The International Federation of Gynecology and Obstetrics (FIGO) recognizes two prognostic factors in its most recent staging (Table 1). For many years, grade and depth of invasion have been recognized as important prognostic factors. In 1988, FIGO decided that endometrial cancer should be surgically staged, thereby increasing our ability to determine the true extent of disease.² Before that time, clinical staging had been used, with replete data in the literature detailing the large number of patients whose disease process was considerably different than the clinical stage. More than 25% of stage I patients had disease outside the uterus. In stage II, approximately half had a different stage; in many instances, they actually had only disease in the uterine fundus, which had tremendous treatment implications. With the new staging, treatment can be better defined. Knowing the depth of invasion and grade of tumor, even in stage I, allows more precise determination of prognosis and treatment.

Table 1. FIGO Staging, Endometrium

Recently, the American Cancer Society (ACS) Task Force on Screening for Endometrial Cancer evaluated risk factors to identify women who might benefit from some type of screening. Multiple risk factors commonly said to be associated with endometrial cancer were reviewed in depth. Women with hereditary nonpolyposis colon cancer (HNPCC) account for only 2% to 10% of all female colon cancers, yet approximately 5% of all endometrial cancers occur in women with this risk factor. These women have 22% to 50% lifetime risk of having endometrial cancer develop, and the disease occurs at a younger age, approximately 15 years younger than women without HNPCC. The greatest risk of HNPCC carriers having endometrial cancer develop is between 40 and 60 years of age, with the absolute risk greater than 1% per year. Only HNPCC was thought to be significantly related to warrant consideration for screening. The ACS recommends annual screening with endometrial biopsy should be offered to this group of women beginning at age 35. Patients should be informed about potential benefits, risks, and limitations of testing for early endometrial cancer detection.⁶

Differentiation

For more than a century, it has been known that tumor differentiation is an important prognostic factor in endometrial cancer.³ This has been substantiated in many studies (Table 2). Patients with well-differentiated cancers have an excellent prognosis with hysterectomy as their only treatment. Patients with poorly differentiated tumors tend to have more deeply invasive cancers and a greater tendency to have extrauterine disease, require more intense therapy, and have a poor prognosis. In several large studies, it would appear that approximately one third of all adenocarcinomas are well differentiated, with approximately one quarter being poorly differentiated.

Table 2. Five-Year Survival of Stage I Carcinoma of the Endometrium*

As depth of invasion increases, prognosis worsens (Table 3). This factor may be even more predictive of prognosis than differentiation of tumor. Depth of invasion appears to be an indicator of tumor volume, which is a most important prognostic factor in any cancer. In a large study carried out by the Gynecologic Oncology Group (GOG), approximately 15% of patients with clinical stage I cancer had disease limited to the endometrium and 40% had significant (middle or deep third) myometrial invasion.³ There appears to be a correlation between grade and depth of invasion. In general, as depth of invasion increases, there is a greater likelihood that the disease process is poorly differentiated. More than one third of grade 3 lesions tends to be deeply invasive; only 7% are limited to the endometrium. In contrast, only 10% of grade 1 lesions are deeply invasive. It appears that patients with grade 3 disease limited to the endometrium have a better prognosis than do patients with grade 1, deeply invasive disease.

Table 3. Relationship Between Depth of Myometrial Invasion and 5-Year Survival Rate (Stage I)

Proper evaluation, both surgical and pathologic, must be performed to evaluate the patient's cancer fully. Without adequate evaluation at the time of surgery, surgical staging is no better than clinical staging, with its inherent problems already discussed. Proper treatment can be applied only when the extent of disease is known. Spread of disease from the corpus to the endocervix not only changes the stage but can also affect survival (Table 4). If the disease extends into the endocervical canal, the incidence of pelvic lymph node metastases increases considerably. In fact, there are considerably more patients with metastases to the pelvic nodes in a corpus et colli than there are patients with primary cervical cancer with disease limited to the cervix. Approximately 10% of stage I endometrial cancers metastasize to the adnexa. Occasionally, this is appreciated because of the enlarged adnexa noted on pelvic examination, but in many instances, discovery is at the time of surgery. Histologic confirmation is required for a patient to be placed into stage III disease based on adnexal metastasis. Obviously, treatment must be adequate for this extrauterine disease.

Table 4. Five-Year Survival in Endometrial Cancer*

For many years, it was thought that endometrial cancer did not go to the lymph nodes, particularly the pelvic nodes. During the 1960s and even before, there were data suggesting that pelvic lymph nodes could be involved with metastases, even with early-stage disease. These data were based on patients who had been primarily treated with radical hysterectomy and pelvic lymphadenectomy. In the early 1970s, an increased amount of information became available to substantiate the fact that patients with clinical stage I cancers had a significant chance of having metastases to the pelvic lymph nodes. In the large GOG study, 9% of patients with clinical stage I had metastases to the pelvic lymph nodes. Almost without exception, the metastases were microscopic and could not be determined on gross evaluation. Palpation of the lymph nodes in both pelvic and para-aortic areas is extremely unreliable in endometrial cancer. The incidence of lymph node metastases is directly related to grade and depth of invasion (Tables 5 and 6). Only 3% of patients with well-differentiated cancers have pelvic node involvement; 18% of patients with poorly differentiated tumors have lymph node metastases. Only 1% of patients with disease limited to the endometrium disease have pelvic node metastases, whereas 25% of patients with deep invasion have pelvic nodes involved. It appears that depth of invasion may be more predictive of pelvic lymph node metastases than grade.³

Table 5. Grade Versus Positive Pelvic and Aortic Nodes

Table 6. Maximal Invasion and Node Metastasis

The possible prognostic role of malignant peritoneal cytology in endometrial cancer has come under considerable discussion during the past several years. Most of these studies suggest that in 10% to 20% of cases thought to be clinical stage I (pre-1988 FIGO stage), malignant cells were present in the peritoneal cytology. On multivariate analysis, this finding has been shown to be highly predictive of other poor prognostic factors, such as intraperitoneal disease and metastases to the lymph nodes.³ Most studies in the literature suggest that the finding of malignant peritoneal cytology is itself a poor prognostic factor. Is malignant peritoneal cytology a poor prognostic factor if there is no other evidence of disease outside the uterus? Several studies suggest it is important; others have not found this relation.

The extent of disease in a patient with adenocarcinoma of the endometrium can be evaluated only with primary surgery. The patient can then be treated in a highly individualized manner instead of being treated with standard therapy, as occurs with all patients. Concern about not giving preoperative irradiation can be alleviated when one realizes that postoperative irradiation is as effective, if not more so, than preoperative irradiation.

Experience has indicated that the proper surgical procedure for evaluating these factors should be peritoneal cytology, a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. Immediately when the peritoneal cavity is opened, cytology should be obtained as noted previously. The usual extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy are then performed. Para-aortic nodes are removed by retracting the small intestines into the upper abdomen and incising the peritoneum over the upper common iliac arteries and lower aorta. The main vessels are outlined and the tissue overlying the vena cava and aorta is removed, beginning at the bifurcation and extending cephalad to the retroperitoneal duodenum. Hemostasis can be managed easily with hemoclips. Lymph node dissection in the pelvis is accomplished by entering the retroperitoneal space in routine fashion. The lower common and external iliac arteries are outlined, as is the hypogastric artery. Any enlarged nodes identified should be removed separately for histologic evaluation. The lymphoid tissue from the lower common iliac and external iliac artery down to the inguinal ligament is removed, as well as the tissue from the obturator fossa superior to the obturator nerve. Using this technique, approximately 25 to 30 lymph nodes will be available for evaluation. All tissue removed is histologically evaluated for differentiation of the tumor, size of the tumor, depth of myometrial invasion, location of the tumor in the uterus, adnexal involvement, peritoneal cytology, and involvement of the pelvic or para-aortic lymph nodes. Specific, individualized radiation therapy is then given, depending on the extent of disease.⁴

For several years, opponents of surgical staging suggested that lymphadenectomies were diagnostic only and therefore only rearranged the staging of patients with adenocarcinoma of the endometrium. Proponents argued that if that were the only accomplishment, then more accurate staging was achieved and better therapy could be applied. Data now suggest that lymphadenectomy appears to be therapeutic as well as diagnostic. Investigators at the University of Alabama at Birmingham found improved survival if a lymphadenectomy was performed, both in low-risk and high-risk patients (Fig. 1).⁵

Recent analysis from Birmingham evaluated 670 patients with endometrial cancer who underwent full surgical staging. There were 334 patients with stage IB, of which 99% did not receive postoperative radiation therapy. There were 16 recurrences, of which 10 occurred in the pelvis. Of these, 10 were salvaged with a mean follow-up of 23 months. There were 84 patients with stage IC, of which 57 did not receive adjuvant therapy. There were seven recurrences with four being salvaged with additional therapy. The authors thought that conservative therapy appears to be a reasonable alternative to adjuvant radiation therapy.

In the last FIGO Annual Report, approximately 94% of all reported patients with endometrial cancer were surgically staged. When 5-year survivals were compared between surgical and clinical staging, a considerable difference is noted. This suggests that knowing the exact extent of disease is important and that clinical staging has a large margin of error regarding identifying spread of disease. For surgical staging, patients with stage I had a 5-year survival of 92%, 89.9%, and 74% for grades 1, 2, and 3, respectively compared to 52.5%, 59.6%, and 35.9% for clinical staging, respectively.

It appears that evaluation of the prognostic factors may identify patients who are at high risk of dying of the disease. The ability to evaluate these items can be obtained only by the primary surgical approach. After extant disease has been identified, therapy as needed can be directed to the involved area. It is hoped that individualized therapy will improve survival. It is important to identify patients who historically may have been treated with radiation therapy. With surgical staging and knowing exact extent of disease, now many of these patients are thought to no longer require adjuvant therapy. Implications regarding cost and morbidity may be tremendous.

1. Greenlee RT, Hill-Harmon MB, Murray T et al: Cancer statistics, 2001. CA Cancer J Clin 51: 15, 2001

2. Pecorelli S (ed): Annual report on the results of treatment in gynecological cancer (Vol 24). J Epid Biostat 6: 45, 2001

3. Creasman WT, Morrow CP, Bundy L et al: Surgical pathological spread patterns of endometrial cancer. Cancer 60: 2035, 1987

4. DiSaia PJ, Creasman WT: Clinical Gynecologic Oncology, p 156. St. Louis: CV Mosby, 1997

5. Kilgore LC, Patridge EE, Alvarez RD et al: Adenocarcinoma of the endometrium: Survival comparison of patients with and without pelvic node sampling. Gynecol Oncol 56: 26, 1995

6. American Cancer Society guidelines for early detection of cancer. CA: A Cancer Journal for Clinicians 51:38, 2001