Endometrial carcinoma is a common gynecologic malignancy that many physicians encounter. A thorough understanding of the epidemiology, pathophysiology, and management strategies allows physicians to identify women at increased risk, to contribute to risk reduction, and to facilitate early diagnosis of this cancer. To address these issues, the American College of Obstetricians and Gynecologists (ACOG) released evidence-based guidelines for the management of endometrial cancer. The recommendations were published in the August 2005 issue of Obstetrics & Gynecology.

Background

Most women with endometrial cancer (90 percent) develop symptomatic bleeding or discharge, which facilitates early diagnosis and results in an increased opportunity for cure. Seventy-two percent of endometrial cancers are diagnosed in stage I; however, 12 percent are in stage II, 13 percent are in stage III, and 3 percent are in stage IV at diagnosis. Despite this favorable stage distribution, endometrial cancer is responsible for 7,310 deaths each year, and the overall incidence is expected to increase secondary to increasing obesity and the aging of the population.

The most common histologic cell type of endometrial cancer is endometrioid adenocarcinoma, comprising more than three fourths of cases. Typically, type I endometrial cancer has lower-grade nuclei, endometrioid histologic cell type, phosphatase and tensin homologue mutation, and a good prognosis. Type II endometrial cancer is more lethal and accounts for 10 percent of patients. It has aggressive, high-grade nuclei or serous and clear cell histology and P53 tumor suppression mutation. There is no clear epidemiologic profile for type II cancers (Table 1).

Obtaining a family history is recommended to alert the physician to women at increased risk of genetically linked cancers (e.g., hereditary nonpolyposis colorectal cancer) in which young age at presentation is important. It also is crucial to identify women at risk to provide them with appropriate screening, prophylactic surgery, and counseling.

The International Federation of Gynecology and Obstetrics surgical staging system, which incorporates important pathologic risk factors associated with prognosis and recurrent disease, emphasizes the overriding prognostic value of surgical staging information as well as its use in postoperative treatment planning. The prognosis of women with endometrial cancer is dictated primarily by the site of metastatic disease. When the disease is confined to the uterine fundus, the prognosis is based on grade, histologic cell type, and depth of invasion. The degree of lymph-vascular space invasion and the patient's age and race are also important prognostic factors.

Clinical Considerations

PREOPERATIVE EVALUATION

Patients with endometrial cancer often have comorbidities such as obesity, hypertension, diabetes, and cardiac and pulmonary dysfunction that make them high-risk or poor surgical candidates.

A physical examination and chest radiography are required for preoperative staging of the usual histology (i.e., type I endometrioid grade 1), clinical stage I patient. Directing all other preoperative testing toward optimizing the surgical outcome is recommended.

If the cervix appears to be enlarged—which suggests possible tumor involvement—the differential diagnosis of cervical adenocarcinoma should be considered. If cervical involvement is confirmed, treatment options include radical hysterectomy or preoperative radiation therapy. The finding of vaginal, parametrial, or adnexal extension of disease can complicate treatment planning, and a subspecialist may be required for complete surgical resection.

SURGICAL STAGING

Most women with endometrial cancer benefit from systematic surgical staging, which includes pelvic washings, bilateral pelvic and para-aortic lymphadenectomy, and complete resection of all disease. Exceptions include young or perimenopausal women with grade 1 endometrioid adenocarcinoma associated with atypical endometrial hyperplasia, and women at increased risk of mortality secondary to comorbidities.

Retroperitoneal lymph node assessment is a critical component of surgical staging and is associated with improved survival rates. Palpation of the retroperitoneum is not recommended because it cannot substitute for surgical dissection of nodal tissue for histopathology. Women who test negative for disease of the pelvic and para-aortic lymph nodes and for abnormal pelvic cytology have better survival rates compared with women who have matched uterine histologic factors and positive results on testing of nodes or cytology.

The incidence and severity of complications associated with extensive surgical staging of women with endometrial cancer often are related to the effects of existing medical comorbidities.

In specific situations, hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy can be completed successfully and safely with less perioperative morbidity using a laparoscopic approach.

POSTOPERATIVE THERAPY

Women who do not receive postoperative radiation with surgical stage I endometrial cancer may have isolated recurrent disease in the vagina. Treatment of these recurrences demonstrates a 60 to 75 percent survival rate; these recurrences can be managed subsequently, avoiding the unnecessary exposure of radiation toxicity. Therefore, postoperative radiation therapy can reduce the risk of local recurrence in patients with surgical stage I disease. When radiation therapy is being considered, the cost and toxicity should be balanced with the evidence that therapy neither improves survival nor reduces distant metastasis.

RADIATION THERAPY

Typically, the primary treatment of endometrial cancer involves hysterectomy. However, in patients who are exceptionally poor surgical candidates (less than 3.5 percent), primary therapeutic radiation may be considered.

Radiation therapy alone does not allow for directed therapy, and it fails to eradicate the uterine cancer in 10 to 15 percent of patients. The cancer-specific five-year survival rates in stage I inoperable patients (80 percent) are less than the rates in stage I operable patients (98 percent) and are related to tumor grade. Therefore, a careful preoperative evaluation and appropriate consultation are recommended before denying any woman the benefits of hysterectomy.

PROGESTIN THERAPY IN ATYPICAL ENDOMETRIAL HYPERPLASIA AND ENDOMETRIAL CANCER

Atypical endometrial hyperplasia and endometrial cancer should be considered as part of a continuum. For women who do not desire fertility, hysterectomy should be recommended for treatment of atypical endometrial hyperplasia because of the high risk of an underlying cancer. However, women who wish to maintain fertility, whether they have a diagnosis of atypical endometrial hyperplasia or grade 1 endometrioid adenocarcinoma, may be treated with progestins to try to reverse the lesion.

Progestational agents have been evaluated as a primary treatment modality of early grade 1 disease in women who want to maintain their fertility or in women who are extremely poor operative candidates. Oral, parenteral, or intrauterine device delivery of progestin has been successful, with response rates ranging from 58 to 100 percent. Long-term outcomes are uncertain, but the disease will likely recur in most patients.

Continued histologic monitoring is vital to ensure the response of medication and exclude recurrence. It is recommended that, after therapy, patients undergo serial complete intrauterine evaluation every three months to document response.

FOLLOW-UP

When the disease is confined to the uterus, the types of recurrence depend on histologic cell type, lymph- vascular invasion, depth of invasion, and the use of radiation therapy.

Recurrent disease in the pelvis, particularly in the vaginal cuff, can be treated successfully with radio-therapy in the nonirradiated patient. Vaginal or pelvic recurrence can be detected and treated successfully in 68 to 88 percent of women who have not received radiation therapy. Monitoring patients with a speculum and rectovaginal examination is recommended every three to four months for two to three years, then twice a year.

When practical and feasible, preoperative consultation with a gynecologic oncologist also is recommended.

Summary of Recommendations

The following recommendations are based on limited or inconsistent scientific evidence.

• Most women with endometrial cancer should undergo systematic surgical staging, including pelvic washings, bilateral pelvic and para-aortic lymphadenectomy, and complete resection of all disease. Exceptions include young or perimenopausal women with grade 1 endometrioid adenocarcinoma associated with atypical endometrial hyperplasia and those at increased risk of mortality secondary to comorbidities.

• Women with atypical endometrial hyperplasia and endometrial cancer who wish to maintain their fertility may be treated with progestin therapy. Following therapy, they should undergo serial complete intrauterine evaluation approximately every three months to document response. Hysterectomy should be recommended for women who do not desire future fertility.

• Women with surgical stage I disease may be counseled that postoperative radiation therapy can reduce the risk of local recurrence, but the cost and toxicity should be balanced with the evidence that it does not improve survival or reduce distant metastasis.

• For those women who have not received radiation therapy, pelvic examinations every three to four months for two to three years, then twice yearly following surgical treatment of endometrial cancer are recommended for detection and treatment of recurrent disease.

The following recommendations are based primarily on consensus and expert opinion.

• Women who cannot undergo systematic surgical staging because of comorbidities may be candidates for vaginal hysterectomy.

• Only a physical examination and chest radiography are required for preoperative staging of the usual histology (i.e., type I endometrioid grade 1), clinical stage I patient. All other preoperative testing should be directed toward optimizing the surgical outcome.