Version May 2024
INTRODUCTION — Epithelial carcinomas of the ovary, fallopian tube, and peritoneum (EOC) can generally be considered one clinical entity, with some distinctions. The incidence of and risk factors for these carcinomas will be reviewed here. Related topics are discussed in detail separately, including:
●Overview (see "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum")
●Histopathology (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology")
●Clinical features and diagnosis (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis" and "Early detection of epithelial ovarian cancer: Role of symptom recognition")
●Staging and surgical treatment (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging")
●Adjuvant therapy (see "Adjuvant therapy of early-stage (stage I and II) epithelial ovarian, fallopian tube, or peritoneal cancer" and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer")
INCIDENCE
●Ovarian carcinoma – In 2020, ovarian cancer accounted for an estimated 314,000 new cancer cases and 207,000 deaths worldwide [1]. It is the third most common gynecologic cancer, after cervical and uterine cancer (age standardized incidence for cervical, uterine, and ovarian cancer: 13.3, 8.7, and 6.6 per 100,000 females, respectively).
In the United States, there are approximately 19,710 new cases and 13,270 cancer-related deaths each year from ovarian cancer, making it the second most common gynecologic malignancy (uterine cancer is most common), the most common cause of death from a gynecologic cancer, and the fifth leading cause of cancer death in females (lung and bronchus, breast, colon and rectum, and pancreatic cancer are more common) [2].
Based on data from the United States National Cancer Database Surveillance, Epidemiology, and End Results (SEER), approximately 1.3 percent of females in the United States will be diagnosed with ovarian cancer at some point during their lifetime [3]. Incidence rates (per 100,000 population) vary based on race/ethnicity:
•Non-Hispanic White American (11.9)
•Hispanic American (10.3)
•Asian American or Pacific Islander (9.4)
•Non-Hispanic Black American (9.2)
•American Indian/Alaska Native (8.1)
Incidence rates have been falling from 16.3 per 100,000 females in 1975 to 10.1 per 100,000 in 2016.
●Fallopian tube carcinoma – Fallopian tube carcinoma had been thought to be uncommon, with an age-adjusted incidence of 0.39 per 100,000 females in the United States [4]. However, the incidence is now thought to be much higher because many high-grade serous carcinomas involving the fallopian tube were formerly classified as advanced ovarian carcinoma but are now thought to have originated in the fallopian tube and spread to the ovary [5].
●Peritoneal carcinoma – Peritoneal carcinoma had also been thought to be uncommon, with an age-adjusted incidence of 0.65 per 100,000 females in the United States [4]. However, the incidence is now thought to be higher because when it involves the ovary, it is indistinguishable from stage III ovarian cancer, which is the stage at which more than 50 percent of serous carcinomas are diagnosed [6].
PROBABLE RISK FACTORS — Major risk factors for EOC are discussed below. Risk factors for fallopian tube and peritoneal carcinoma are less well defined than for ovarian carcinoma but have generally been found to be the same.
Older age — The incidence of EOC increases with increasing age. An analysis of data from the Nurses' Health Study found that the risk increased approximately 2 percent for each additional year of age in patients <50 years old and 11 percent in patients ≥50 years old [7].
The median age at diagnosis of ovarian cancer is 63 years old [3]. The proportion of new cases by age group is:
●<20 years old – 1.3 percent
●20 to 34 – 4.0 percent
●35 to 44 – 6.7 percent
●45 to 54 – 17.5 percent
●55 to 64 – 24.7 percent
●65 to 74 – 22.6 percent
●75 to 84 – 15.3 percent
●>84 – 7.9 percent
In patients younger than 20 years of age, germ cell tumors predominate; borderline tumors typically occur in patients in their 30s and 40s; and after age 50 years, EOC predominates [5].
The average age at diagnosis of ovarian cancer is earlier among patients with a hereditary ovarian cancer syndrome than in sporadic cases. The mean age at diagnosis in patients with Lynch syndrome (hereditary nonpolyposis colon cancer [HNPCC]) was 43 and 49 years in two retrospective studies [8,9]. For BRCA1 and BRCA2 carriers, the median age at diagnosis was 54.0 and 59.5 years, respectively, in a prospective study [10]. (See 'Genetic factors' below.)
Early menarche or late menopause — Early menarche (before age 12) has been associated with a slightly increased risk of EOC in some, but not all, studies [11-15]. Late age at menopause (after age 52) also appears to be associated with an increased EOC risk (relative risk [RR] 1.46, 95% CI 1.06-1.99 compared with menopause at ≤45 years [11]).
The risk of EOC appears to increase by 2 to 7 percent for each additional year of ovulation (RR 1.07, 95% CI 1.05-1.08) [7,11]. The proposed mechanism for the association is that early menarche or late menopause increases the total number of ovulations in a patient's lifetime. Repeated ovulation results in minor trauma to the ovarian epithelium, which in turn may lead to malignant transformation [16]. Support for this hypothesis is derived from the observation that patients with periodic suppression of ovulation as a result of oral contraceptive use, pregnancy, or lactation have a lower incidence of EOC.
Genetic factors — Studies suggest that a patient who has one first-degree relative with ovarian cancer has an approximate 5 percent risk of ovarian cancer, a 3.5 percent risk if the patient has one second-degree relative, and a 7 percent risk if the patient has two affected relatives [17,18]. Much of this risk may be due to pathogenic variants in BRCA1 and BRCA2 and, to a lesser extent, in other genes associated with ovarian cancer (eg, RAD51C, RAD51D, BRCA1-interacting protein 1 [BRIP1], as well as the mismatch repair genes associated with Lynch syndrome). It is estimated that heritable pathogenic variants account for up to one-quarter of ovarian cancer cases [19-23].
BRCA variants — Patients with pathogenic variants of BRCA1 and BRCA2 have a greatly increased risk of ovarian and breast cancer (table 1). The evidence establishing the association and the approach to counseling BRCA carriers without a cancer diagnosis are reviewed separately. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Breast and ovarian cancer'.)
Lynch syndrome — Lynch syndrome (HNPCC) is associated with several other cancers besides colon cancer: in particular, endometrial, ovarian, urogenital, and other gastrointestinal primaries. Colorectal cancer is the hallmark disease for Lynch syndrome; endometrial cancer is the second most common malignancy in affected patients (occurring in up to 71 percent), but ovarian cancer is also increased in frequency. The lifetime risk of ovarian cancer in patients with Lynch syndrome is up to 38 percent (depending on the genetic variant) compared with approximately 1.5 percent in the general population (table 2). Patients with Lynch syndrome account for 1 percent of ovarian cancers [24] and develop ovarian cancer at a younger age than other patients (age 43 to 48 versus 60 years) [8,9].
Ovarian cancer in patients with Lynch syndrome is reviewed in detail separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)
Other genetic factors — BRCA1 and BRCA2 are among a family of genes in the Fanconi anemia pathway that play a role in homologous recombination. One of the genes for Fanconi anemia, FANCD1, is the same as BRCA2. Data suggest that certain biallelic mutations result in Fanconi anemia, while certain monoallelic genetic variants result in an increased risk of cancers associated with BRCA1 [25]. Some genetic variants in this pathway are associated with an increased risk of breast cancer, while others are associated with ovarian cancer [26]. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics'.)
In an unselected patient population of ovarian cancer, genetic variants in BRIP1, RAD51C, RAD51D, PALB2, and BARD1 were all more frequent in patients with ovarian cancer than in the general population [27]. Compared with the more highly penetrant BRCA1 and BRCA2, the lifetime risk for ovarian cancer in BRIP1 is approximately 5.8 percent and in RAD51C and RAD51D is 5.2 and 12.0 percent, respectively [28,29]. (See "Overview of hereditary breast and ovarian cancer syndromes".)
A variant in a gene that encodes for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may be protective against ovarian cancer. HMG-CoA reductase is the rate-limiting step in cholesterol biosynthesis and is the target of statin medications. In a case-control study of over 63,000 patients, patients with genetic variants that led to decreased activity of HMG-CoA reductase had lower rates of epithelial ovarian cancer in both the general population (odds ratio 0.60, 95% CI 0.43-0.83) and in BRCA1 and BRCA2 mutation carriers (hazard ratio [HR] 0.69, 95% CI 0.51-0.93) [30]. However, this study did not evaluate risk reduction from statins themselves, and further research is needed to determine if a direct association exists.
Nulliparity — Parous patients have a reduced risk of developing ovarian cancer. (See 'Parity' below.)
Endometriosis — Endometriosis appears to be associated with some subtypes of EOC (eg, endometrioid, clear cell), but the overall risk appears to be low. This association is reviewed in detail separately. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact", section on 'Ovarian cancer risk'.)
Asbestos — A meta-analysis of 18 cohort studies found that exposure to asbestos was associated with an increased risk of death from EOC (standardized mortality ratio 1.77, 95% CI 1.37-2.28) [31]. Talc may be contaminated with asbestos. (See 'Talc' below.)
Pelvic radiation — A history of pelvic radiation for treatment of primary rectal carcinoma may increase the risk for developing ovarian cancer, although the overall incidence is small. In one cohort study including over 20,000 female patients with rectal cancer, treatment with radiotherapy plus surgery compared with surgery alone was associated with an increase in ovarian cancer (0.98 versus 0.29 percent, adjusted HR 2.08, 95% CI 1.22-3.56) after a five-year latency period [32]. (See "Approach to the long-term survivor of colorectal cancer", section on 'Second malignancies'.)
UNLIKELY OR CONTROVERSIAL RISK FACTORS
Menopausal hormone therapy — We believe that EOC risk is not an important factor for consideration by patients who are deciding whether to take menopausal hormone therapy for relief of menopausal symptoms because the absolute risk of EOC with hormone therapy is at most very low. The data regarding the association are reviewed in detail separately. (See "Menopausal hormone therapy: Benefits and risks", section on 'Ovarian cancer'.)
Obesity — In two systematic reviews, high body mass index appeared to modestly increase ovarian cancer risk (odds ratios [OR] 1.3 [33] and 1.1 [34]), but another systematic review concluded available data were limited and inconsistent, precluding a clear assessment of risk [35]. (See "Overweight and obesity in adults: Health consequences", section on 'Cancer'.)
Polycystic ovary syndrome — Systematic reviews regarding risk of ovarian cancer in patients with polycystic ovary syndrome (PCOS) are inconclusive [36-38]. Confounders include an increased prevalence of infertility and obesity in patients with PCOS.
Family history of breast cancer — In families with breast cancer but without ovarian cancer or another hereditary breast and ovarian genetic syndrome, there does not appear to be an increased risk of ovarian cancer. Historically, a personal or family history of breast cancer had been thought to be a risk factor for ovarian cancer; however, pathogenic variants of BRCA1 and BRCA2 appear to account for most of this increased risk. (See 'BRCA variants' above and "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)
Talc — There are no conclusive data to support the association between ovarian cancer and genital tract talc use.
In a 2018 meta-analysis of this issue (24 case-control [13,421 cases] and 3 cohort studies [890 cases, 181,860 person-years]), any perineal talc use was associated with an increased risk of ovarian cancer in case-control studies (OR 1.35, 95% CI 1.27-1.43) but was not statistically significant in cohort studies (OR 1.06, 95% CI 0.90-1.25) [39]. A high risk of recall bias is a major limitation of the case-control studies. Subsequently, a study using prospectively collected pooled data from four cohort studies (n >250,000) to estimate the association between use of powder in the genital area and ovarian cancer (2168 cases) found no significant increase in risk by age 70 [40]. Ovarian cancer incidence in ever-users and never-users was 61 and 55 cases per 100,000 person-years, respectively (estimated risk difference at age 70 years 0.09 percent, 95% CI -0.02 to 0.19; estimated hazard ratio [HR] 1.08, 95% CI 0.99-1.17). HRs for ovarian cancer were not significantly increased for frequent versus never users or for long-term versus never users. Subgroup analyses were conducted for 10 variables; the tests for heterogeneity were not statistically significant for any of these comparisons. Importantly, while the estimated HR for the association between ever use of powder in the genital area and ovarian cancer risk among patients with a patent reproductive tract (intact uterus and no tubal ligation) was 1.13 (95% CI 1.01-1.26), the statistical test for heterogeneity was not significant when this subgroup was compared with patients with nonpatent genital tracts, supporting the conclusion that use of powder in the genital area does not increase ovarian cancer risk. Although larger than previous analyses, this study may have been underpowered to detect true small increases or decreases in cancer risk. A limitation of this study was that the type of powder could not be ascertained, but the increase in HR for ovarian cancer in older cohorts (who were more likely to have used talc powder contaminated with asbestos) was statistically nonsignificant (HR 1.09, 95% CI 0.99-1.19).
The US Food and Drug Administration states that studies have not conclusively demonstrated a link between talc and ovarian cancer [41,42]. An International Agency for Research on Cancer monograph concluded that perineal use of talc-based body powder is possibly carcinogenic to humans [43]. Health Canada issued a warning in 2019 regarding use of talc as a possible cause of ovarian cancer, advising health care professionals to tell patients to avoid female genital exposure to products containing talc [44].
Cigarette smoking — In a systematic review, current or past smoking appeared to increase the risk of mucinous ovarian cancer (relative risk [RR] 2.1, 95% CI 1.7-2.7) but not other types of EOC (serous, endometrioid, clear cell) [45]. The risk increased with increasing levels of cigarette smoking. Smoking also decreased survival in patients with ovarian cancer [46].
Diet — Many studies have addressed the role of diet in EOC risk, but high-quality data are not available and no dietary recommendations to avoid EOC risk can be made at this time. Consumption of dairy products [47-49], soy [50], fat from animal sources [51], various vitamin supplements [52,53], nitrates [53], red meat [53], fruits and vegetables [53], tea [54,55], and a healthy or unhealthy diet [56] are among the dietary factors that have been studied without clear findings.
Exercise — There is no clear relationship between physical activity and ovarian cancer risk [7,57]. At best, there is a modest decrease in risk in patients with high levels of activity [58-60]; however, at least two studies suggested an increase in risk with vigorous activity [61,62].
Infertility and infertility treatment — Infertility and infertility treatment do not appear to be independent risk factors for EOC. An association between infertility and EOC observed in some studies may have been related to endometriosis or nulliparity. The evidence regarding infertility and infertility treatment and ovarian cancer risk is reviewed in detail separately. (See "Overview of ovulation induction", section on 'Cancer risks' and "Assisted reproductive technology: Pregnancy and maternal outcomes", section on 'Ovarian cancer and borderline tumors'.)
Other
●A meta-analysis found no association between alcohol intake and the risk of EOC [63].
●Population-based studies have reported an association between a history of pelvic inflammatory disease and ovarian cancer [64,65].
●A population-based study reported that occupational exposure to paint, welding, and other chemical processes was associated with an increased risk of fallopian tube carcinoma [66].
●Meta-analyses have reported an association between diabetes and ovarian cancer (RR 1.32, 95% CI 1.14-1.52 [67] and RR 1.17, 95% CI 1.02-1.33 [68]).
●Spontaneous or induced abortion does not appear to be associated with an increased risk of EOC [69].
PROTECTIVE FACTORS — The factors with the strongest association with a reduced risk of ovarian cancer include (table 3):
●Bilateral salpingo-oophorectomy
●Use of oral contraceptives
●Tubal ligation
●Hysterectomy
●Breastfeeding
●Parity
Bilateral salpingo-oophorectomy — Bilateral salpingo-oophorectomy is the most effective means for reducing the risk of developing ovarian cancer, but some patients may still develop peritoneal carcinoma, which is rare. The fallopian tubes must be removed because tubal neoplasia plays an important role in the pathogenesis of EOC. The evidence for reduction of EOC and decision making regarding the procedure are reviewed separately.
●(See "Elective oophorectomy or ovarian conservation at the time of hysterectomy".)
●(See "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction".)
●(See "Cancer risks and management of BRCA1/2 carriers without cancer".)
Hysterectomy — Hysterectomy without bilateral salpingo-oophorectomy was associated with a 20 percent reduction in the risk of ovarian cancer (odds ratio [OR] 0.81, 95% CI 0.72-0.92) in a meta-analysis of 20 studies (5 cohort, 13 case-control studies, 1 nested case-control, 1 pooled analysis of case-control studies) [70]. When preserving the ovaries, hysterectomy with opportunistic salpingectomy may be considered, but this requires a thorough review with the patient regarding risks and benefits [71].
Oral contraceptives — Studies have consistently shown that prolonged use of oral contraceptives reduces the risk of ovarian cancer. There are no data regarding the use of nonoral estrogen-progestin contraceptives (ring, patch) for ovarian cancer prevention.
In a meta-analysis of 24 studies of oral contraceptive pills as primary prevention for ovarian cancer, ever-use was associated with a reduction in ovarian cancer compared with never use (OR 0.73, 95% CI 0.66-0.81), with more than 50 percent reduction among patients with ≥10 years of use [72]. The participants of this study included people who desired prevention of pregnancy and those who were attempting to reduce their risk for ovarian cancer. Other meta-analyses have reported similar benefits in patients at high risk for ovarian cancer [73,74].
●(See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Oral contraceptives'.)
Intrauterine device — Both the levonorgestrel and copper intrauterine devices (IUD) may be associated with lower rates of ovarian carcinoma, but data are conflicting [75]. In a meta-analysis of case-control and cohort studies of IUD use and incident ovarian cancer, IUD use was associated with a reduced incidence of ovarian cancer (OR 0.68, 95% CI 0.62-0.75) [76]. However, limitations of the analysis, such as a high risk of bias in the included studies, inability to analyze the data by type of IUD and duration of use, and the potential for confounding factors, limit confidence in this finding. This is also discussed separately. (See "Intrauterine contraception: Background and device types", section on 'Benefits'.)
Tubal ligation — Tubal ligation is associated with a decrease in ovarian cancer risk. These data are reviewed in detail separately. (See "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction", section on 'Efficacy of tubal ligation in cancer reduction'.)
Breastfeeding — In a meta-analysis including 5 cohort and 35 case-control studies on the association between breastfeeding and ovarian cancer, breastfeeding was associated with a 30 percent reduction in ovarian cancer compared with not breastfeeding (OR 0.70, 95% CI 0.64-0.76) [77]. The magnitude of risk reduction increased with the total duration of breastfeeding: for <6, 6 to 12, and >12 months, the reductions were 15, 27, and 36 percent, respectively.
In another meta-analysis, compared with nulliparous patients with no history of breastfeeding, the combined effect of two births and <6 months of breastfeeding resulted in 50 percent reduction in EOC [78].
Parity — Parous patients appear to be at decreased risk for ovarian cancer compared with nulliparous patients, and the risk appears to decrease with increasing parity [11,15,79-82]. In one study, risk of EOC decreased by 8 percent for each additional pregnancy [11]. The mechanism for the reduction may be the decrease in the total number of ovulations in the parous patient's lifetime.
Other
●A history of multiple gestation [83-85] or later age (>35 years old) at last pregnancy have been associated with a reduction in risk of EOC [86,87].
●Aspirin, but not non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, may be associated with a reduction in ovarian cancer risk, but study results are conflicting [88-93]. There is no clear association, however, between aspirin or other NSAID use and ovarian cancer survival [94].
Use of aspirin in primary prevention of cardiovascular disease and cancers is discussed in detail separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Other cancers'.)
RISK MANAGEMENT
●Whether to screen and whom to screen for ovarian cancer. (See "Screening for ovarian cancer".)
●Approach to patients who have a family history suggestive of a hereditary ovarian cancer syndrome. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)
●Patients with a pathogenic genetic variant associated with an increased risk for ovarian cancer.
•(See "Cancer risks and management of BRCA1/2 carriers without cancer".)
•(See "Overview of hereditary breast and ovarian cancer syndromes".)
●Patients at average risk for ovarian cancer considering options for risk reduction:
•(See "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction".)
•(See "Elective oophorectomy or ovarian conservation at the time of hysterectomy".)
•(See 'Breastfeeding' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)
SUMMARY AND RECOMMENDATIONS
●Clinical significance – Epithelial ovarian carcinoma (EOC), fallopian tube, and peritoneal carcinomas can generally be considered one clinical entity, with some distinctions. (See 'Introduction' above.)
●Incidence – Ovarian cancer is the second or third most common gynecologic malignancy in many countries and has a high mortality rate. The lifetime risk of ovarian cancer in the general population is approximately 1.3 percent. (See 'Incidence' above.)
While fallopian tube and peritoneal carcinomas were thought to be uncommon, the incidence is likely much higher because many of these carcinomas were formerly classified as advanced ovarian carcinoma but are now thought to have originated in the fallopian tube or peritoneum. (See 'Incidence' above.)
●Risk factors
•The main risk factors for ovarian cancer include increasing age, early age at menarche or late menopause, nulliparity, endometriosis, and hereditary ovarian cancer syndromes (BRCA gene mutations, Lynch syndrome) (table 3). Risk factors for fallopian tube and peritoneal carcinomas are less well defined but have generally been found to be the same. (See 'Probable risk factors' above.)
•Unlikely or controversial risk factors include (but are not limited to) menopausal hormone therapy, obesity, polycystic ovary syndrome (PCOS), infertility, and infertility treatments. (See 'Unlikely or controversial risk factors' above.)
●Protective factors – Protective factors include bilateral salpingo-oophorectomy (which is the most effective protective intervention), use of oral contraceptives, intrauterine device use, tubal ligation, hysterectomy, breastfeeding, and parity (table 3). (See 'Probable risk factors' above.)
●Risk management – Decisions regarding whether to screen and whom to screen, options for patients at increased risk for ovarian cancer, and those at average risk are discussed in detail separately. (See 'Risk management' above.)
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