Endometrial Carcinoma

Corpus cancer is the most frequently occurring female genital cancer. In developed countries, adenocarcinoma of the endometrium is the most common gynecological cancer; however, in developing countries, it is much less common than carcinoma of the cervix.

Approximately 63,230 new US cases of endometrial cancer are expected to have been diagnosed in 2018 (3.6% of all new US cancer cases); of these women, approximately 11,350 will die from this disease (1.9% of all cancer deaths).[2]  In the early part of the 20th century, cancer of the cervix killed more US women than any other cancer, but in the ensuing decades, the incidence for uterine cervical malignancy decreased precipitously. This decrease has been credited to the impact of screening with the Papanicolaou test (Pap smear). In less-developed countries, screening for cervical cancer is performed very infrequently, and therefore, cancer of the cervix is quite prevalent.

For patient education resources, see the Women's Health Center and Cancer Center, as well as Vaginal Bleeding and Cervical Cancer.

Multiple epidemiological risk factors have been identified in patients who have adenocarcinoma of the endometrium.

Endogenous factors

Obesity

Nulliparity

An individual who has had a late menopause (aged >52 y)

Unopposed estrogen

Unopposed estrogen, either as replacement therapy or endogenously produced (eg, granulosa cell tumor, polycystic ovarian disease), increases the risk of endometrial cancer.

Obesity is known to increase endogenous estrogen because the presence of fat appears to be responsible for the conversion of androstenedione to estrogen compounds at a much higher rate than if fat is not present.

Anovulation, which may be secondary to unopposed estrogen, also appears to contribute to this situation.

Tamoxifen

The most widely used anticancer drug is tamoxifen, and this drug has been suggested by some studies to cause an increased incidence of adenocarcinoma of the endometrium. These data were derived from retrospective analyses in which adenocarcinoma of the endometrium was not an end point in multiple prospective randomized studies evaluating the role of tamoxifen in patients with breast cancer. [3]

A case control study using the SEER database indicates that when confounding factors have been corrected, the risk of endometrial cancer does not appear to be increased in patients taking tamoxifen.[4]  This study is very reassuring because the potential for an increased number of women taking tamoxifen is becoming apparent, particularly as the prophylactic role of tamoxifen has been recommended for high-risk women.

Combination oral contraceptives

In contrast to tamoxifen, increasing data indicate that the use of combination oral contraceptives (OCs) decreases the risk of developing endometrial cancer.

Several studies have noted that women who use OCs at some time have a 0.5 relative risk of developing endometrial cancer compared with women who have never used OCs. This protection occurs in women who have used OCs for at least 12 months, and the protection continues for at least 10 years after OC use. Protection is most notable for nulliparous women.

Cigarette smoking

Smoking apparently decreases the risk of developing endometrial cancer. The effects of smoking are related to body weight. Heavier women who smoke have the greatest reduction in risk.

Women who smoke are known to undergo menopause 1-2 years earlier than women who do not smoke.

Although smoking apparently reduces the risk of developing early stages of endometrial cancer, this advantage is strongly outweighed by the increased risk of lung cancer and other major health problems associated with smoking.

Associated medical conditions

Some associated medical conditions have been found to increase the incidence of endometrial cancer. Breast, colon, and ovarian cancers are frequently observed in women with endometrial cancer.

Data suggest that women who have had breast cancer have a 2- to 3-fold increased risk of subsequently developing endometrial cancer.

Women who have hereditary nonpolyposis colon cancer (HNPCC) appear to have a markedly increased risk for developing endometrial cancer. Women with HNPCC account for only 2-10% of all female cases of colon cancer, but approximately 5% of all endometrial cancers occur in women with this risk factor. These women have a 27-60% lifetime risk of developing endometrial cancer, and the disease tends to occur at a younger age (46-54yo). The greatest risk of developing endometrial cancer in women with HNPCC occurs from age 40-60 years, at which time the absolute risk is greater than 1% per y.

Currently, no data indicate that annual screening of women with HNPCC will detect endometrial cancer at a sufficiently early stage to improve survival compared with those whose diagnosis is made when symptoms appear. Nevertheless, because of the high risk of endometrial cancer in these individuals and because of the potential life-threatening nature of this disease, HNPCC patients should be so informed and screening is certainly suggested. According to American Cancer Society guidelines, women with HNPCC should be offered screening with an endometrial biopsy by age 35 years.

Bjorge et al found that metabolic syndrome is associated with an increased risk of endometrial carcinoma and fatal uterine corpus cancer. Particularly in women with a high body mass index, the association appears to go beyond the risk conferred by obesity alone.[5]

Family history

Individuals with a family history of endometrial cancer appear to be at increased risk.

Phenotype characteristics

At one time, a classic phenotypic characteristic was thought to exist for a woman who would develop endometrial cancer. This phenotype included patients who were obese, nulliparous, and anovulatory in many instances. More recently, the existence of 2 pathogenic types of endometrial cancer was appreciated.

The first type occurs in women who fall into the classic category. These women are obese and have hyperlipidemia, signs of hyperestrogenism, uterine bleeding, infertility, and late onset of menopause. They may have hyperplasia of the ovary and endometrium. These patients tend to be white, obese, nulliparous, and have well-differentiated superficially invasive cancers that are sensitive to progesterone. They have a very favorable prognosis, and extrauterine disease is unusual in this group of patients. Fortunately, most women with endometrial cancer are in this category.

The second type occurs in women who have none of the disease states present in the classic presentation. These individuals tend to have poorly differentiated tumors, deep myometrial invasion, a high degree of metastasis to the lymph nodes and other sites, decreased sensitivity to progestins, and a poor prognosis. These patients tend to be thin, multiparous, and African American.

United States statistics

The most recent Surveillance, Epidemiology, and End Results (SEER) data are from 2011-2015 cases, which reveal a total age-adjusted incidence of 26 cases per 100,000 women.[2]  The incidence in white women is 26.6 cases per 100,000 compared to the incidence in black women which is 25.4 cases per 100,000.[2]

Race- and age-related demographics

Mortality is higher in black women (8.3 deaths per 100,000) than in white women (4.3 deaths per 100,000). Asian/Pacific Islander women have the lowest mortality (2.9% deaths per 100,000) among all races.

Endometrial adenocarcinoma occurs during the reproductive and menopausal years. The median age of women with this malignancy is 62 years; most patients are aged 55-64 years.[2]  

Approximately 63,230 new US cases of endometrial cancer are expected to have been diagnosed in 2018 (3.6% of all new US cancer cases); of these women, approximately 11,350 will die from this disease (1.9% of all cancer deaths).[2]  On the basis 2013-2015 data, an estimated 2.9% of women will be diagnosed with endometrial cancer in their lifetime.[2]

Multiple prognostic factors exist for endometrial cancer. These prognostic factors generally are related to surgical pathologic findings. As in all cancers, the stage of the disease is the most important prognostic factor. Obviously, the surgical procedure helps determine the stage. Listed below are prognostic factors that may relate specifically to the stage of the disease and, thereby, may affect overall survival.

Prognostic factors - histopathologic subtypes

Most endometrial carcinomas are endometrioid adenocarcinomas. Adenoacanthomas (benign squamous components) and adenosquamous carcinoma (malignant squamous components) make up the next largest category.

Clear cell and papillary serous adenocarcinomas represent approximately 10% of all endometrial cancers and are considered to be poor histopathologic subtypes. These latter subtypes tend to have deeply invasive myometrial involvement, and they have a propensity for extrauterine spread, even though the myometrium may be superficially involved.

Previously, a patient with an adenosquamous carcinoma was thought to have a poor prognostic histotype because of the malignant squamous component.

Contemporary data suggest that irrespective of whether a squamous component is present (either benign or malignant), prognosis is related directly to the grade of the adeno component and not the fact that a squamous malignancy is present. If a malignant squamous component is present, a greater tendency exists for a more poorly differentiated adeno component to be present.

More recently, considerable evidence suggests that carcinosarcomas (CS) are not true sarcomas, as it appears they are derived from an epithelial origin. As a result CSs are now considered as a subset of endometrial cancers (type 2).[6]

Histologic differentiation

The degree of histologic differentiation of endometrial cancer has long been accepted as a sensitive indicator of prognosis. Patients with well-differentiated adenocarcinomas tend to have involvement of the endometrium or superficial myometrium, and extrauterine disease is unusual.

However, if a poorly differentiated lesion is present, these cancers tend to be much more aggressive, involving significant myometrial invasion, and often have extrauterine metastasis, either with positive peritoneal cytology, retroperitoneal spread, or involvement of the pelvic and/or para-aortic lymph nodes.

Because papillary and clear cell carcinomas are associated with a relatively poor prognosis, these subtypes are not usually graded but are considered in the same category as a poorly differentiated cancer.

Myometrial invasion

The degree of myometrial invasion continues to be a consistent indication of tumor virulence. As the depth of myometrial invasion increases, the chance of having extrauterine disease is greater.

As noted above, grade and depth of invasion, as a generalization, are interrelated. As the grade of the tumor increases, an increase usually occurs in the depth of myometrial invasion; however, exceptions exist in that a grade 1 lesion can have deep myometrial invasion and a grade 3 lesion can be limited to the endometrium.

When grade and depth of invasion are evaluated separately, the depth of invasion appears to be a more important prognostic factor than the grade of the tumor.

Peritoneal cytology

Cytologic evaluation of the peritoneum appears to be an important prognostic factor. Although no universal agreement has been reached about the significance of cytologic evaluation findings, the vast majority of data in the literature suggest that they represent an independent prognostic factor.

Cytologic evaluation findings also appear to correlate with other prognostic factors, such as depth of myometrial invasion and lymph node metastasis.

The FIGO staging system states that positive cytology should be reported separately without changing the stage. If ascitic fluid is not present at the time of the exploratory laparotomy, a saline lavage of the pelvis and lower abdomen is performed and the specimen is submitted for cytologic evaluation.

Lymph node metastasis

A considerable number of patients who were thought to have clinical stage I endometrial cancer were, in fact, found to have lymph node metastasis when histopathologic evaluation was performed on the lymph nodes.

Again, a correlation among multiple prognostic factors has been shown to be present. Patients with poorly differentiated cancers, papillary serous and clear cell carcinomas, deep myometrial invasion, positive peritoneal cytology, or adnexal metastasis tend to have an increased risk of having lymph node metastasis.

Subsequent therapy after primary surgery depends on prognostic factors and spread of the disease. If the disease is limited to the uterus, surgery appears to be adequate treatment, with the possible exception of patients who have poorly differentiated deeply invasive myometrium. In these patients, data suggest that, possibly, postoperative irradiation may be of benefit. In patients who have disease outside of the uterus, radiation therapy may be effective; however, this has not been evaluated in a prospective randomized study. Most investigators irradiate the appropriate area if lymph node metastasis is present.

In patients with advanced disease (ie, intraperitoneal disease, disease outside of the peritoneal cavity), systemic chemotherapy may be of benefit. Studies suggest that carboplatin and paclitaxel are the drugs of choice when systemic chemotherapy is needed.

According to the SEER database, the 5-year survival rate for Uterine Cancer from 2008-20014 was 81.1%. The survival by stage for Uterine Cancer from 2008-2014 was[7] :

• Localized (comprises 67% of cases)- confined to Primary site:  94.9% 5-year relative survival
• Regional (comprises 21% of cases)- spread to regional lymph nodes: 68.6% 5-year relative survival
• Distant (comprises 9% of cases)- cancer has metastasized: 16.3% 5-year relative survival
• Unknown (comprises 3% of cases)- unstaged: 52% 5-year relative survival

Increasingly, data suggest that lymphvascular space involvement in the myometrium predicts extant disease and a poor prognosis. Whether the poor prognosis remains when other prognostic factors are evaluated is less well defined.

L1CAM

A study found expression of the cell adhesion molecule L1CAM in early stage endometrial tumors to be a strong predictor of cancer recurrence. In a retrospective analysis of L1CAM expression in 1021 paraffin-embedded specimens of stage I, type I endometrial cancer, researchers found that 17.7% of the specimens were positive for L1CAM and that during a median follow-up of 5.3 years, recurrence rates were 51.4% among the L1CAM-positive cases, compared with just 2.9% among L1CAM-negative cases. Median overall survival was 8.9 years in patients with L1CAM-positve tumors, whereas median survival had not been reached in the L1CAM-negative patients.[8, 9]

In the study, L1CAM had sensitivities of 0.74 for recurrence and 0.77 for death, and specificities of 0.91 and 0.89, respectively. These data suggest that L1CAM is the best prognostic factor in stage I, type I endometrial cancer so far published.

Complications

Complications that may occur from therapy include complications that are normally expected from the surgical procedure itself. Because a lymphadenectomy is performed, increased bleeding could develop; however, unique complications from the procedure do not usually occur.

Postoperative complications can be expected, depending on the preoperative clinical condition of the patient. As noted previously (see Causes), many of these patients have comorbidities such as hypertension, obesity, diabetes, and increased age.

One postoperative complication that may be somewhat more common is thromboembolism because this is increased in patients who have cancer, are obese, and are older. In current practice, most physicians use some type of prophylaxis, either external pneumatic compression, low-dose heparin or a combination of the two.

Postmenopausal period

Because approximately 75% of women with endometrial cancer are postmenopausal, the most common symptom is postmenopausal bleeding.

Investigate all bleeding during menopause unless the patient is on cyclic replacement therapy with normally anticipated withdrawal bleeding. The duration or amount (staining vs gross) of bleeding does not make any difference.

The fact that only approximately 20% of postmenopausal bleeding is due to cancer is appreciated, but obviously, the diagnosis must be eliminated in these patients.

Perimenopausal/premenopausal period

Because 25% of endometrial cancers are in patients who are perimenopausal or premenopausal, symptoms suggestive of cancer may be more subtle. The idea that any type of bleeding during the perimenopausal period is probably due to menopause is a common misconception. This irregular bleeding is often ignored by the patient and even health care providers. Remember that the normal bleeding pattern during this time should become lighter and lighter and further and further apart. Heavy frequent menstrual periods or intermenstrual bleeding must be evaluated.

Because bleeding usually occurs from the endometrium, pelvic examination findings may be entirely normal, with no gross evidence of disease on the cervix and with a normal-sized uterus. Note the following:

• Bleeding leads to an evaluation of the endometrium. In the vast majority of cases, no gross evidence of disease is noted.

• The uterus may be of normal size upon pelvic examination.

• Cancer can be present upon cervical evaluation and, less frequently, in the upper vagina or periurethrally. In current practice, occult cervical involvement is very unusual, as is clinically evident metastasis, such as in the vagina.

Vaginal ultrasonography

Some investigators believe that this should be the first diagnostic procedure because vaginal ultrasonography is less invasive than endometrial biopsy.

One of the difficulties with using the endometrial stripe as a criterion for further diagnostic tests (eg, endometrial biopsy) is that several conditions may be present that yield a false reading on the endometrial stripe. This is particularly true in a patient who might have an endometrial polyp, is obese or diabetic, or who has been taking tamoxifen.

Hydroultrasonography

If a thickened endometrium is present, obtain a hydroultrasonogram to make sure a false-positive result is not present. This is accomplished by placing a small volume of saline into the endometrial cavity and then repeating the vaginal ultrasonogram.

Another problem that arises is that the thickness of the endometrium can vary considerably depending on different factors. The thickness of the endometrium depends on whether or not the patient is obese or diabetic, whether she is perimenopausal or postmenopausal (and for how long), whether she is taking hormone replacement therapy, and whether the therapy includes estrogen alone or estrogen plus progesterone. Currently, no generally accepted guidelines exist for each of these different clinical scenarios.

Biopsy

Endometrial biopsy

Although fractional dilatation and curettage was historically the definitive diagnostic procedure to help rule out endometrial cancer, in current practice endometrial biopsy as an office procedure is quick, well tolerated, and quite sensitive for making the diagnosis.

If endometrial pathology is not present on biopsy specimens and the patient has no further bleeding, no additional diagnostic tests need to be performed.

If the patient continues to be symptomatic, then further evaluation of the endometrial cavity is necessary.

Hysteroscopically directed biopsy

Another diagnostic procedure that has been advocated by some as an even more accurate way of determining the status of the endometrium is a hysteroscopically directed biopsy (see the video below); however, studies have shown that when results are compared with the histopathology, both false-positive and false-negatives results may be noted using this technique.

Dilatation and curettage

The current role of the formal dilatation and curettage is probably very limited because the diagnosis can usually be made in the office.

Examination with the patient under anesthesia

This may be necessary in patients who are bleeding and have a cervical os that is very stenotic. Anesthesia may be required to perform adequate dilatation for endometrial sampling.

Pathological diagnosis is obviously the criterion standard for evaluation of the endometrial cavity. A high index of suspicion must be maintained if a diagnosis of endometrial cancer is considered.

Endometrioid adenocarcinoma is the most common histopathologic subtype. A squamous component, either benign (adenocanthoma) or malignant (adenosquamous), does not affect prognosis, but the grade of the adeno component does affect prognosis. Papillary serous and clear cell histotypes confer a poor prognosis but, fortunately, are uncommon compared with adenocarcinoma. Secretory carcinomas are the least frequently occurring cancers and are associated with a good prognosis.

More recent data would suggest that mixed müllerian tumors originally thought to be a sarcoma are in actuality epithelial in origin and should be included here instead of as a primary sarcoma.

The International Federation of Gynecology and Obstetrics (FIGO), 2008 staging system for carcinoma of corpus uteri is as follows[12] :

• Stage IA* - No or less than half myometrial invasion

• Stage IB* - Invasion equal to or more than half of the myometrium

• Stage II* - Tumor invades cervical stroma but does not extend beyond the uterus**

• Stage III - Local and/or regional spread of the tumor

• Stage IIIA* - Tumor invades the serosa of the corpus uteri and/or adnexa†

• Stage IIIB* - Vaginal metastasis and/or parametrial involvement†

• Stage IIIC* - Metastases to pelvic and/or para-aortic lymph nodes

• Stage IIIC1* - Positive pelvic nodes

• Stage IIIC2* - Positive para-aortic lymph nodes with or without positive pelvic nodes

• Stage IV* - Tumor invasion of bladder and/or bowel mucosa and/or distant metastases

• Stage IVA* - Tumor invasion of bladder and/or bowel mucosa

• Stage IVB* - Distant metastases, including intra-abdominal and/or inguinal lymph node

Cases of carcinoma of the corpus should be classified (or graded) according to the degree of histologic differentiation. The histopathology and degree of differentiation is as follows:

• Class G1 - Nonsquamous or nonmorular solid growth pattern of 5% or less

• Class G2 - Nonsquamous or nonmorular solid growth pattern of 6-50%

• Class G3 - Nonsquamous or nonmorular solid growth pattern of more than 50%

* Either G1, G2, or G3.

** Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II.

† Positive cytology has to be reported separately without changing the stage.

Standard management of endometrial cancer at diagnosis involves surgery, followed by chemotherapy and/or radiation therapy.[1]  In the setting of recurrent disease, secondary cytoreduction has been associated with progression-free (PFS) and overall (OS) survival.[13] Prognostic factors for improved long-term OS were the absence of residual disease following surgical resection and histotype.[13]

Lymph node metastasis is an important concern in patients with high-risk early or advanced endometrial cancer.[14, 15] In evaluating data from 523 French surgical patients over a 12-year period, Bendifallah et al developed a predictive model to identify those at high risk for lymph node metastases using the histopathologic features of histologic grade, tumor diameter, depth of myometrial invasion, and status of lymphovascular space involvement.[14] In a different study, Fotopoulou et al reported that, on the basis of anatomic distribution of positive lymph nodes, when lymphadenectomy is performed for those with high-risk early or advanced disease, the procedure should contain pelvic and para-aortic areas up to the renal vessels to ensure accuracy in the evaluation of all potential positive nodes.[15]

Two randomized trials by Seagle et al examined the association of lymphadenectomy with overall survival in women with stage I endometrioid and node-negative, stage I to IIIB endometrial cancer. One study reported that performance of pelvic lymphadenectomy was associated with increased survival compared with no lymphadenectomy (5-year survival [95% CI], 91.4% [90.2% to 92.6%] v 87.3% [85.9% to 88.8%]; HR, 0.71 [95% CI, 0.64 to 0.78]; P< .001). This study also reported that the addition of para-aortic lymphadenectomy was associated with increased survival compared with pelvic lymphadenectomy alone (5-year survival [95% CI], 91.0% [89.8% to 92.2%] v 89.8% [88.4% to 91.1%]; HR, 0.85 [95% CI, 0.77 to 0.95]; P = .003).[16] Another study concluded that increased lymph node count is associated with a 1% to 14% decreased risk of death per each additional five lymph nodes removed and a 5% to 20% increased 5-year survival among women with pathologically node-negative endometrioid and serous endometrial cancers.[17]

Surgery should be used in conjunction with chemotherapy with a taxane and a platinum compound (eg, paclitaxel plus carboplatin). For more information on chemotherapy regimens, see Endometrial Cancer Treatment Protocols.

Since 1988, FIGO, whose Gynecologic Oncology Committee was responsible for the staging of gynecological cancer, recommended that corpus cancer be staged surgically. Previously, clinical evaluation was used for staging, and multiple studies noted the inaccuracy of clinical staging compared with surgical pathological findings. Therefore, once the diagnosis of endometrial cancer has been made, routine presurgical evaluation is performed to assess operability.

Note the following:

• Special studies, such as CT scans of the abdomen and pelvis or MRIs, are not routinely performed.

• Once preoperative evaluation, which may include a chest radiograph, ECG, and appropriate blood studies, has been performed and the results are found to be normal, the patient is deemed a surgical candidate. Then, a total hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, and pelvic and para-aortic lymphadenectomy are performed.

• Obviously, if intraperitoneal disease is identified at the time of surgery, attempts are made at surgical removal.

• Staging is then determined based on surgical pathologic findings (see Staging). Subsequent therapy, if needed, is then determined, depending on the surgical pathological findings of the operative procedure.

• Data extracted from the SEER database indicate that among women younger than 60 years with stage 1B and 1C endometrioid adenocarcinoma who underwent lymphadenectomy were less likely to undergo full pelvic radiation and more likely to receive brachytherapy; furthermore, the extent of lymphadenectomy influenced the receipt of radiotherapy.[18]

A 2012 review found that for early stage primary endometrioid adenocarcinoma of the endometrium, laparoscopy and laparotomy are associated with similar rates of disease-free and overall survival and that laparoscopy is associated with reduced operative morbidity and shorter hospital stays.[19]

Treatment of endometrial cancer needs to be individualized depending on patient factors and disease stage (eg, limit disease to the uterus, review suspected or gross cervical involvement, review suspected extrauterine disease). Although surgery is the mainstay of therapy for most endometrial cancers, nonsurgical treatments, such as radiation therapy, chemotherapy, and hormonal therapy, can play a role. The majority of these therapies are used as adjuvant/adjunctive therapy, in the treatment of recurrences or metastatic disease, or in patients who are unable to have surgery.

For women who are not surgical candidates and have uterine-confined disease, external beam radiotherapy (EBRT) and/or brachytherapy is the preferred treatment. The use of adjuvant radiotherapy (RT) improves pelvic control in patients with selected risk factors and may improve progression-free survival (PFS) but failed to improve overall survival (OS) in clinical trials. However, many of the subjects in these trials were at low risk (ie, had low-risk intrauterine pathologic risk factors). Studies have shown that PFS improved, but there was no OS advantage with adjuvant sequential chemotherapy/RT in patients with the highest-risk uterine-confined disease.[20]

In the adjuvant setting, carboplatin/paclitaxel is the preferred regimen for high-risk uterine-confined disease. For patients with extrauterine disease, systemic therapy is recommended as adjuvant therapy. For stage IIIA to IIC disease, systemic therapy and/or EBRT, with or without vaginal brachytherapy, is recommended. For stage IVA/IVB disease, systemic therapy and EBRT, with or without vaginal brachytherapy, is the mainstay of treatment.[20]

Guidelines Contributor: Jori S Carter, MD, MS Assistant Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Screening

Currently, no major organization recommends screening for cancer of the uterus for asymptomatic women. According to the National Cancer Institute (NCI) PDQ cancer information summary for endometrial cancer screening, no evidence suggests that transvaginal sonography reduces mortality from endometrial cancer, and there is inadequate evidence that endometrial sampling (biopsy) reduces mortality. The early clinical presentation and high early detection rate (85%) make it unlikely that screening will have a successful impact on earlier detection and increased survival rate.[21]

The American Cancer Society (ACS) recommends that at the time of menopause, all women should be made aware of the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physician.[22]

Additionally, the NCI’s PDQ cancer information summary and ACS agree that for women at increased risk for endometrial cancer due to a history of receiving either estrogen therapy or tamoxifen therapy, there is no indication that routine screening would improve early detection or survival rates. As with women at average risk, these women generally present with symptoms at an early stage when the prognosis is good.[21, 22]

The Spanish Society of Medical Oncology (SEOM) and the Spanish Group for Investigation in Ovarian Cancer (GEICO) do not recommend routine screening for endometrial cancer in women who are at average or high risk for endometrial cancer and do not have abnormal uterine bleeding; this recommendation includes patients who are taking tamoxifen. Metrorrhagia should always be investigated in postmenopausal women or those with risk factors, using transvaginal ultrasound with a cutoff level of 3 mm.[23]

Lynch Syndrome

Women with Lynch syndrome (hereditary nonpolyposis colorectal cancer) have up to an 80% increased risk for colorectal cancer and a 60% increased risk for endometrial cancer.[24]  

The National Comprehensive Cancer Network (NCCN) guidelines endorse universal immunohistochemistry (IHC) or microsatellite instability (MSI) testing, regardless of family history, on all individuals diagnosed with colorectal or endometrial cancers to identify which patients should have genetic testing for Lynch syndrome. In addition, Lynch syndrome genetic testing should be done for all women diagnosed with endometrial cancer before age 50 and family members of anyone with Lynch syndrome.[24]  

The NCCN guidelines include the following recommendations for surveillance and risk reduction in women with Lynch syndrome:

• Hysterectomy and bilateral salpingo-oophorectomy should be offered to women who have completed child bearing and carry MLH1, MSH2, or MSH6 mutations

• Annual endometrial sampling for carriers of MLH1 or MSH2

• Annual colonoscopy (to decrease risk of colorectal cancer)

• Routine transvaginal ultrasound and serum CA-125 testing are not recommended

In 2014, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) published joint guidelines that recommend that all women who are diagnosed with endometrial cancer should be screened for Lynch syndrome. Genetic testing is preferred when resources are available, but clinical screening that includes focused family history is acceptable. Asymptomatic women with a first-degree relative diagnosed with either endometrial or colorectal cancer before age 60 should also be tested.[25]

The ACOG/SGO recommendations for surveillance and risk reduction include the following:

• Colonoscopy every 1-2 years, beginning at age 20-25

• Endometrial sampling every 1-2 years beginning at age 30-35

• Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered to women in their early to mid-40s

Consensus guidelines issued jointly by the European Society for Medical Oncology, the European Society of Gynaecological Oncology, and the European Society of Radiotherapy and Oncology (ESMO/ESGO/ESTRO) recommends annual surveillance by transvaginal ultrasound and biopsy starting from the age of 35 until hysterectomy for all Lynch syndrome mutation carriers. In addition, for management of women with Lynch syndrome, recommendations include[26] :

• Annual screening beginning at age 35
• Regular hysteroscopy and endometrial biopsies 
• The application of local progesterone using the levonorgestrel intrauterine device
• Treatment of premalignant disease (i.e, atypical endometrial hyperplasia or endometrial intraepithelial neoplasia)
• Hysterectomy and bilateral oophorectomy

In women with Lynch syndrome, the SEOM and the GEICO recommend screening for endometrial cancer with annual endometrial sampling, transvaginal ultrasound (TVUS), and CA125 measurement, beginning at age 30-35, or 5-10 years prior to the earliest age of first diagnosis of Lynch-associated cancer of any kind.[23]

National Cancer Institute

The NCI’s PDQ cancer information summary notes that the use of oral contraceptives containing estrogen and progesterone for at least 1 year reduces the risk for developing endometrial cancer. The decreased risk is proportionate to duration of use, and the benefit persists for at least 15 years after cessation. However, use of oral contraceptives is also associated with increased risk for blood clots, stroke, and myocardial infarction, particularly in women who smoke and are older than 35.[21]

American Cancer Society

The ACS recommends the following measures to reduce the risk of developing endometrial cancer[22] :

• Asymptomatic women who have Lynch syndrome or a family history of colon cancer should be tested annually with endometrial biopsy beginning at age 35
• Progestin should added to estrogen in hormone replacement therapy

Women who are undergoing surgery for colorectal cancer and who do not wish to preserve fertility should be offered prophylactic hysterectomy and/or oophorectomy

The National Comprehensive Cancer Network (NCCN) guidelines provide the following recommendations for the initial evaluation for suspected endometrial cancer[20] :

• History and physical examination
• Endometrial biopsy
• Expert pathology review to determine histopathologic subtype
• Because of a high false-negative rate (10%), a negative biopsy in symptomatic patients requires followup with a fractional dilation and curettage (D&C) under anesthesia.
• Imaging studies (eg, CT, MRI, PET) and optional CA-125 testing for evaluation of extrauterine disease

The Society of Gynecologic Oncology (SGO) and European Society of Medical Oncology (ESMO) guidelines provide overall similar recommendations, but both include hysteroscopy with biopsy as another diagnostic option.[27, 28] Because of its high accuracy, the SGO considers hysteroscopy with biopsy the gold standard for diagnosis.[27]

The following two major staging systems are commonly used in endometrial cancer:

• The International Federation of Gynecology and Obstetrics (FIGO) system, developed in collaboration with the World Health Organization (WHO) and revised in 2009[12]

• The TNM system, developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)[29]

• See Endometrial Cancer Staging for details.

In the past, uterine sarcomas were staged as endometrial cancers. This did not reflect clinical behavior, however, so a new corpus sarcoma staging system was developed, based on the criteria used in other soft tissue sarcomas. See the Table below.

Table. Uterine Sarcomas (Leiomyosarcoma, Endometrial Stromal Sarcoma, and Adenosarcoma) (Open Table in a new window)

Positive cytology is an adverse risk factor. Although peritoneal cytology results do not affect staging, FIGO and AJCC continue to recommend that peritoneal cytology be obtained and reported.[12, 29]

The European Society of Medical Oncology (ESMO) guidelines stratify patients into treatment groups based on the estimated risk of disease recurrence, as follows[28] :

• Low risk: Endometrioid cancers that are confined to the endometrium
• Intermediate risk: Disease that is confined to the uterus but invades the myometrium, or demonstrates occult cervical stromal invasion; includes some patients with stage IA disease, stage IB disease, and a subset of patients with stage II disease
• High risk: Includes gross involvement of the cervix (a subset of stage II disease; stage III or IV disease, regardless of grade; papillary serous or clear cell uterine tumors)

The National Comprehensive Cancer Network guidelines use the following categories for delineating endometrioid cancer treatment groups[20] :

• Disease limited to the uterus
• Suspected or gross cervical involvement
• Suspected extrauterine disease

The major guidelines are in agreement that the primary treatment for stage I disease limited to the uterus is surgery (total hysterectomy and bilateral salpingo-oophorectomy) and complete surgical staging including pelvic washings, bilateral pelvic and paraaortic lymphadenectomy.[20, 27, 28, 30, 26]

The recommended surgical approach varies among the guidelines. The National Comprehensive Cancer Network (NCCN) considers that hysterectomy and adnexectomy may be performed through laparotomy, vaginally, or via minimally invasive techniques such as laparoscopy or robotic surgery.[20]  The European Society for Medical Oncology, the European Society of Gynaecological Oncology, and the European Society of Radiotherapy and Oncology (ESMO/ESGO/ESTRO) recommends minimally invasive surgery because of the significant reduction in complications reported.[26]

The Society of Gynecologic Oncology (SGO) recommends laparoscopy as the standard approach, and finds robotic-assisted techniques acceptable. Both the American College of Obstetricians and Gynecologists (ACOG) and SGO reserve vaginal hysterectomy for selected women who are at high risk for surgical morbidity.[27, 30]

In younger women with noninvasive, grade 1 cancers who wish to preserve fertility, NCCN, SGO, and ACOG all recommend progestin therapy. Total hysterectomy and bilateral salpingo-oophorectomy is indicated when childbearing is complete, or sooner if cancer is still present after 6-9 months of therapy or disease progression occurs. Women receiving fertility-sparing treatment should be monitored closely with endometrial biopsy every 3 months.[20, 30, 31]

For patients who are medically inoperable, radiation therapy or hormone therapy are options, according to both the NCCN and ESMO/ESGO/ESTRO guidelines.[20, 26]  

American Society of Radiation Oncology

In 2014, the American Society of Radiation Oncology (ASTRO) published evidence-based guidelines for the role of postoperative radiation therapy. The recommendations include the following[32] :

• After total hysterectomy, no radiation therapy is required for patients with grade 1 or 2 tumors with < 50% myometrial invasion
• Vaginal brachytherapy is an option for patients with grade 3 tumors without myometrial invasion or grade 1 or 2 tumors with high risk factors
• Vaginal brachytherapy is comparable to pelvic radiation in preventing recurrence for patients with grade 1 or 2 tumors ≥50% myometrial invasion; or grade 3 tumors with < 50% myometrial invasion; vaginal brachytherapy is preferred
• Pelvic radiation for patients with grade 3 tumors with ≥50% myometrial invasion or cervical stroma invasion; or grade 1 or 2 tumors with ≥50% myometrial invasion with high risk factors
• For patients with positive nodes, or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum: external beam radiation therapy as well as adjuvant chemotherapy
• Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted
• For patients with metastatic disease, concurrent chemoradiation followed by adjuvant chemotherapy is indicated; alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable

Spanish Society of Medical Oncology (SEOM) and Spanish Group for Investigation in Ovarian Cancer (GEICO)

The standard surgical treatment recommended by the Spanish Society of Medical Oncology (SEOM) and the Spanish Group for Investigation in Ovarian Cancer (GEICO) in early-stage endometrial cancer is total hysterectomy and bilateral salpingo-oophorectomy without vaginal cuff resection, using a minimally invasive surgery approach.[23]

In low-risk endometrial cancer, systematic lymph node dissection (LND) is not recommended. In intermediate and high-risk cases, LND is recommended to guide surgical staging and adjuvant therapy. Sentinel lymph node biopsy can be considered for staging purposes.

Adjuvant treatment recommendations are as follows:

• Low-risk patients – Adjuvant treatment not required
• Intermediate-risk patients – Vaginal brachytherapy (VBT); VBT plus pelvic radiation in patients with no surgical nodal staging
• High-risk patients - Adjuvant chemotherapy (carboplatin-paclitaxel) with concurrent or sequential external beam radiation therapy, or chemotherapy alone

Hormonal therapy could be an appropriate therapeutic alternative for patients with low-grade, hormone-receptor–positive disease, without rapidly progressive metastatic disease. The treatment of choice is progestogens or progestogens alternating with tamoxifen.

Pembrolizumab plus lenvatinib should be considered for second-line treatment, particularly for mismatch repair (MMR)–proficient tumors; dostarlimab or pembrolizumab can be considered for second-line therapy of MMR-deficient tumors.

The European Society of Medical Oncology (ESMO) and the Society of Gynecologic Oncology (SGO) offer similar recommendations for treatment of advanced and metastatic disease that include the following[31, 28] :

• Combination chemotherapy and radiation therapy should be considered before a single-modality treatment

• Chemotherapy with a paclitaxel with carboplatin regimen is as effective as other regimens and had less toxicity

• For treatment of metastatic disease, hormonal therapy with progestational agents may be considered; tamoxifen and aromatase inhibitors are also acceptable[28]

• Based on preliminary studies, a targeted agent such as temsirolimus or ridaforolimus may be considered as a second-line agent[28]

• National Comprehensive Cancer Network (NCCN) guidelines for relapse or metastatic disease are as follows:[20]

• Hormone therapy followed by chemotherapy on progression for low-grade metastases

• Chemotherapy and palliative radiation therapy for symptomatic, high-grade, or large-volume metastases

• Persistent progression should be treated with best supportive care and enrollment in a clinical trial

American College of Obstetricians and Gynecologists (ACOG) and European Society of Medical Oncology (ESMO) guidelines concur that following surgical treatment, patients should receive a pelvic exam every 3-4 months for the first 2-3 years, then every 6 months until year 5 to monitor for recurrent disease.[30, 28] The Society of Gynecologic Oncology (SGO) and the National Comprehensive Cancer Network (NCCN) recommend review of symptoms and pelvic exam every 3 to 6 months for the first 2 years and every 6 to 12 months thereafter.[20, 33]

ESMO and SGO guidelines prefer PET/CT over CT alone for assessment of suspected recurrence.[28, 33]

According to the Spanish Society of Medical Oncology (SEOM) and the Spanish Group for Investigation in Ovarian Cancer (GEICO), surveillance consists mainly of monitoring symptoms and physical examination that includes a speculum and pelvic examination every 3-6 months for 2 years, and every 6-12 months thereafter. Patients with low-risk endometrial cancer can be followed less frequently: 6-12 months for first 2 years, then yearly thereafter. Follow-up imaging may be useful in selected high-risk patients.[23]

Class Summary

Antineoplastic agents inhibit cell growth and proliferation. Several antineoplastic agents elicit a response in patients whose disease is resistant to platinum-based therapies.

Cisplatin

Indicated in established combination therapy or single-line therapy in patients with metastatic, recurrent, or high-risk endometrial carcinoma. The proposed mechanisms of action are by intrastrand cross-linking of DNA and inhibition of DNA precursors.

Carboplatin

The proposed mechanisms of action are intrastrand cross-linking of DNA and inhibition of DNA precursors.

Paclitaxel (Taxol)

Indicated as subsequent therapy for the treatment of advanced endometrial carcinoma. As first-line therapy, paclitaxel is indicated in combination with carboplatin. The mechanism of action of paclitaxel is tubulin polymerization and microtubule stabilization.

Paclitaxel protein bound (Abraxane)

Paclitaxel protein bound is a microtubular inhibitor (albumin-conjugated formulation) and a natural taxane that prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition. It is used as a substitute for patients with a hypersensitivity to paclitaxel.

Doxorubicin

Doxorubicin is a cytotoxic anthracycline that inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. It blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition. It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix.

This agent is also a powerful iron chelator. The iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells. Maximum toxicity occurs during the S phase of the cell cycle.

Doxorubicin liposomal (Doxil)

Liposomal doxorubicin interferes with synthesis of nucleic acid by intercalating with DNA nucleotide pairs and topoisomerase II inhibition. Indicated for the treatment of patients with endometrial cancer whose disease has progressed or recurred after platinum-based chemotherapy.

Docetaxel (Taxotere)

Docetaxel is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division, leading to cell death.

Ifosfamide

Ifosfamide inhibits DNA and protein synthesis and, thus, cell proliferation, by causing DNA cross-linking and denaturation of double helix.  

Topotecan (Hycamtin)

Topotecan binds to the topoisomerase I‑DNA complex and prevents religation of single-strand breaks. Indicated as monotherapy for the treatment of patients with metastatic endometrial cancer after disease progression on or after initial or subsequent chemotherapy.

Class Summary

Monoclonal antibodies have been engineered to react against specific antigens on cancer cells, which can help to enhance the patient’s immune response and prevent cancer cell growth.

Trastuzumab (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, trastuzumab-dkst, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-qyyp)

Trastuzumab is a monoclonal antibody that binds to extracellular HER2. It mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2. Used in combination with carboplatin and paclitaxel for patients with HER-2 positive uterine serous carcinoma.

The combination of trastuzumab and an anthracycline is associated with significant cardiac toxicity.

Bevacizumab (Avastin)

Bevacizumab is a murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). It inhibits new blood vessel formation, denying blood, oxygen, and other nutrients needed for tumor growth. It may be considered in patients who have progressed on prior cytotoxic chemotherapy for recurrent, metastatic, or high-risk endometrial cancer. 

Class Summary

Monoclonal antibodies that bind the programmed cell death-1 protein (PD-1) ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production.

Pembrolizumab (Keytruda)

It is indicated in combination with lenvatinib for the treatment of advanced endometrial cancer who have disease progression following prior systemic therapy. The indication applies to patients who are not candidates for curative surgery or radiation and who have disease that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). It is also indicated for unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mut/Mb] solid tumors in patients that have progressed following prior treatment and who have no alternative treatment options.

Class Summary

Inhibits the kinase activities of various subtypes of vascular endothelial growth factor (VEGF) receptors.

Lenvatinib (Lenvima)

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet-derived growth factor receptor alpha (PDGFR-α); KIT; and RET. It is indicated in combination with pembrolizumab for the treatment of advanced endometrial cancer who have disease progression following prior systemic therapy. 

Class Summary

Selective estrogen receptor modulators (SERMs) stimulate or inhibit the estrogen receptors of various target tissues. Hormonal therapy is typically used for lower-grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace.

Tamoxifen (Soltamox)

Tamoxifen is a nonsteroid with potent antiestrogenic effects in the breast; however, it may be an estrogen agonist in the uterus. 

Class Summary

Aromatase inhibitors play a role in adjuvant therapy in endometrial cancer. These agents work by inhibiting aromatase, the enzyme responsible for converting other steroid hormones into estrogen. Hormonal therapy is typically used for lower-grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace.

Letrozole (Femara)

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. It inhibits the conversion of androgens to estrogens. 

Class Summary

All progestational agents act by decidualization and atrophy of the endometrium. Use of this category of drugs relies on high-dose hormones to suppress the hypothalamus through negative feedback. This results in a hypoestrogenic state. Hormonal therapy is typically used for lower-grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace.

Medroxyprogesterone (Depo-SubQ Provera 104, DepoProvera, MPA)

Medroxyprogesterone inhibits secretion of gonadotropins, thereby inhibiting ovulation and decreasing the thickness of the endometrium.

Levonorgestrel intrauterine (Kyleena, Liletta, Mirena)

The levonorgestrel-releasing intrauterine device inhibits secretion of gonadotropins, thereby inhibiting ovulation and decreasing the thickness of the endometrium.

Class Summary

Mesna is indicated in the prevention of hemorrhagic cystitis in patients being treated with ifosfamide.

Mesna (Mesnex)

Mesna detoxifies metabolites of ifosfamide and cyclophosphamide. The usual total dose should be at least 60% of the total dose of the alkylating agent.