Endometrial

Written by:
Robert J. Lotocki, M.D., F.R.C.S.(C)
Professor, University of Manitoba
Division Gynecological Oncology
Gynecology Head, St. Boniface General Hospital
Winnipeg, Manitoba

• Introduction
• Presentation
• Etiology
• Staging
• Histology
• Management of Endometrial Cancer
• Hormone Replacement Therapy
• References

INTRODUCTION

Endometrial cancer is the most common cancer of the female genital tract seen in Canada and other industrialized countries. It is the fifth most common cancer seen in women and ranks ninth as a cause death. For the year 2001, 3500 new cases and 670 deaths are estimated with a resulting 0.19 death/case ratio1.

Endometrial carcinoma has been inappropriately referred to as a "benign cancer", because of relatively high cures rates with low-risk disease in the majority of patients. However, high-risk histology and advanced surgical stage are associated with a poor prognosis.

In recent years, there is an increasing desire to individualize treatment of endometrial cancer to avoid over-treatment in patients at low and intermediate risk of recurrence and more aggressive treatment in those patients at high risk of recurrence.

PRESENTATION

The median age for endometrial cancer is 61 years. Although it is essentially a disease of the postmenopausal years, 20% of cases will be diagnosed before the menopause and 5% below the age of 40 years.

Endometrial cancer develops in the layer of tissue that lines the inside of the uterus. Most women (90%) will experience abnormal uterine bleeding as an early symptom. Any abnormal bleeding or brownish discharge in the postmenopausal patient should be evaluated. Persistent intermenstrual bleeding or heavy prolonged bleeding in the perimenopausal or anovulatory premenopausal women should be considered abnormal and be evaluated.

On occasion, a patient may present with an abnormal smear, with a central mass due either to a hematometra or pyometra, or rarely, with symptoms of distant disease such as ascites, bony pain or shortness of breath as a result of chest metastases.

There are cases of endometrial cancer occurring in individuals who had been treated with uterine ablation for dysfunctional uterine bleeding. Ablations may not destroy the entire endometrium. The frequency or patterns of presentation of endometrial cancer in patients having had an endometrial ablation needs to be defined.

ETIOLOGY

Increased risk is seen association with women whose menopause occurs at a late age, women who are overweight, women who have never been pregnant and women who have the gene for hereditary nonpolyposis colorectal cancer (HNPCC)2.

Late menopause, defined as greater or equal to 52 years of age, has 2.4 fold-increased risks. The average age of menopause in Canada is 51.9 years.
Obese women have an increased risk. If 21 to 50 pounds overweight, women have three times the risk and if they are over 50 pounds overweight, then the risk is rises to almost 10 times.

The significance of diabetes mellitus as an independent risk factor is controversial. A study has suggested a 2.5 risk after controlling for age and body weight - others found no increased risk.

Hypertension does not appear to be an independent risk factor after controlling for weight.
The risk with nullipariety is twice as high when compared to women with a single child and more than three times as high for women with five or more children. Usually, this is an individual who has anovulatory cycles due to polycystic ovaries and has not been able to conceive. This is in contrast to an individual who has made the choice not to have children, but is having ovulatory cycles or is using oral contraceptives.
Other malignancies such as breast, ovary and colon occur in the same women with greater frequency than can be explained by chance alone. In a small number there is an identified gene that links these cancers.

Prolonged estrogen replacement therapy without progesterone, increases the risk of endometrial cancer by 4 to 11 times when compared to those women not using estrogens3. Risk remains with the varied methods of estrogen exposure - continuous oral estrogen, cyclic oral estrogen, topical application with vaginal estrogen, skin patches, or injectable. Similarly, the risk with various "natural" non-pharmaceutical products available through health food stores and natural paths will vary dependent on the estrogen content of these products. In contrast, combined estrogen and progesterone therapy prevents this increased risk4.

Despite tamoxifen's anti-estrogen effect (antagonist) in breast cancer, long-term use of tamoxifen in the management of breast cancer is associated with estrogen stimulation (agonist) effect on the uterus. Tamoxifen estrogen agonist effect on the uterus results in an increased incidence of uterine fibroids, endometrial polyps, endometrial hyperplasia and endometrial cancer5. Studies suggest that the relative risk of developing endometrial cancer while using tamoxifen to be twofold to threefold higher6.

Prevention of endometrial cancer is reduced with prior and current use of oral contraceptives, the concomitant use of progestational agents while using estrogen replacement, menopause earlier than age 49, individuals that are of expected weight, multipariety and in smokers.

STAGING

The current 1988 international Federation of Gynecology and Obstetrics (FIGO) staging for carcinoma of the endometrium is surgical (Table 1). Staging system requires hysterectomy, bilateral salpingo-oophorectomy, washings for cytology, pelvic nodal sampling, para-aortic nodal sampling, and biopsy of any suspicious area for staging to be complete. With high histology, papillary serous, clear cell and perhaps the grade 3 adenocarcinoma, a more extensive staging should be performed.

Complete staging, as suggested by the FIGO surgical staging, is not being routinely performed for several reasons. Routine lymphadenectomy may not be done because of technical difficulties in obese patients, some physicians may lack the necessary surgical skills, and perhaps lymphadenectomy may not be required in early disease. Some data suggests that para-aortic nodes are positive in less than 2% if the pelvic nodes are negative7.

Nevertheless, more accurate information can be obtained with surgical staging.
Three groups can be identified according to their risk of recurrence using surgical-pathologic data8. Future studies can focus on adjuvant therapy for this high-risk group and reducing the use of radiotherapy in the intermediate group (Table 2).

Table 1

Table 2

PRECURSOR LESIONS

As with cervical cancer, the endometrium may exhibit certain patterns that suggest a precursor to endometrial cancer. These are generally grouped together under the generic term "endometrial hyperplasias". There are several nomenclatures for a finite number of histology patterns.

Cystitic Hyperplasia

The endometrium displays enlarged and cystically dilated endometrial glands. The actual endometrium in most instances is thin and atrophic. Cystic hyperplasia is often seen in the menopausal years and has no premalignant implication.

Adenomatous Hyperplasia

The endometrial glands are more prominent, proliferating at the expense of the surrounding stroma. The cells of the glands are not cytological atypical. Adenomatous hyperplasia may be seen at any age and is often the product of sustained estrogen stimulation without any progestational exposure. Adenomatous hyperplasia is seldom premalignant.

The lesion may be reversed with progestational agents. This needs to be verified by repeating an endometrial biopsy.

Atypical Adenomatous Hyperplasia

The histology of atypical adenomatous hyperplasia is associated with atypical cytologic atypia and a proliferation of glands. Histology studies suggest that approximately 15 to 25% of patients with atypical adenomatous hyperplasia will progress to carcinoma.

Often when the uterus is examined after hysterectomy, a coexisting well-differentiated adenocarcinoma will be present. Because of its premalignant nature and frequent association with cancer, atypical adenomatous hyperplasia is best managed with hysterectomy. Where fertility is desired, progestins may be tried, but with careful histology follow-up.

HISTOLOGY

With a better definition of the histology subtypes, histology has become a distinctive prognostic feature.

The most common endometrial cancer cell type is endometriod adenocarcinoma (75 to 80%). It is composed of malignant glandular elements: an admixture of squamous metaplasia is not uncommon. Three grades of adenocarcinoma are recognized: grade 1 is well differentiated, grade 2 is moderately differentiated with partly solid areas, and grade 3 is predominantly solid.

Papillary serous and clear cells are similar to those noted in the ovary and the fallopian tube. Extra-uterine disease and nodal metastases are seen more frequently.

METHODS FOR SCREENING (OR EARLY DIAGNOSIS)

Currently, there is no proven method of routine screening for endometrial carcinoma in the asymptomatic population.
Historically, dilatation and curettage has been used in the diagnostic evaluation of the symptomatic patient presenting with postmenopausal bleeding, dysfunctional uterine bleeding or abnormal endometrial features on ultrasound. Because an operative room setting and analgesia are required, dilatation and curettage does not lend itself to screening.

Direct sampling of the endometrium in an office setting is possible with a variety of commercially available flexible aspiration devices that yield a histology sample9. These are well tolerated in an office setting. The presence of cervical stenosis may prevent successful endometrial sampling but is relatively infrequent. The accuracy of endometrial sampling is approximately 90 percent, negating the need for diagnostic dilatation and curettage. Since in the majority of women with postmenopausal bleeding the endometrium is atrophic, it is common to obtain minimal tissue. Hence, obtaining a pathology report reported as insufficient tissue for diagnosis is considered as an acceptable report.

Transvaginal ultrasound can be used to assess the endometrium where endometrial biopsy is inconclusive and abnormal uterine bleeding persists or where endometrial biopsy is impossible because of cervical stenosis. Patients, who's endometrium is less than five millimeters in double thickness, do not have endometrial pathology and have an atrophic endometrium10. False positive assessments can occur with patients using estrogen replacement or tamoxifen11. Any endometrial thickening greater than 5 millimeters will require that an endometrial biopsy be performed.

Several studies have demonstrated the value of Hysteroscopy for the diagnosis of anatomical lesions within the endometrial cavity12. Hysteroscopy can be performed in the office or operating room and should be combined with biopsy to obtain a tissue diagnosis.

The Papanicoloau cervical smear is not reliable as a screening procedure in endometrial cancer because it samples the cervix and not the area at risk. Only 50 percent of women with endometrial carcinoma will have malignant cells detected by cervical cytology13. Few of these patients will be asymptomatic. There is a strong correlation between positive cytology and high-risk disease. In the asymptomatic postmenopausal patient, the presence of normal-appearing endometrial cells is associated with endometrial carcinoma in 6%. The presence of abnormal-appearing endometrial cells is associated with endometrial hyperplasia in 13% and carcinoma in 25%.

The progesterone challenge test is a simple clinical test that can assess whether there has been estrogen stimulation of the endometrium. A negative test, when the patient does not have a withdrawal bleed, indicates that the patient has an atrophic endometrium.
A patient with a positive test, whom has a withdrawal, warrants an endometrial biopsy. The progesterone challenge test has not been widely accepted. However, the progesterone challenge test may be justified for high-risk asymptotic individuals.

MANAGEMENT OF ENDOMETRIAL CANCER

Despite the frequency of adenocarcinoma of the endometrium, a consensus on optimal surgical staging and adjuvant therapy is lacking. Nevertheless, significant advances in our knowledge of endometrial cancer have occurred in the past two decades. Focus has been directed toward defining risk factors that are associated with poor clinical outcomes and where more aggressive adjuvant therapy may improve outcome.

Surgery has emerged as the primary management, providing therapy and staging. Few patients will not be surgical candidates because of associated high-risk medical conditions. Preoperative radiotherapy has largely been abandoned.

Adjuvant therapy can be tailored according to the surgical-pathologic findings (Table 2). In the absence of nodal biopsies, pelvic radiation is given to individuals with intermediate risk endometrial cancer because of the risk of nodal disease. Current investigation is being done to evaluate if these individuals with significant invasion and negative nodes can be managed without pelvic radiation and its potential morbidity.

With staging, high-risk patients with endometrial cancer and patients with high-risk histology can be evaluated in clinical trials to find treatments that will improve their prognosis.

HORMONE REPLACEMENT THERAPY

Estrogen replacement therapy has traditionally been considered contra-indicated in patients with endometrial carcinoma. With good prognostic lesions, estrogen replacement should not be withheld. Estrogen replacement has not been shown to compromise patients with Stage I disease but has been shown to improve survival14.

Further there does not appear to be any untoward effects with high histology such as papillary serous and clear cell. Survivors of endometrial cancer should not be denied the opportunity to benefit from the positive results of estrogen replacement therapy.

REFERENCES

1. Canadian Cancer Statistics: 2001 National Cancer Institute of Canada
   
   
2. Danforth's Obstetrics and Gynecology. Seventh edition. Lippincott Company, 1994.
   
   
3. Jick, S.S., Walker, A.M., Jick, H.: Estrogens, progesterone,and endometrial cancer. Epidemiology; 4(1): 20-24, 1993.
   
   
4. Jick, S.S.: Combined estrogen and progesterone use and endometrial cancer. Epidemiology; 4(4): 384-389, 1993.
   
   
5. Kedar RP, Bourne TH, Powles TJ, et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomized breast cancer prevention trial. Lancet 1994; 343: 1318-1321.
   
   
6. Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen- treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. Journal of the National Cancer Institute 1994; 86: 527-537.
   
   
7. Faught, W., Krepart, G.V., Lotocki, R.J., Heywood, M. Should selective paraaotic lymphadenectomy be part of surgical staging for endometrial staging? Gynecol Oncol; 55: 51-55, 1994.
   
   
8. Morrow, C.P., Bundy, B.N., Kurman, R.J. et al. Relationship between surgical- pathologic risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group Study. Gynecol Oncol; 40: 55-65, 1991.
   
   
9. Hofmeiser, F.J. Endometrial biopsy: another lok. Am J Obstet Gynecol; 118:773- 7, 1974.
   
   
10. Bourne, T.H., Campbell, S., Steer C.V., et al. Detection of endometrial cancer by transvaginal ultrasonography with colour flow imaging and blood flow analysis: a preliminary report. Gynecol Oncol; 40: 253-9, 1991.
    
    
11. Anteby, E., Yagel, S., Palti, Z., Hochner-Celniker, D. False sonographic appearance of endometrial neoplasia in postmenopausal women treated with tamoxifen. Lancet; 1:433-444, 1992.
    
    
12. Cacciator B, Ramsey T, Lehtorvirta P, Ylostalo P. Transvaginal Sonography and Hysteroscopy in Postmenopausal Bleeding. Acta Obstet Gynecol Scand 1994: 73: 413-416.
    
    
13. DuBeshter B, Washal DP, Angel c, et al. Endometrial carcinoma: the relevance of cervical cytology. Obstet Gynecol 1991; 77: 458-462.
    
    
14. Creasman, W.T., Henderson, D., Hinshaw, W., Clarke-Pearson, D.L. Estrogen replacement therapy in the patient treated for endometrial cancer. Obste Gynecol; 67:326-30, 1986.