Endometrial cancer: Clinical features, diagnosis, and screening Authors Lee-may Chen, MD Jonathan S Berek, MD Section Editor Barbara Goff, MD Deputy Editor Sandy J Falk, MD

Last literature review version 17.1: January 2009|This topic last updated: January 28, 2009(More)

INTRODUCTIONEndometrial carcinoma (show picture 1) is the most common gynecologic malignancy in the United States; approximately 40,100 cases are diagnosed annually and 7470 deaths occur [1] . Women have a 2.5 percent lifetime risk of developing endometrial cancer and it accounts for 6 percent of all cancers in women. Fortunately, most cases are diagnosed at an early stage when surgery alone may be adequate for cure. Five-year survival rates for localized, regional, and metastatic disease are 95, 67, and 23 percent, respectively [1] .

Differences in epidemiology and prognosis suggest that two forms of endometrial cancer exist: those related to and those unrelated to estrogen stimulation [2] . Type I endometrial carcinoma is estrogen-related, usually presents histologically as a low grade endometrioid tumor, and is associated with atypical endometrial hyperplasia. These patients tend to have risk factors such as obesity, nulliparity, endogenous or exogenous estrogen excess, diabetes mellitus, and hypertension. Type II endometrial carcinomas appear unrelated to estrogen stimulation or endometrial hyperplasia, and tend to present with higher grade tumors or poor prognostic cell types, such as papillary serous or clear cell tumors. These patients are often multiparous, and do not have an increased prevalence of obesity, diabetes, or hypertension. They also tend to be older than women with endometrioid tumors [3] . (See "Uterine papillary serous and clear cell cancer").

Clinical features of endometrial cancer are reviewed here. Staging, treatment, and follow-up of this disorder are discussed separately. (See "Endometrial cancer: Staging, treatment, and follow-up").

INCIDENCE AND EPIDEMIOLOGYUterine corpus cancer is the most common gynecologic malignancy in the United States, with over 40,000 new cases diagnosed annually [1] . Incidence rates are higher in whites than in black, Hispanic or Asian/Pacific Islander women. However, mortality is almost two-fold higher in blacks than in whites (7.1 versus 3.9 per 100,000 women) [4] , likely due to the higher incidence of aggressive cancer subtypes, as well as issues of access to, and quality of, healthcare services [5] .

RISK FACTORSOur current understanding of risk factors only helps to identify women at risk for type I endometrial cancer, which is the more common type (80 percent of cases are type I, 20 percent of cases are type II) (show table 1) [6] . As discussed above, the etiology of this type of endometrial cancer stems from the effects of excess estrogen, either from exogenous or endogenous sources, in the absence of adequate exposure to progestins [7-9] . Exogenous exposure to estrogenic influences include estrogen replacement therapy and tamoxifen, while endogenous exposure may result from obesity, anovulatory cycles, or estrogen-secreting tumors. (See "Histopathology and pathogenesis of endometrial cancer").

Long-term estrogen exposure

Exogenous estrogenTreatment of postmenopausal women with estrogen therapy provides significant short and long-term benefits by reducing hot flashes and vaginal dryness and maintaining bone density. Treatment with estrogen alone, however, increases the risk for endometrial hyperplasia and carcinoma. Endometrial hyperplasia can be demonstrated within one year in 20 to 50 percent of women receiving estrogen therapy without a progestin [10,11] . Multiple case-control and prospective studies have shown an increased incidence of endometrial carcinoma, with the relative risk ranging from 3.1 to 15 [12,13] . The risk is related to both estrogen dose and duration of use. (See "Postmenopausal hormone therapy: Benefits and risks").

If one assumes that the absolute risk of endometrial carcinoma in postmenopausal women is about 1 in 1000, then the absolute risk in women taking estrogen alone increases to approximately 1 in 100 [12,14] . Although some reports suggest that endometrial carcinoma in these women is less aggressive than in hormone nonusers [15] , others have found an increased risk of metastases [16] .

The excess risk of endometrial hyperplasia and carcinoma can be significantly reduced by the concomitant administration of progestins [17,18] . There are several accepted regimens that may be chosen, based upon the characteristics and desires of the individual woman. (See "Postmenopausal hormone therapy: Benefits and risks", section on Protective effect of progesterone and see "Preparations for postmenopausal hormone therapy").

Endogenous estrogenExcessive endogenous conversion of adrenal precursors to estrone and estradiol by adipose cells and endogenous estrogen production from functional ovarian tumors are associated with an increased risk of endometrial cancer; conversion of adrenal precursors to estrone is far more common than functional ovarian tumors [19] . Several studies have demonstrated that a postmenopausal woman's risk of developing endometrial cancer is correlated with higher circulating estrogen and androgen levels, and lower sex hormone binding globulin (SHBG) levels, compared to unaffected controls [20-23] .

Chronic anovulationThe normal menstrual cycle is characterized by cyclic changes in pituitary and gonadal hormones. (See "The normal menstrual cycle"). Many women with chronic anovulation have an adequate amount of biologically active estrogen since androgens can be converted peripherally to estrogens in the absence of normal ovarian function; however, their anovulatory cycles lack the progesterone secretion normally present in the luteal phase. The classic example is women with polycystic ovary syndrome (PCOS) who are hyperandrogenic at baseline. These women have constant estrogenic stimulation of the endometrium leading to endometrial hyperplasia and, in some cases, endometrial cancer. In fact, the majority of cases of endometrial cancer in young women occur in association with PCOS [24] . (See "Clinical manifestations of polycystic ovary syndrome in adults").

Tamoxifen useTamoxifen is a competitive inhibitor of estrogen binding to estrogen receptors that also has partial agonist activity (ie, tamoxifen is a weak estrogen). It is used for adjuvant therapy in women with early stage breast cancer, as treatment for recurrent disease, and for reduction of breast cancer incidence in high-risk women. The site-specific activity of tamoxifen in different tissues is well recognized, suppressing the growth of breast tissue, but also stimulating the endometrial lining. Tamoxifen use has been linked to development of endometrial pathology, both benign and malignant [25] . (See "Use of selective estrogen receptor modulators in postmenopausal women", section on Adverse effects).

ObesityThe incidence of endometrial cancer is higher in obese women. In a metaanalysis of 19 prospective studies including over 3 million women, each increase in BMI of 5 kg/m2 incurred a significantly increased risk of developing endometrial cancer (RR 1.59, 95% CI 1.50-1.68) [26] .

One explanation for these findings is that obese women have high levels of endogenous estrogen due to the conversion of androstenedione to estrone and the aromatization of androgens to estradiol, both of which occur in peripheral adipose tissue. Unlike some other disorders, however, the risk of developing endometrial cancer is not related to the distribution of adipose tissue [27-29] .

Obese women also can have lower circulating levels of SHBG, alterations in the concentration of insulin-like growth factor and its binding proteins, and insulin resistance, all of which may contribute to the increased risk of endometrial cancer in these women [30,31] . Premenopausal obese women, especially those with polycystic ovary syndrome, are often anovulatory, as well (see "Chronic anovulation" above).

Higher body mass index (BMI) is also associated with an increased risk of death from endometrial cancer. The magnitude of this risk was illustrated in a prospective cohort study of 495,477 women followed for 16 years (1982 to 1998) in the Cancer Prevention Study II [32] . The relative risk of dying from endometrial cancer among those with the highest BMI ( 40 kg/m2) was 6.25-fold higher than that of normal weight women (BMI 18.5 to 24.9 kg/m2). Higher BMI is also associated with endometrial cancer presenting at less than 45 years of age (see "Age" below) [33] .

Paradoxically, among women who are diagnosed with endometrial cancer, those with BMI greater than 40 kg/m2 are more likely than those with BMI less than 30 kg/m2 to have stage I disease (77 versus 61 percent) or low grade histology (44 versus 24 percent) [34] . This is likely due to a higher likelihood of the less aggressive histology (ie, endometrioid rather than papillary serous or clear cell) in women with BMI over 40 kg/m2 (87 versus 75 percent).

As discussed below, use of combination (estrogen/progestin) oral contraceptive pills (OCPs) reduces the risk of developing endometrial cancer (see "Oral contraceptives" below). However, a decision analysis of endometrial cancer prevention strategies for obese women concluded that giving OCPs to obese women would not be cost-effective, except in women with a 13-fold risk for endometrial cancer over the general population (eg, morbid obesity [BMI 40 kg/m2] and a chronic anovulation) [35] .

Diabetes and hypertensionWomen with diabetes mellitus and hypertension are at increased risk for endometrial cancer. Comorbid factors, primarily obesity, account for much of this risk [29,36] , but some studies have found independent effects, as well [7,37-44] . The risk of developing endometrial cancer is higher in type 2 than type 1 diabetics. Diets high is carbohydrates and associated hyperinsulinemia, insulin resistance, and elevated levels of insulin-like growth factors may play a role in endometrial proliferation and development of endometrial cancer; this is an area of active investigation [6,38,45-47] .

AgeEndometrial cancer usually occurs in postmenopausal women (mean age early 60s). Twenty-five percent of cases are diagnosed in premenopausal women, and 5 to 10 percent of these are in women under age 40 [48] . The disease has been reported in women under 30 years of age. The overall probability of developing endometrial cancer between birth and age 39 is about 0.05 percent [49] .

The characteristics of young women with endometrial cancer are illustrated in the following studies: A series in which 12 percent (188/1531) of all patients with endometrial adenocarcinoma were under 50 years of age reported common features of disease in young women were obesity (56 percent had a BMI 30 kg/m2), nulliparity (44 percent), and hypertension and diabetes (both 23 percent) [50] . In this cohort, 89 percent of endometrial cancers were endometrioid histology and there was a high incidence of synchronous primary ovarian cancers (19 percent).

Normal weight women in the above series were often nulliparous, subfertile, and had irregular menstrual cycles [51] . They were also more likely to have synchronous tumors of the endometrium and ovary when compared with the general population. In another series of 396 women with endometrial cancer, women under age 45 years were more likely than women over age 65 to have endometrioid histology (95 versus 79 percent) and stage IA (64 versus 26 percent) and grade 1 (48 versus 20 percent) tumors [52] . Papillary serous/clear cell histology occurred in 5 percent of young, but 21 percent of older women. Older women presented with higher stage and grade disease, even after controlling for tumor histology. Mean BMI in young women was 40.3 kg/m2. Four of the 55 young women had positive lymph nodes, indicating that advanced disease is not uncommon even in young women. A prospective study of 100 women under age 50 with endometrial cancer found that 9 percent carried germline Lynch syndrome mutations (see below) [53] . Risk factors for the presence of this genetic mutation included a first degree relative with a Lynch syndrome-associated cancer, lower BMI (BMI 29 versus 34 in controls without the mutation), loss of MSH2 expression, and high microsatellite instability.

Familial predisposition and geneticsA familial tendency toward isolated endometrial cancer has been suggested for first degree relatives [54,55] , although no candidate genes have been identified consistently. Other familial associations with endometrial cancer include:

Lynch syndromeThe Lynch syndrome is characterized by the presence of hereditary nonpolyposis colorectal cancer (HNPCC) and a high risk of extracolonic tumors, the most common of which are endometrial carcinomas (in up to 43 percent of females by age 70 in affected families) (show table 2) [56] . Five to 9 percent of endometrial cancer patients under age 50 carry deleterious mismatch repair mutations associated with Lynch syndrome [53,57]

Other sites at increased risk for neoplasms in these families include the ovary, stomach, small bowel, hepatobiliary system, and renal pelvis or ureter. Importantly, endometrial and ovarian cancers in affected women precede development of colon cancer in about one-half of cases. In approximately 50 percent of women who carry Lynch syndrome mutations, endometrial or ovarian cancer preceded development of colon cancer, on average by 11 and 5.5 years, respectively [58] . (See "Clinical features and diagnosis of Lynch syndrome (hereditary nonpolyposis colorectal cancer)").

Germline mutations of one or another of the DNA mismatch repair (MMR) genes (MSH2, MLH1, or MSH6) are believed to account for the great majority of HNPCC kindreds. Loss of mismatch repair can also occur in sporadic endometrial cancers [59-62] . However, sporadic tumors with defective MMR do not contain MMR gene mutations; instead, they have somatic epigenetic changes such as promoter hypermethylation that silence gene expression. In either case, failure of MMR leads to the accumulation of single base-pair mismatches, as well as small insertions or deletions in tandem repeats known as microsatellites. This manifests as microsatellite instability (MSI), the biologic "footprint" of defective MMR, which can be quantitated by genotyping of paired tumor and nontumor tissue DNA from the same individual. (See "Clinical features and diagnosis of Lynch syndrome (hereditary nonpolyposis colorectal cancer)", section on Microsatellite instability).

Approximately 20 percent of endometrial cancers are MSI-positive; fewer than 5 percent are thought attributable to HNPCC. The clinicopathologic features of MSI-positive endometrial tumors are less well characterized than with colorectal cancers. At least some data suggest a strong association with endometrioid, rather than nonendometrioid, histologic subtype. In a series of 473 endometrial cancers, nonendometrioid histology accounted for 20 percent of all tumors, but only 6 percent of the 93 that were MSI-positive [62] . Despite deeper myometrial invasion and more advanced tumor stage at diagnosis, MSI-positive tumors had a better prognosis overall (disease free survival hazard ratio 0.3, 95% CI 0.2-0.7). This has not been a consistent finding in other studies, however. (See "Molecular genetics of colorectal cancer", section on Mismatch repair genes).

Breast cancerA history of breast cancer is a risk factor for development of endometrial cancer, in part because both diseases share some common risk factors (eg, obesity, nulliparity). In one study, women with a history of breast cancer who developed endometrial cancer had a significantly higher proportion of serous tumors than women with no history of breast cancer, 13/43 (24 percent) versus 120/1112 (11 percent) [63] .

BRCAIt is unclear whether the breast cancer susceptibility gene BRCA1 plays a role in development of endometrial cancer. A multinational cohort study involving 11,847 individual mutation carriers reported BRCA1 was associated with a small, but significantly increased risk of uterine cancer (RR = 2.65, 95% CI 1.69-4.16) [64] . However, data from a retrospective series showed no increased risk [65] while data from a prospective series suggested that the risk of endometrial cancer was significantly elevated only for BRCA mutation carriers taking tamoxifen [66] . Further investigation is required. (See "Genetic testing for breast and ovarian cancer" and see "Risk assessment and clinical characteristics of women with a family history of breast and/or ovarian cancer", section on Cancer risk).

There is some evidence of an increased risk of papillary serous carcinoma of the endometrium in BRCA carriers. (See "Risk reducing salpingo-oophorectomy in women at high risk of epithelial ovarian cancer" section on Concurrent hysterectomy).

NulliparityIn epidemiological studies, the risk of endometrial cancer is inversely related to parity [67-69] . Nulliparity by itself does not appear to increase the risk of endometrial cancer; instead, the association probably lies with the high frequency of anovulatory cycles in infertile women.

DietThere is insufficient evidence to make any recommendations regarding dietary changes to reduce the risk of endometrial cancer. A randomized trial in which the intervention group reduced their percentage of caloric energy from fat by 8 to 11 percent consistently over a period of six years did not find a significant reduction in the incidence of endometrial cancer after eight years follow-up [70] . Large epidemiologic studies on the effect of diet on endometrial cancer risk have reported conflicting results [71-78] .

Long-term use of soy phytoestrogen supplements for up to five years has been associated with an increased occurrence of endometrial hyperplasia [79] . The benefits and risks of these agents are discussed in detail separately. (See "Preparations for postmenopausal hormone therapy" section on Phytoestrogens).

Alcohol intakeAlcohol use is associated with elevated estrogen levels. Epidemiological studies have generally not found a significant association between alcohol intake and endometrial cancer [80-82] , although one such study suggested that postmenopausal women who consume two or more alcoholic drinks per day have an increased risk of endometrial cancer [83] .

CoffeeA meta-analysis of comparative studies found a decreased risk of endometrial cancer proportional to the quantity of coffee consumed [84] . The reduction in risks were: low-to-moderate coffee drinkers, RR 0.87 (95% CI, 0.78-0.97) and heavy coffee drinkers, RR 0.64 (95% CI, 0.48-0.86).

Early menarche and late menopauseEarly age at menarche is a risk factor for endometrial cancer in some studies; late menopause is less consistently associated with increased risk of the disease [7,68,85,86] . Prolonged estrogen stimulation without the protection of progesterone is the presumed mechanism for this association.

Physical activityThe effect of occupational or recreational physical activity on endometrial cancer risk is unclear. Some observational studies have suggested a protective effect [87-90] , but others have not [91] . Several plausible biological mechanisms have been proposed to explain a possible association between high levels of physical activity and reduced cancer risk; these include decreased obesity and central adiposity, favorable changes in immune function and in endogenous sexual and metabolic hormone levels and growth factors [92] .

Protective factors

Oral contraceptivesThe use of OCPs decreases the risk of endometrial cancer by 50 to 80 percent [93-99] . In a classic study, women using combination OCPs for at least 12 months had a relative risk of endometrial cancer of 0.6 (95% CI 0.3-0.9) compared to nonusers [99] . The protective effect persisted for at least 15 years after cessation of use.

This benefit is likely related to the progestin component of OCPs, which suppresses endometrial proliferation. Other types of hormonal contraception that include progestins (eg, depot medroxyprogesterone acetate, progestin-releasing intrauterine devices) also provide endometrial protection against development of neoplasia [100-102] .

Postmenopausal combined hormone replacementAs with oral contraceptives, most studies have shown that long-term estrogen users who are receiving a daily progestational agent (continuous combined hormone therapy) have a lower rate of endometrial cancer than in hormone nonusers [103] . (See "Postmenopausal hormone therapy: Benefits and risks" section on Risk of endometrial hyperplasia and carcinoma).

SmokingSmoking is associated with a decreased risk of developing endometrial cancer in postmenopausal women; obviously, the major health risks associated with tobacco use far outweigh this benefit. The effect in premenopausal women is uncertain. In a metaanalysis of 34 prospective and case-control studies, the risk reduction in current and former smokers was significant after (RR 0.71, 95% CI 0.65-0.78), but not before (RR 1.06, 95% CI 0.88-1.28) menopause [103] . The mechanism suggest for this effect is that smoking stimulates hepatic metabolism of estrogens, leading to a reduced incidence of endometrial abnormalities.

PATHOGENESIS AND HISTOPATHOLOGY(See "Histopathology and pathogenesis of endometrial cancer").

CLINICAL PRESENTATION

OverviewThe cardinal symptom of endometrial carcinoma is abnormal uterine bleeding, which occurs in 90 percent of cases [104] . Even one drop of blood in a postmenopausal woman not on hormone replacement constitutes a symptom and is an indication for diagnostic testing to exclude endometrial cancer. Overall, 5 to 20 percent of postmenopausal women with uterine bleeding will have endometrial cancer; the probability of cancer increases with the number of years beyond menopause. The amount of bleeding does not correlate with the risk of cancer.

Pre- and peri-menopausal women with abnormal uterine bleeding also should be evaluated for endometrial cancer, particularly if they have other risk factors, such as family or personal history of ovarian, breast, colon, or endometrial cancer; tamoxifen use; chronic anovulation; obesity; estrogen therapy; prior endometrial hyperplasia; or diabetes mellitus.

(See "Terminology and evaluation of abnormal uterine bleeding in premenopausal women" and see "The evaluation and management of uterine bleeding in postmenopausal women").

Endometrial cells on cervical cancer screeningAsymptomatic women with endometrial carcinoma occasionally come to medical attention because of abnormalities noted during cervical cancer screening. The presence of endometrial cells on cervical cytology is noted if the woman is 40 years of age. Their presence may reflect physiologic shedding (especially in the first half of the menstrual cycle) or shedding in response to a pathological process. However, cervical cytology is not a sensitive test for endometrial cancer.

Benign appearing endometrial cells are usually not associated with endometrial cancer; the risk is higher when atypical endometrial cells are noted. The diagnostic evaluation of asymptomatic women with benign or atypical endometrial cells noted on cervical cytology is discussed in detail separately. (See "Cervical cytology report" section on Benign endometrial cells and see "Management of atypical and malignant glandular cells on cervical cytology").

DIAGNOSISEndometrial cancer is a histological diagnosis, therefore tissue must be obtained.

Endometrial samplingWe prefer endometrial biopsy as the initial diagnostic test to rule out endometrial cancer. A blind endometrial biopsy performed in the office setting using a Pipelle sampling device is simple to perform, does not require anesthesia, and is generally well tolerated by the patient. This procedure has high sensitivity, a low complication rate, and low cost. The evidence supporting this approach is discussed in detail separately. (See "Evaluation of the endometrium for malignant or premalignant disease").

Hysteroscopy with dilation and curettage (D & C) is another acceptable approach; however, this procedure sometimes requires anesthesia and is associated with a number of potential complications. If the specimen is negative for malignancy but there remains a high suspicion of cancer (eg, hyperplasia with atypia, necrosis, pyometra, or persistent bleeding), we perform hysteroscopy with directed biopsy and curettage.

It should be noted that the tumor is often undergraded when grading is based on sampling procedures rather than hysterectomy [105,106] . A higher grade may be assigned in as many as 30 percent of cases when the hysterectomy specimen is reviewed.

Transvaginal ultrasonographyTransvaginal ultrasonography is a noninvasive means of distinguishing postmenopausal women with bleeding due to atrophy, the most common cause of bleeding in this age group, from those with anatomic lesions that require tissue sampling to exclude carcinoma or for treatment. Postmenopausal women with an endometrial thickness of less than 4 to 5 mm measured by transvaginal ultrasound examination have a low risk of endometrial disease [107,108] . A thicker lining is evaluated further by office biopsy, hysteroscopy with directed biopsy, or D & C. Cancer becomes increasingly more frequent relative to benign disease as the endometrial thickness approaches 20 mm. In one study, 20 mm was the mean endometrial thickness in 759 women with endometrial cancer [108] . The sensitivity of this approach is discussed in detail separately. (See "Evaluation of the endometrium for malignant or premalignant disease").

Transvaginal ultrasound is less useful for evaluating the endometrium of premenopausal women, since these women normally have a thick endometrium.

We prefer endometrial biopsy to ultrasound examination as the initial test for women with abnormal uterine bleeding. For those postmenopausal women who are initially evaluated by transvaginal ultrasound examination and found to have a thin endometrium, persistent bleeding in the setting of normal sonographic findings requires further evaluation by endometrial sampling or hysteroscopy with directed biopsy.

SonohysterographySonohysterography involves placement of fluid within the endometrial cavity to enhance examination of the endometrial lining. It helps to identify women with focal abnormalities best biopsied under direct hysteroscopic visualization from those with global abnormalities that can be sampled blindly. (See "Saline infusion sonohysterography" and see "Evaluation of the endometrium for malignant or premalignant disease").

SCREENING

General populationScreening women for endometrial cancer is generally not warranted, except those with HNPCC (see below). The American Cancer Society suggests that women at average or increased risk of developing endometrial cancer (except those with HNPCC) be informed about their risks of developing the disease, educated about its symptoms (especially any unexpected bleeding) at the onset of menopause, and strongly encouraged to report such symptoms to their health care provider promptly [109] . This approach was based on expert opinion, there was insufficient evidence from high quality studies to recommend for or against screening asymptomatic women.

A good screening test should be sensitive early in the disease, when the subsequent course can still be altered, and should also have a high specificity to reduce the number of individuals with false-positive results who require diagnostic evaluation. Since endometrial cancer commonly causes abnormal uterine bleeding, most cases will be detected early without screening. Seventy-two percent of women with endometrial cancer are diagnosed while in stage I [104] .

Furthermore, a good, inexpensive, noninvasive screening test is not currently available. As discussed above, the sensitivity of cervical cytology for detection of endometrial cancer is low and not sufficient to recommend it as a screening tool [109-111] . The sensitivity of conventional Pap smear is 40 to 55 percent; the sensitivity of liquid based preparations is higher, 60 to 65 percent [112,113] .

Endometrial biopsy is a sensitive diagnostic test that could also be used for screening, but it is uncomfortable, invasive, and the potential for yielding insufficient tissue for diagnosis is high.

The thickness of the endometrium on transvaginal sonography is also a sensitive test for detecting endometrial cancer; however, sensitivity is estimated to be 20 percent lower in asymptomatic compared to symptomatic women and specificity is low (the false positive rate is high), thus many women would end up needing an endometrial biopsy.

These issues are discussed in detail elsewhere. (See "Evaluation of the endometrium for malignant or premalignant disease", section on Asymptomatic women).

Women on tamoxifenThere are no evidence-based recommendations for uterine cancer screening in women taking tamoxifen. This topic is discussed in detail separately. (See "Use of selective estrogen receptor modulators in postmenopausal women", section on Screening for uterine tumors).

Women at risk of HNPCCWomen who are at risk of HNPCC are at high risk (40 to 60 percent) of developing endometrial cancer. In fact, the risk of developing endometrial cancer may be slightly higher than the risk of developing colon cancer and endometrial cancer may be the first manifestation of malignancy [114] . These women also have a 12 percent lifetime risk of developing ovarian cancer [115] .

Because of the high risk for development of endometrial cancer in women with or at risk of HNPCC, the American Cancer Society recommends that annual screening by endometrial biopsy be initiated by age 35 [116] . These recommendations cover the following: Women who are known to carry HNPCC-associated mutations Women who have a family member known to carry this mutation Women from families with an autosomal dominant predisposition to colon cancer in the absence of genetic testing

At present, there are no data regarding the efficacy of this approach, nor is there a consensus on the optimal age (25 to 35) to begin screening. Annual or biennial pelvic ultrasonography is not effective for early detection of endometrial cancer in these populations [117] . (See "Screening and management strategies for patients and families with familial colon cancer syndromes").

These women should also be counseled about preventive measures, such as the option of prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy at completion of childbearing, which appears to be an effective preventive intervention [118-120] . There are no randomized trials comparing outcomes of the different approaches to prevention and risk-reduction. (See "Risk reducing salpingo-oophorectomy in women at high risk of epithelial ovarian cancer", section on Concurrent hysterectomy).

Screening for HNPCC in women with endometrial cancerA separate but related issue is the selection of women with endometrial cancer who warrant genetic testing for mismatch repair gene mutational analysis. Women at highest risk are those with endometrial cancer diagnosed before the age of 50 and at least one first-degree relative with an HNPCC-related cancer. Twenty to 40 percent of such women have a gene mutation identified [53,121] . This topic is discussed in detail elsewhere. (See "Molecular genetics of colorectal cancer", section on Mismatch repair genes).

Obese womenA decision analysis based on a United States national cancer database calculated that routine screening with endometrial biopsy (performed annually or biannually starting at age 30) is not a cost-effective strategy in obese women [35] .

INFORMATION FOR PATIENTSEducational materials on this topic are available for patients. (See "Patient information: Endometrial cancer diagnosis and staging" and see "Patient information: Endometrial cancer treatment"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS Two types of endometrial cancer exist, each has its own risk factors and prognosis. Type I (endometrioid tumors) accounts for 80 percent of cases and is estrogen-related; whereas type II (papillary serous or clear cell tumors) accounts for 20 percent of cases is unrelated to estrogen stimulation. (See "Introduction" above). Risk factors only help to identify women at risk for type I endometrial cancer, which is the more common type. Excessive exposure to estrogen, either from exogenous or endogenous sources, in the absence of adequate exposure to progestins is a major risk factor. Women with conditions associated with long-term exposure to excessive estrogen are at increased risk of developing endometrial cancer. These conditions include: tamoxifen use, obesity, type 2 diabetes, and anovulation. Use of oral contraceptives decreases risk. (See "Risk factors" above). The cardinal symptom of endometrial carcinoma is abnormal uterine bleeding, which occurs in 90 percent of cases. Even one drop of blood in a postmenopausal woman not on hormone replacement is an indication for diagnostic testing to exclude endometrial cancer. The probability of cancer increases with the number of years beyond menopause. Nevertheless, most postmenopausal women with uterine bleeding do not have endometrial cancer.

Pre- and peri-menopausal women with abnormal uterine bleeding should also be evaluated for endometrial cancer if they have other risk factors, such as family or personal history of ovarian, breast, colon, or endometrial cancer; tamoxifen use; chronic anovulation; obesity; estrogen therapy; prior endometrial hyperplasia; or diabetes mellitus. (See "Clinical presentation" above). We suggest endometrial biopsy as the initial diagnostic test to rule out endometrial cancer. If the specimen is negative for malignancy but there remains a high suspicion of cancer (eg, hyperplasia with atypia, necrosis, pyometra, or persistent bleeding), we perform hysteroscopy with directed biopsy and curettage. (See "Diagnosis" above). We suggest not screening the general population (pre- or post-menopausal women) for endometrial cancer (Grade 2C). (See "General population" above). Women who are at risk of hereditary nonpolyposis colorectal cancer (HNPCC) are at high risk (40 to 60 percent) of developing endometrial cancer and endometrial cancer may be their first manifestation of malignancy. For such women who wish to maintain their potential for childbearing, we suggest annual screening for endometrial cancer (Grade 2C). Screening should be started by age 35, and can be initiated as early as age 25. For those who have completed childbearing, we suggest total abdominal hysterectomy and bilateral salpingo-oophorectomy (Grade 2C). (See "Screening for HNPCC in women with endometrial cancer" above and see "Women at risk of HNPCC" above).

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