Endometrial cancer is the most common type of female genital cancer in the United States, with an estimated 32,000 new cases and 5,600 deaths per year. During the first half of the 20th century, the incidence of cervical cancer was greater than cancer of the endometrium by a ratio of more than three to one, but this trend reversed around the middle of the century. Endometrial cancer is a disease predominantly of postmenopausal women with the peak incidence occurring in the ages of 58 to 60 years. The following guidelines refer primarily to endometrioid endometrial adenocarcinomas, which represent the most common type and are associated with unopposed estrogen exposure, obesity, and the precursor lesions known as endometrial hyperplasia. In contrast, the serous and clear cell subtypes represent an entirely different clinical and pathologic entity, with associated poor prognosis, hormonal unresponsiveness, and without identifiable precursor lesions.

Screening

A screening test should be safe, inexpensive, have a high predictive value, and be able to diagnose the disease in a premalignant or early stage. By these criteria, there is no satisfactory screening method for endometrial carcinoma. The prevalence for endometrial carcinoma is 5 per 1,000 among asymptomatic women over age 45 years. Endometrial sampling and ultrasonography are screening modalities for this malignancy but do not meet screening test criteria. Cervical cytology will be abnormal in less than half of the endometrial carcinomas, while endometrial sampling (cytology or histology) has a higher degree of diagnostic reliability for both endometrial hyperplasia and carcinoma. Diagnosis by transvaginal ultrasound is based on endometrial thickness, with a 5-mm “cut-off” for normal thickness yielding the best predictive values in postmenopausal women.

Neither sampling nor sonography is an inexpensive screening method, and therefore, with the low prevalence in asymptomatic women, it is difficult to justify routine screening. Women with certain high-risk factors may, however, benefit from screening: age over 40 with abnormal uterine bleeding, massive obesity, history of endometrial hyperplasia, or unopposed estrogen or tamoxifen(Drug information on tamoxifen) (Nolvadex) use. Since many women on tamoxifen have benign thickening of the endometrial lining, the screening recommendations for these women are still under investigation.

If one can adequately perform sampling (some patients have cervical stenosis or large fibroids that prevent adequate sampling), the risk of missing a cancer is very low. There is little evidence to justify the routine use of dilation and curettage (D&C) over office sampling, but D&C is indicated when faced with cervical stenosis. Hysteroscopy (office or operative) is a controversial screening modality that may offer superior sensitivity but at added costs.

Diagnosis

Microscopic analysis of endometrial tissue is required to make the diagnosis of endometrial carcinoma. The classical method for obtaining the tissue specimen is the fractional curettage. This consists of a circumferential endocervical canal scrape followed by a systematic, comprehensive endometrial curettage. The two specimens are submitted to the laboratory separately. Fractionating the curettage serves to detect an occult endocervical carcinoma and to determine if the endometrial carcinoma involves the cervix.

Today, office endometrial biopsy (EMB) with endocervical curettage (ECC), rather than a formal curettement in the operating room, is the accepted first step in evaluating postmenopausal bleeding or suspected endometrial pathology. The EMB consists of multiple strokes with a suction or other curet, sampling as much of the uterine cavity as feasible. If the suspicion for cancer is high and the biopsy inconclusive, hysteroscopy may be employed to assist in making a correct diagnosis. When the cervical canal is stenotic or patient tolerance does not permit adequate office evaluation of the endometrium and endocervix, a curettage under anesthesia is necessary. Patients with postmenopausal bleeding whose pelvic examination is unsatisfactory may also be evaluated with transvaginal sonography to rule out concomitant adnexal pathology.

Staging

Clinical Staging

In 1988, the International Federation of Gynecology and Obstetrics (FIGO) staging for endometrial carcinoma was changed from a clinical to a surgical staging system (Table 1). Histopathologic factors and/or surgical findings determine the need for adjunctive therapies. However, clinical staging is still important in terms of preoperative evaluation and planning for surgery, and still correlates well with prognosis. The most important elements are the physical examination and the fractional curettage. In more than 75% of the cases there is no clinical evidence of extrauterine involvement. For these patients the only additional studies required are chest x-ray and the usual preoperative chemistries. A serum CA-125 may also be of value in following advanced disease. More extensive preoperative evaluation, such as MRI, CT scan, or barium enema, may be indicated for patients whose disease has features that put them at high risk for metastases (poorly differentiated, papillary serous, clear cell, or sarcomatous histology). Evaluation for metastases is indicated in patients with abnormal liver function tests, an elevated serum CA-125 value, clinical evidence of metastases, and parametrial or vaginal tumor extension. For locally advanced disease, cystoscopy and/or barium enema should be obtained. Bone and brain scans are not indicated in the absence of symptoms.

Hysteroscopy and hysterography have been used to determine the extent of tumor and its proximity to the cervix, but both have the theoretical potential to push cancer cells through the fallopian tubes or into uterine lymph-vascular spaces. Their use should be limited to cases in which a diagnosis is not forthcoming by the usual procedures. Transvaginal sonography may be helpful for evaluating the degree of myometrial invasion preoperatively. Magnetic resonance imaging may be a more accurate but less cost-effective technique.

Surgical-Pathologic Staging

The inherent inaccuracy of clinical staging for endometrial carcinoma has been a serious impediment to the selection of optimal therapy, and over the years has resulted in both overtreatment and undertreatment. The magnitude of clinical understaging is on the order of 15% to 25%. Node metastases, myometrial invasion, intraperitoneal implants, adnexal metastases, lymph-vascular space involvement (LVSI), and peritoneal cytology cannot be readily evaluated clinically. Up to 20% of tumors have a worse histologic grade based on the hysterectomy specimen than the curettings.

In the Gynecologic Oncology Group (GOG) surgical-pathologic staging studies of endometrial carcinoma, 18% of the patients had demonstrable evidence of extrauterine spread, including 10% with pelvic and 7% with aortic node metastases. The metastasis rate to the pelvic and aortic chains ranges from 15% to 35% for grade 2 and 3 lesions with outer one-third myometrial invasion. Nonendometrioid histologic subtype, LVSI, and positive peritoneal cytology confer a worse prognosis. The role in treatment planning of tumor size, DNA ploidy, or molecular biological markers has not been established. Estrogen- and progesterone(Drug information on progesterone)-receptor status remain standard prognostic and treatment planning variables.

Preoperative Radiation vs Surgical Staging

There are two approaches regarding the initial treatment of endometrial carcinoma. The classic approach is to administer preoperative irradiation followed by surgery. More recently, surgery with staging to determine the need for additional adjunctive therapy has gained wide acceptance. Both protocols have merit.

The preoperative irradiation approach calls for irradiation, either intracavitary brachytherapy or external radiation, prior to surgical procedures for high-risk lesions. In clinically stage I patients, intracavitary brachytherapy is the treatment of choice. Surgery may be performed within a day or two after completion of the brachytherapy. By this technique, the radiation does not significantly affect the pathologic evaluation of the tumor. External pelvic irradiation would be preferable only if there was gross cervical or parametrial involvement. Further therapy (external irradiation or chemotherapy) can be added if indicated after preoperative irradiation and surgical staging. The disadvantage of preoperative irradiation is that some patients will have less disease than believed and therefore would receive irradiation that was not necessary.

The surgical staging approach mandates washings and removal of the uterus, tubes, and ovaries with sampling of pelvic and para-aortic nodes. The decision for adjunctive therapy is based upon these findings. The disadvantage to this technique is that irradiation following surgery has a higher incidence of complications.

When one examines the complication and survival data from these two management protocols, they are approximately the same. Therefore, either of these techniques is acceptable. However, it must be emphasized that both techniques require analysis of findings to determine if additional therapy is necessary.

The Staging Procedure

The abdomen is opened with a vertical, lower abdominal incision, and peritoneal washings are taken of the pelvis and abdomen. Careful exploration is then carried out looking and feeling for evidence of omental, liver, peritoneal, cul de sac, and adnexal metastases. The aortic and pelvic areas are palpated for nodal metastases.

An extrafascial, total hysterectomy with bilateral salpingo-oophorectomy is then performed. No instruments should be placed on the uterus itself, and ligation or clipping of the distal tubes prevents possible tumor spillage during manipulation. Removal of the adnexa, even if they appear normal, is part of the therapy, since they may contain microscopic metastases. It is not necessary to remove a margin of vaginal cuff, nor does there appear to be any benefit from excising parametrial tissue in the usual case. In cases in which an endocervical primary cannot be ruled out with certainty and there is definite endocervical disease, a modified (Rutledge type II) radical hysterectomy may be the most prudent action in experienced hands. The entire cervix, in any case, is removed.

The uterus is opened off the field to determine the extent of the growth. If the depth of invasion is not grossly evident, it may be determined by frozen-section analysis. Though an integral part of the FIGO staging system for endometrial carcinoma, the indications for lymph node sampling must always be evaluated in light of the risk to the patient and the likelihood of their involvement based on operative findings. The node-bearing retroperitoneum should first be evaluated with the peritoneum opened to identify enlarged or suspicious lymph nodes. If these are positive on frozen section, node dissection may be unnecessary unless clinically positive nodes can be excised with minimal risk to the patient.

Indications for aortic node sampling include: (1) suspicious aortic or common iliac nodes; (2) grossly positive adnexa; (3) grossly positive pelvic nodes; (4) any grade carcinoma with outer-half myometrial invasion; and (5) clear cell, papillary serous, or carcinosarcoma histologic subtypes.

In the aortic region, a selective node dissection consists of removing the node- bearing tissue over the vena cava from the inferior mesenteric artery (IMA) origin down to the bifurcation of the common iliac artery. Left-sided para-aortic nodes should also be excised, as these may also harbor metastatic disease. Patients with aortic node metastases should have a postoperative CT scan of the liver and thorax prior to initiating radiotherapy. If the aortic node metastases are large or multiple, a scalene fat pad dissection is warranted, since node metastasis at this level would be a contraindication to aortic field radiation therapy.

Indications for pelvic node dissection include: (1) suspicious pelvic nodes; (2) aortic node sampling not feasible; (3) cases in which the nodal findings would be the basis for deciding whether the patient would receive postoperative radiation therapy. Pelvic node sampling consists of removing the node-bearing tissue from the medial aspect of the external iliac artery and vein, as well as the obturator fat pad superior to the obturator nerve.