PDQ® Treatment Health Professionals
(Separate summaries containing information on screening for endometrial cancer and prevention of endometrial cancer are also available in PDQ.)
Cancer of the endometrium is the most common pelvic gynecologic malignancy and accounts for 13% of all cancers in women. It is a highly curable tumor. To detect endometrial cancer, a technique that directly samples the endometrial tissue is mandatory. The Pap smear is not reliable as a screening procedure in endometrial cancer, although a retrospective study found a strong correlation between positive cervical cytology and high-risk disease (i.e., high-grade tumor and deep myometrial invasion)  as well as an increased risk of nodal disease. Degree of tumor differentiation has an important impact on the natural history of this disease and on treatment selection. An increased incidence of endometrial cancer has been found in association with prolonged, unopposed estrogen exposure.[3,4] In contrast, combined estrogen and progesterone therapy prevents the increase in risk of endometrial cancer associated with unopposed estrogen use.[5,6] In some patients, an antecedent history of complex hyperplasia with atypia can be demonstrated. An increased incidence of endometrial cancer has also been found in association with tamoxifen treatment of breast cancer, perhaps related to the estrogenic effect of tamoxifen on the endometrium.[7,8] Because of this increase, patients on tamoxifen should have follow-up pelvic examinations and should be examined if there is any abnormal uterine bleeding.
The pattern of spread is partially dependent on the degree of cellular differentiation. Well-differentiated tumors tend to limit their spread to the surface of the endometrium; myometrial extension is less common. In patients with poorly differentiated tumors, myometrial invasion occurs much more frequently. Myometrial invasion is frequently a harbinger of lymph node involvement and distant metastases and is often independent of the degree of differentiation.[9,10] Metastatic spread occurs in a characteristic pattern. Spread to the pelvic and para-aortic nodes is common. Distant metastases can occur and most commonly involve the lungs, inguinal and supraclavicular nodes, liver, bones, brain, and vagina.
Another factor found to correlate with extrauterine and nodal spread of tumor is involvement of the capillary-lymphatic space on histopathologic examination. Three prognostic groupings of clinical stage I disease become possible by careful operative staging. Patients with grade 1 tumors involving only endometrium and no evidence of intraperitoneal disease (i.e., adnexal spread or positive washings) have a low risk (< 5%) of nodal involvement. Patients with grade 2 or 3 tumors and inner one third superficial myometrial invasion with no intraperitoneal disease have a 5% to 9% incidence of pelvic nodes and a 4% incidence of para-aortic nodes. Patients with deep muscle invasion and high-grade tumors and/or intraperitoneal disease have a significant risk of nodal spread, 20% to 60% to pelvic nodes and 10% to 30% to para-aortic nodes. One study was directed specifically at stage I, grade 1 carcinomas of favorable histologic type. The authors identified 4 statistically significant adverse prognostic factors: myometrial invasion, vascular invasion, 8 or more mitoses per ten high-power fields, and an absence of progesterone receptors.
Another group identified aneuploidy and a high S-phase fraction as predictive of poor prognosis. A Gynecologic Oncology Group (GOG) study related surgical-pathologic parameters and postoperative treatment to recurrence-free interval and recurrence site. For patients without extrauterine spread, the greatest determinants of recurrence were grade 3 histology and deep myometrial invasion. In this study, the frequency of recurrence was greatly increased with positive pelvic nodes, adnexal metastasis, positive peritoneal cytology, capillary space involvement, involvement of the isthmus or cervix, and, particularly, positive para-aortic nodes (includes all grades and depth of invasion). Ninety-eight percent of the cases with aortic node metastases were in patients with positive pelvic nodes, intra-abdominal metastases, or tumor invasion of the outer one third of the myometrium.[15,16]
When the only evidence of extrauterine spread is positive peritoneal cytology, the influence on outcome is unclear. The value of therapy directed at this cytologic finding is not well founded.[17-22] The preponderance of evidence, however, would suggest that other extrauterine disease must be present before additional postoperative therapy is considered.
One report found progesterone receptor levels to be the single most important prognostic indicator of 3-year survival in clinical stage I and II disease. Patients with progesterone receptor levels greater than 100 had a 3-year disease-free survival of 93% compared with 36% for a level less than 100. Only cervical involvement and peritoneal cytology were significant prognostic variables after adjusting for progesterone receptor levels. Other reports confirm the importance of hormone receptor status as an independent prognostic factor. Additionally, immunohistochemical staining of paraffin-embedded tissue for both estrogen and progesterone receptors has been shown to correlate with International Federation of Gynecology and Obstetrics (FIGO) grade as well as survival.[25-27] On the basis of these data, progesterone and estrogen receptors, assessed either by biochemical or immunohistochemical methods, should be included, when possible, in the evaluation of stage I and II patients. Oncogene expression, DNA ploidy, and the fraction of cells in S-phase have also been found to be prognostic indicators of clinical outcome. For example, overexpression of the HER-2/neu oncogene has been associated with a poor overall prognosis. A general review of prognostic factors has been published.
The most common endometrial cancer cell type is endometrioid adenocarcinoma, which is composed of malignant glandular epithelial elements; an admixture of squamous metaplasia is not uncommon. Adenosquamous tumors contain malignant elements of both glandular and squamous epithelium; clear cell and papillary serous carcinoma of the endometrium are tumors that are histologically similar to those noted in the ovary and the fallopian tube, and the prognosis is worse for these tumors. Mucinous, squamous, and undifferentiated tumors are rarely encountered. Frequency of endometrial cancer cell types is as follows:
B. Secretory adenocarcinoma
C. Papillary or villoglandular
D. Adenocarcinoma with squamous differentiation
III. Mucinous (1%)
IV. Clear cell (4%)
VI. Mixed (10%)
A hysterectomy is required to determine the degree of myometrial invasion. The following surgical staging has been adopted by the International Federation of Gynecology and Obstetrics (FIGO) and by the American Joint Committee on Cancer (AJCC):[1-3]
-- Stage I -- Stage I endometrial cancer is carcinoma confined to the corpus uteri. stage IA: tumor limited to endometrium stage IB: invasion to less than one half of the myometrium stage IC: invasion to greater than one half of the myometrium -- Stage II -- Stage II endometrial cancer involves the corpus and the cervix, but has not extended outside the uterus. stage IIA: endocervical glandular involvement only stage IIB: cervical stromal invasion -- Stage III -- Stage III endometrial cancer extends outside of the uterus but is confined to the true pelvis. stage IIIA: tumor invades serosa and/or adnexa and/or positive peritoneal cytology stage IIIB: vaginal metastases stage IIIC: metastases to pelvic and/or para-aortic lymph nodes -- Stage IV -- Stage IV endometrial cancer involves the bladder or bowel mucosa or has metastasized to distant sites. stage IVA: tumor invasion of bladder and/or bowel mucosa stage IVB: distant metastases, including intra-abdominal and/or inguinal lymph nodes Endometrial cancer can be grouped with regard to the degree of differentiation of the adenocarcinoma, as follows: G1: 5% or less of a nonsquamous or nonmorular solid growth pattern G2: 6% to 50% of a nonsquamous or nonmorular solid growth pattern G3: more than 50% of a nonsquamous or nonmorular solid growth pattern FIGO staging for endometrial cancer: Stage IA G123: tumor limited to endometrium Stage IB G123: invasion to less than one half the myometrium Stage IC G123: invasion to more than one half the myometrium Stage IIA G123: endocervical glandular involvement only Stage IIB G123: cervical stromal invasion Stage IIIA G123:tumor invades serosa and/or adnexa, and/or positive peritoneal cytology Stage IIIB G123:vaginal metastases Stage IIIC G123:metastases of pelvic and/or para-aortic lymph nodes Stage IVA G123: tumor invasion of bladder and/or bowel mucosa Stage IVB: distant metastases including intra-abdominal and/or inguinal lymph nodes
Patients with endometrial cancer who have localized disease are usually curable by hysterectomy and bilateral salpingo-oophorectomy. Best results are obtained with either of 2 standard treatments: hysterectomy or hysterectomy and adjuvant radiation therapy (when deep invasion of the myometrial muscle [one half the depth] or grade 3 tumor with myometrial invasion is present). Some patients have regional and distant metastases that, although occasionally responsive to standard hormone therapy, are rarely curable. For these patients, standard therapy is inadequate.
Progestational agents have been evaluated as adjuvant therapy in a randomized clinical trial of stage I disease and have been shown to be of no benefit. These studies, however, were not stratified according to level of progesterone receptor in the primary tumor. No trials of adjuvant progestins in more advanced disease are reported. Determination of progesterone receptors in the primary tumor is encouraged, and entry onto an appropriate adjuvant trial (if receptor levels are high) should be considered. If no trial is available, data from receptors on the primary tumor may help guide therapy for recurrent disease, should it occur.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
For all other cases and cell types, a periaortic and selective pelvic node
sampling should be combined with the total abdominal hysterectomy and
bilateral salpingo-oophorectomy if there are no medical or technical
contraindications. One study found that node dissection per se did not
significantly add to the overall morbidity from hysterectomy. If both
periaortic and selective pelvic node sampling are negative, the patient
should receive pelvic irradiation because of the frequency of pelvic and
vaginal cuff recurrence. While the irradiation will reduce the incidence of
local and regional recurrence, improved survival has not been proven.[3-5]
If the pelvic nodes are positive and the periaortic nodes are negative,
total pelvic irradiation, including the common nodes, should be given. This
careful patient selection for postoperative external-beam radiation is
mandated because external radiation can be associated with complications.
The incidence of bowel complications is approximately 4%, and it can be even
higher if the radiation is given after pelvic lymphadenectomy. If the
surgery is done using a retroperitoneal approach, the toxic effects are
lessened. If the periaortic nodes are positive, the patient is a candidate
for clinical trials that could include radiation and/or chemotherapy.
Patients who have medical contraindications to surgery should be treated with
radiation therapy alone, but inferior cure rates below those attained with
surgery may occur.[1,7,8]
Many combinations of preoperative intracavitary and external-beam radiation therapy with hysterectomy and bilateral salpingo-oophorectomy are used for treatment of stage II endometrial cancer, with careful biopsy of the para-aortic nodes at the time of surgery. When microscopic cervical stromal involvement is found, postoperative irradiation (external-beam and vaginal irradiation) should be used.
Stage IIA (endocervical glandular involvement only) should be treated the same as stage I disease.
2. Preoperative intracavitary and external-beam radiation therapy followed by hysterectomy and bilateral salpingo-oophorectomy. (A biopsy of the para-aortic nodes should be done at the time of surgery.)
3. Radical hysterectomy and pelvic lymphadenectomy in selected cases.
The most common hormonal treatment has been progestational agents,
which produce good antitumor responses in up to 15% to 30% of patients.
These responses are associated with significant improvement in survival.
Progesterone and estrogen hormone receptors have been identified in
endometrial carcinoma tissues. Responses to hormones are correlated with
the presence and level of hormone receptors and the degree of tumor
differentiation. Standard progestational agents include
hydroxyprogesterone (Delalutin), medroxyprogesterone (Provera), and
For localized recurrences (pelvis and periaortic lymph nodes) or distant metastases in selected sites, irradiation may be an effective palliative therapy. In rare instances, pelvic irradiation may be curative in pure vaginal recurrence when no prior radiation has been used. Patients positive for estrogen and progesterone receptors respond best to progestin therapy. Among 115 patients with advanced endometrial cancer who were treated with progestins, 75% (42 of 56) of those with detectable progesterone receptors in their tumors before treatment responded, compared to only 7% without detectable progesterone receptors (4 of 59). A receptor-poor status may predict not only poor response to progestins, but also a better response to cytotoxic chemotherapy. There is evidence to suggest that tamoxifen (20 milligrams twice a day) will give a response rate of 20% in those who do not respond to standard progesterone therapy. Clinical trials are appropriate for patients whose disease recurs with distant metastases and who are unresponsive to hormonal therapy. Doxorubicin is the most active anticancer agent employed, with useful but temporary responses obtained in up to one third of patients with metastatic disease. Paclitaxel also has significant activity.
Date Last Modified: 05/1999