Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening

INTRODUCTION — Uterine cancer is the most common gynecologic malignancy in high-income countries and the second most common in low- and middle-income countries (cervical cancer is more common). Adenocarcinoma of the endometrium (lining of the uterus) is the most common histologic site and type of uterine cancer (picture 1).

Abnormal uterine bleeding is the cardinal symptom of endometrial cancer. A minority of patients present with abnormal findings on cervical cytology. Most patients are diagnosed when disease is still confined to the uterus and thus have a greater than 90 percent five-year survival rate.

The clinical features, diagnosis, and prognosis of patients with endometrial cancer will be reviewed here. Issues related to screening will also be discussed. Other important issues are discussed in detail separately, including:

●Epidemiology and risk factors (see "Endometrial carcinoma: Epidemiology, risk factors, and prevention")

●Histopathology and pathogenesis (see "Endometrial cancer: Pathology and classification")

●Staging and surgical treatment (see "Endometrial carcinoma: Staging and surgical treatment")

●Medical therapy (see "Overview of resectable endometrial carcinoma", section on 'Role of adjuvant therapy' and "Treatment of low-risk endometrial cancer" and "Adjuvant treatment of high-risk endometrial cancers" and "Adjuvant treatment of intermediate-risk endometrial cancer" and "Management of locoregional recurrence of endometrial cancer")

●Posttreatment issues and surveillance (see "Overview of approach to endometrial cancer survivors")

CLINICAL PRESENTATION

Abnormal uterine bleeding — Endometrial carcinoma typically presents with abnormal uterine bleeding (AUB), which is present in 75 to 90 percent of cases [1-3]. The amount of AUB does not correlate well with the risk of endometrial cancer; however, in patients with AUB, age and risk factors affect the likelihood of the disease. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)

●Most cases of endometrial cancer occur in patients ≥55 years of age. In a meta-analysis of observational studies, the pooled prevalence of postmenopausal bleeding among patients with endometrial cancer was 91 percent (95% CI 87-93), irrespective of tumor stage [4]. The pooled risk of endometrial cancer among patients with postmenopausal bleeding was 9 percent (95% CI 8-11), with estimates varying by use of hormone therapy (risk range 7-12 percent) and geographic region (risk 5 percent in North America to 13 percent in Western Europe).

●The risk of cancer is less in premenopausal patients with AUB, although patients ages 45 to 54 account for 17 percent of endometrial cancer cases and patients ages 35 to 44 account for 5 percent of cases.

•In patients age 45 to menopause, bleeding may be intermenstrual, frequent (interval between the onset of bleeding episodes is less than 21 days), heavy (total volume of >80 mL), or prolonged (longer than 7 days). In addition, they may have prolonged periods of amenorrhea (six or more months) due to anovulation.

•In patients younger than age 45, AUB tends to be persistent and occurs in the setting of a history of unopposed estrogen exposure (obesity, chronic anovulation), failed medical management of the bleeding, or in patients at high risk of endometrial cancer (eg, Lynch syndrome) (table 1).

The diagnostic evaluation of patients with AUB, which may lead to a diagnosis of endometrial cancer, is reviewed in detail separately (see "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Approach to the patient with postmenopausal uterine bleeding", section on 'Initial evaluation'). The differential diagnosis of AUB is also discussed separately. (See "Causes of female genital tract bleeding".)

Abnormal cervical cytology — Patients with endometrial cancer may present with abnormal cytologic findings on cervical cancer screening. These findings may include endometrial cells (reported in the results in patients ≥40 years of age), atypical glandular cells, or adenocarcinoma (which may be endocervical or endometrial). The sensitivity of conventional Pap smear for endometrial carcinoma is 40 to 55 percent; the sensitivity of liquid-based preparations is higher at 60 to 65 percent [5-7].

The diagnostic evaluation of patients with abnormal cervical cytology, which may lead to a diagnosis of endometrial cancer, is reviewed in detail separately. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells" and "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Benign-appearing endometrial cells'.)

Incidental finding on imaging — A thickened endometrial lining is sometimes found incidentally on ultrasound, computed tomography (CT), or magnetic resonance imaging performed for another indication (eg, abdominal CT in a patient undergoing diagnostic evaluation of acute diverticulitis).

The diagnostic evaluation of asymptomatic patients with a thickened endometrium, which may lead to a diagnosis of endometrial cancer, is reviewed in detail separately. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Incidental finding on TVUS for another indication'.)

Incidental finding after hysterectomy or during abdominopelvic surgery — Endometrial carcinoma is sometimes discovered incidentally when hysterectomy is performed for benign disease. To minimize this occurrence and optimize the surgical procedure performed, all patients with AUB undergoing hysterectomy should have endometrial sampling, and the results should be available before surgery.

In a database study including nearly 230,000 patients who underwent a hysterectomy for benign indications, 0.96 percent (95% CI 0.92-1.00) had occult uterine cancer of which 75 percent were endometrial carcinoma and 22 percent were sarcoma [8]. The risk for occult uterine cancer was low (0.10 percent) in patients 18 to 29 years old and much higher (4.40 percent) in patients ≥75 years old. The risk of occult uterine cancer was significantly associated with race/ethnicity, obesity, comorbidity, personal history of malignancy, and reason for hysterectomy (risk in hysterectomy because of endometriosis, fibroids, postmenopausal bleeding: 0.14, 0.62, and 8.43 percent, respectively).

If abdominopelvic metastases are encountered intraoperatively, management depends upon the experience of the surgeon. Intraoperative consultation from a gynecologic oncologist should be requested, if available, as staging procedures performed by a gynecologic oncologist appear to lead to better patient outcomes [9]. If a gynecologic oncologist is not available and the surgeon is not experienced in operative management of the cancer (eg, lymphadenectomy), we suggest terminating surgery and arranging for prompt postoperative consultation with a specialist to plan a second procedure. (See "Overview of resectable endometrial carcinoma", section on 'Epidemiology'.)

CLINICAL FINDINGS

Physical examination — Pelvic examination is usually normal in patients with early-stage endometrial carcinoma since they do not typically have an enlarged or tender uterus. In more advanced disease, the uterus may be enlarged and/or fixed.

Laboratory — Laboratory results are usually normal, except in patients with substantial abnormal uterine bleeding, who may be anemic.

Ultrasound — In postmenopausal patients, the risk of cancer increases relative to benign disease as the endometrial thickness approaches 20 mm on transvaginal ultrasound (endometrial thickness <4 mm is associated with a low risk of endometrial disease). In premenopausal patients, endometrial thickness does not correlate with risk of cancer. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Transvaginal ultrasound'.)

DIAGNOSIS

Tissue sampling for histopathology — Endometrial carcinoma is a histologic diagnosis, based upon characteristic findings on an endometrial biopsy, curettage, or hysterectomy specimen. (See "Endometrial cancer: Pathology and classification", section on 'Classification' and "Endometrial carcinoma: Staging and surgical treatment", section on 'Staging system'.)

Blind endometrial biopsy is generally sufficient as the initial diagnostic procedure but is most reliable when at least 50 percent of the endometrium is affected by the disease. The sensitivity for endometrial sampling is 90 percent or higher. Risk factors for false-negative endometrial sampling include a personal history of colorectal cancer, endometrial polyps, and class II obesity (ie, body mass index [BMI] ≥35 kg/m²) [10]. A biopsy result of endometrial hyperplasia with atypia (also referred to as endometrial intraepithelial neoplasia [EIN]) may also harbor an underlying endometrial cancer. Hysteroscopy with targeted biopsy is likely to detect focal lesions missed by blind biopsy but requires more skill and is more costly and invasive. These issues are discussed in detail separately. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Natural history' and "Endometrial sampling procedures".)

Dilation and curettage (D&C), with or without hysteroscopy, is a reasonable initial procedure in some patients, such as those who cannot tolerate an office biopsy or in whom the office procedure is unsuccessful, those with heavy bleeding (D&C is both a diagnostic and therapeutic procedure), and those at very high risk of endometrial cancer (eg, patients with Lynch syndrome).

Approach to patients with nondiagnostic histopathology — In patients in whom endometrial carcinoma is suspected but blind endometrial biopsy shows insufficient endometrial cells for diagnosis, we may repeat the office biopsy but often move on to hysteroscopy and D&C as the next step. Cervical stenosis, a common cause of an unsuccessful biopsy, can be managed with preprocedure cervical preparation or dilation. Ultrasound guidance may be useful to aid endometrial sampling as well. (See "Endometrial sampling procedures", section on 'Cervical preparation and dilation'.)

Approach to selected patients with benign histopathology — In patients in whom endometrial carcinoma is suspected because of persistent or recurrent abnormal uterine bleeding despite endometrial sampling with benign findings, further evaluation for cancer is required if another etiology for the bleeding was not established. In our practice, we reevaluate such cases after three to six months. Transvaginal ultrasound, sonohysterography, or diagnostic hysteroscopy are performed to exclude structural lesions (leiomyomas, endometrial polyp). (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

In addition, it is essential to repeat endometrial sampling to exclude endometrial hyperplasia or carcinoma, especially in patients with risk factors for malignancy. Reported rates of endometrial neoplasia in patients evaluated for persistent or recurrent postmenopausal bleeding vary widely, from 4 to 21 percent [11,12].

POST-DIAGNOSTIC MANAGEMENT

Postmenopausal patients not on hormone therapy — Development of endometrial carcinoma in postmenopausal patients requires assessment of endogenous and exogenous sources of estrogen since unopposed estrogen is a risk factor for the disease. In the absence of common sources of estrogen (eg, estrogen therapy, obesity, selective estrogenic receptor modulators, or some herbs), the possibility of an estrogen-producing tumor (eg, sex cord-stromal) should be considered, and a pelvic ultrasound or other imaging study is appropriate to assess for an adnexal mass.

Testing for Lynch syndrome — Lynch syndrome is a genetic syndrome that includes increased risk for endometrial cancer. The National Comprehensive Cancer Network recommends universal mismatch repair protein testing or microsatellite instability testing of endometrial carcinomas. The American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncology concur with this strategy for genetic assessment for Lynch syndrome in patients diagnosed with endometrial cancer but also attempt to identify at-risk patients based on a personal or family history of Lynch syndrome-associated cancers [13-16]. Although lower uterine segment tumors account for a small proportion of Lynch-associated endometrial cancers, patients with Lynch syndrome have a higher proportion of tumors in this location than other endometrial cancer patients; therefore, a finding of tumor at this site should also prompt risk assessment for Lynch syndrome [17].

Testing for Lynch syndrome based on history and/or immunohistochemistry of the uterine tumor for loss of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) is discussed in detail separately. Multiple patterns have been detected, including deficiencies of both MLH1 and PMS2, both MSH6 and PMS2, isolated MSH6 loss, and isolated MSH2 loss. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Identification of individuals at risk for Lynch syndrome'.)

Staging and treatment — Patients with endometrial carcinoma should undergo staging and treatment, as appropriate.

●(See "Overview of resectable endometrial carcinoma".)

●(See "Endometrial carcinoma: Staging and surgical treatment".)

●(See "Treatment of low-risk endometrial cancer".)

●(See "Adjuvant treatment of intermediate-risk endometrial cancer".)

●(See "Adjuvant treatment of high-risk endometrial cancers".)

It should be noted that an endometrial tumor may be undergraded when grading is based on sampling procedures rather than hysterectomy [18,19]. A higher grade may be assigned in as many as 30 percent of cases when the hysterectomy specimen is reviewed. The grade assigned by the endometrial sample alone is important mainly for patients who are incompletely surgically staged or inoperable.

PROGNOSIS — The prognosis of endometrial carcinoma is determined primarily by disease stage, grade, and histology (table 2 and table 3) [20]. Most patients with endometrial carcinoma have a favorable prognosis since the majority of patients have endometrioid histology and present with early-stage disease. Survival rates by stage are presented in the graphic (figure 1).

Prognostic factors, including molecular prognostic factors, are discussed in detail separately. (See "Overview of resectable endometrial carcinoma", section on 'Prognostic factors'.)

SCREENING

General recommendations — In most patients, including those on tamoxifen without vaginal bleeding, we suggest not screening for endometrial carcinoma with imaging, tissue sampling, or cervical cytology as no high-quality data support the efficacy of such screening for reducing endometrial cancer mortality (all patients should be asked about and told to report abnormal uterine bleeding [AUB]). However, patients with Lynch syndrome (hereditary nonpolyposis colon cancer) have a markedly increased risk of endometrial cancer; thus, such patients should be counseled about screening and risk-reducing hysterectomy. (See 'Patients with Lynch syndrome' below.)

Our recommendation is consistent with advice from the American Cancer Society, which suggests informing patients at average or increased risk of developing endometrial cancer (except those with Lynch syndrome) about their risks of developing the disease, educating them about its symptoms (especially any unexpected bleeding) at the onset of menopause, and strongly encouraging them to report such symptoms to their health care provider promptly [21].

Endometrial carcinoma has several characteristics that inform the recommendation against routine screening. As noted above, 75 to 90 percent of patients with endometrial carcinoma are symptomatic (ie, they present with AUB) [1-3]. The presence of a common, bothersome symptom when the disease is often still confined to the uterus and the availability of effective therapy results in high survival rates without screening.

Furthermore, no noninvasive test for endometrial cancer is sufficiently sensitive and specific for screening. The sensitivity of conventional Pap smear for endometrial carcinoma is 40 to 55 percent, and the sensitivity of liquid-based preparations is 60 to 65 percent [5-7]. The thickness of the endometrium on transvaginal sonography is a sensitive test for detecting endometrial cancer in postmenopausal patients; however, sensitivity is estimated to be 20 percent lower in asymptomatic compared with symptomatic patients, and specificity is low (the false-positive rate is high); thus, many patients would end up needing an endometrial biopsy. The use of serum biomarkers or epigenetic testing for endometrial cancer is under investigation [22-24]. Endometrial biopsy is a sensitive and specific test, but it is invasive and uncomfortable. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Transvaginal ultrasound'.)

Patients with Lynch syndrome — Patients with Lynch syndrome have a lifetime risk of endometrial cancer of 13 to 71 percent, compared with 3 percent in the general population. Strategies for screening and prevention of endometrial cancer in these patients include endometrial sampling and risk-reducing hysterectomy. Screening for endometrial cancer in patients with Lynch syndrome is discussed separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)

Patients with Cowden syndrome — Cowden syndrome is a rare autosomal dominant syndrome that derives from a mutation in the PTEN tumor suppressor gene. Patients with Cowden syndrome have a lifetime risk of endometrial cancer of 13 to 28 percent [25-28]. There are no established guidelines for endometrial screening or prevention for Cowden syndrome [29]. Potential strategies include endometrial sampling and risk-reducing hysterectomy on completion of childbearing, similar to Lynch syndrome.

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: Uterine cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Uterine cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Endometrial cancer diagnosis, staging, and surgical treatment (Beyond the Basics)" and "Patient education: Endometrial cancer treatment after surgery (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation

•Endometrial carcinoma typically presents with abnormal uterine bleeding (AUB). Other presentations include abnormal cervical cytology findings on cervical cancer screening, abnormal findings on imaging, or discovered incidentally when hysterectomy is performed for benign disease. (See 'Clinical presentation' above.)

•While approximately 91 percent of postmenopausal patients with endometrial cancer will present with AUB, the overall risk of endometrial cancer among postmenopausal patients with AUB is approximately 9 percent; estimates vary by use of hormone therapy and geographic region. (See 'Abnormal uterine bleeding' above.)

●Clinical findings – Pelvic examination is usually normal in patients with early-stage disease. In more advanced disease, the uterus may be enlarged and/or fixed in the pelvis. In postmenopausal patients, uterine imaging may show a thickened endometrium. (See 'Clinical findings' above.)

●Diagnosis

•Endometrial carcinoma is a histologic diagnosis based upon the results of evaluation of an endometrial biopsy, curettage sample, or hysterectomy specimen. (See 'Tissue sampling for histopathology' above.)

•In patients with AUB in whom endometrial carcinoma is suspected but blind endometrial biopsy showed insufficient endometrial cells for diagnosis, we suggest hysteroscopy and dilation and curettage as the next step in the diagnostic evaluation. (See 'Approach to patients with nondiagnostic histopathology' above.)

•In patients with persistent or recurrent AUB and benign findings on initial endometrial sampling, further evaluation for cancer is required if another etiology for the bleeding was not established. In our practice, we reevaluate these patients after three to six months. Transvaginal ultrasound, sonohysterography, or diagnostic hysteroscopy is performed to exclude structural lesions (leiomyomas, endometrial polyp). In addition, it is essential to repeat endometrial sampling to exclude endometrial hyperplasia or carcinoma, especially in patients with risk factors for malignancy. Reported rates of endometrial neoplasia in patients evaluated for persistent or recurrent postmenopausal bleeding vary widely, from 4 to 21 percent. (See 'Approach to selected patients with benign histopathology' above.)

●Sources of estrogen – In postmenopausal patients, development of endometrial carcinoma requires assessment of endogenous and exogenous sources of estrogen. In the absence of common sources of estrogen (eg, estrogen therapy, obesity, selective estrogenic receptor modulators, or some herbs), such patients should be evaluated with pelvic ultrasound or other imaging for an adnexal mass, which could be an estrogen-producing sex cord-stromal tumor of the ovary. (See 'Postmenopausal patients not on hormone therapy' above.)

●Prognosis – Most patients with endometrial carcinoma have a favorable prognosis (figure 1). Prognosis is determined primarily by disease stage, grade, histology, and molecular classification (if known) (table 2 and table 3). (See 'Prognosis' above.)

●Screening – For most patients, we suggest not performing screening tests (eg, imaging, tissue sampling, cervical cytology) for endometrial carcinoma (Grade 2C); all patients should be asked about and told to report AUB. The exception is patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer) and Cowden syndrome who have a lifetime risk of endometrial cancer between 13 and 71 percent compared with 3 percent in the general population. Strategies for screening and prevention of endometrial cancer in these patients include endometrial sampling and risk-reducing hysterectomy. (See 'Screening' above and 'Patients with Lynch syndrome' above and 'Patients with Cowden syndrome' above.)