED Abstract]
Mørch LS, Løkkegaard E, Andreasen AH, et al.: Hormone therapy and ovarian cancer. JAMA 302 (3): 298-305, 2009. [PUBMED Abstract]
Beral V, Gaitskell K, Hermon C, et al.: Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 385 (9980): 1835-42, 2015. [PUBMED Abstract]
Braem MG, Onland-Moret NC, van den Brandt PA, et al.: Reproductive and hormonal factors in association with ovarian cancer in the Netherlands cohort study. Am J Epidemiol 172 (10): 1181-9, 2010. [PUBMED Abstract]
Lawrie TA, Kulier R, Nardin JM: Techniques for the interruption of tubal patency for female sterilisation. Cochrane Database Syst Rev (9): CD003034, 2015. [PUBMED Abstract]
Fortner RT, Ose J, Merritt MA, et al.: Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: Results from the EPIC cohort. Int J Cancer 137 (5): 1196-208, 2015. [PUBMED Abstract]
Yang HP, Trabert B, Murphy MA, et al.: Ovarian cancer risk factors by histologic subtypes in the NIH-AARP Diet and Health Study. Int J Cancer 131 (4): 938-48, 2012. [PUBMED Abstract]
Feng LP, Chen HL, Shen MY: Breastfeeding and the risk of ovarian cancer: a meta-analysis. J Midwifery Womens Health 59 (4): 428-37, 2014 Jul-Aug. [PUBMED Abstract]