T Perez-Medina, J Bajo, G Folgueira, et al (Getafe Univ, Madrid)
Atypical Endometrial Hyperplasia treatment with Progestogens and Gonadotropin-releasing Hormone Analogues : Long-term Follow-up.
Gynecol Oncol 73: 299-304, 1999.
Atypical endometrial hyperplasia (AH) is characterised by abnormal growth of the endometrial glands with atypia in the nuclei. This condition can progress to malignancy. Although it is usually treated surgically, this is not appropriate for all women.
The study group consisted of 19 women, aged 29 to 65 years with a diagnosis of complex AH. Patients refused surgery because of a desire to preserve fertility in 2 cases, medical perclusion of surgery in 15 cases, and bad anesthetic experiences in 5 patients. The treatment consisted of 500mg of medroxyprogesterone given intramuscularly each week for 3 months and monthly injections of Triptorelin releasing depot for 6 months. Endometrial response was evaluated by hysteroscopy and biopsy during 5 years of follow-up.
Findings: Bleeding was arrested in all patients by the end of the treatment period. One patient progressed to adenocarcinoma and underwent surgery. At 5-year follow-up, regression was observed in 16 patients, persistence in 1, recurrence in 1, and progression in 1 patient.
Conclusions: Combined therapy with progestogens and GnRH-a was very effective as an alternative to surgical treatment for women with atypical endometrial hyperplasia. At 5-year follow-up there was an 84.5% cure rate. A prospective, randomized clinical trial with a larger series of patients is necessary to confirm and expand these results.
Editorial comment: Unfortunately, we do not know whether the 6 postmenopausal patients had received prior estrogen replacement therapy, nor is it known what proportion of the patients were very obese.
RF Vale, MS Baggish, (Northwestern Univ, Chicago; Good Samaritan Med Ctr, Cincinnati, Ohio)
Endometrial Carcinoma After Endometrial Ablation: High-Risk Factors Predicting its Occurrence.
Am J Obstet Gynecol 179: 569-572, 1998.
Carcinoma of the endometrium has been described in 8 women who underwent endometrial ablation.
Patient Selection: Dysfunctional uterine bleeding that does not respond to medical treatment and has no anatomic cause is the indication for endometrial ablation. Therefore, a complete examination to rule out malignant conditions must be part of the selection criteria for these patients.
Findings: Of the 8 patients reported in the literature with endometrial carcinoma after endometrial ablation, most had several risk factors for endometrial neoplasia. These factors were diabetes mellitus and obesity in 6 patients, hypertension in 3, postmenopausal bleeding unresponsive to hormone treatment in 6, carcinoma of the colon or polycystic ovary disease in 5, endometrial complex hyperplasia in 5, failure of progestin treatment in 5 and persistent hyperplasia on biopsy in 5 patients. In this high-risk group of patients, hysterectomy would be a better choice of treatment.
Conclusions: For those women with risk factors for endometrial carcinoma, a preablation biopsy demonstrating normal endometrium is necessary. Persistent hyperplasia which does not respond to hormone therapy is an indication that hysterectomy should be considered.
Editorial comment: The authors note that adequate endometrial evaluation, including hysteroscopy and endometrial sampling should be performed prior to the procedure. In case of endometrial hyperplasia if the patient is a poor operative candidate, ablation may be done. However, periodic long-term follow-up which probably should include vaginal ultrasound, and if possible, endometrial sampling of the residual endometrium should be performed.
E Weiderpass, JA Baron, H-O Adami, et al (Karolinska Inst, Stockholm, Sweden; Dartmouth Med School, Hanover, NH; Falun Hosp, Sweden; et al)
Low-Potency Oestrogen and Risk of Endometrial Cancer: A Case-Control Study.
Lancet 353: 1824-1828, 1999
Urogenital symptoms in postmenopausal women, which occur commonly, may be relieved by low-potency estrogen formulations given orally or vaginally. Such formulations are thought to have few, if any, adverse effects on the endometrium. However, the risk of endometrial neoplasia has not been established. The occurrence of endometrial cancer among postmenopausal women in Sweden was investigated in a nation wide, population based, case-control study.
Methods: Data on hormone replacement were obtained from 789 women with endometrial cancer and 3368 population control subjects. After a histologic review, 80 cases, were reclassified as endometrial atypical hyperplasia.
Findings: A multivariate analysis, with adjustment for covariates, showed that the oral use of estriol, 1 to 2 mg daily, increased the relative risk of endometrial cancer and endometrial atypical hyperplasia. Compared with “never use,” at least 5 years of use had an odds ratio of 3.0 for endometrial cancer and 8.3 for endometrial atypical hyperplasia. The association was stronger for well-differentiated cancers, and cancers with limited invasion. This excess relative risk declined rapidly after treatment was stopped. Vaginal application of low-potency estrogen formulations was only weakly associated with the relative risk of endometrial neoplasia.
The authors suggest adding of a progestogen to protect the women who are on low-dose estrogen.
Editorial comment : Estrogen alone is indeed a risk factor for endometrial neoplasia.
K Fukuda, M Mori, M Uchiyama, et al (Saga Med School, Japan)
Preoperative Cervical Cytology in Endometrial Carcinoma and its Clinicopathologic Relevance.
Gynecol Oncol 72: 273-277, 1999.
The study group consisted of a series of 99 consecutive patients age 31 to 86 years with primary endometrial carcinoma. Cervical cytologic smears were examined before surgical treatment. The average follow-up was 5.8 years. Of the 99 patients, 17.2% died of their primary disease during follow-up.
Findings: Normal cervical cytology was detected in 68 patients, suspicious cervical cytology was detected in 1 patient, and malignant cytology was detected in 30 patients. There was no association between cervical cytology and patient’s age or peritoneal cytology. Univariate analysis demonstrated that preoperative cervical cytology was related to survival.
Conclusion : Patients with endometrial carcinoma who have suspicious or malignant preoperative cervical cytologic smears are at increased of advanced high stage, invasive, and metastatic cancer. This indicates that cervical cytology can play a useful role in the preoperative analysis of endometrial cancer. However, multivariate analysis indicated that cervical cytology was not an independent prognostic factor and probably should not influence treatment decisions.
Editorial comment: DuBesheter notes that the authors report that positive cervical cytology had a positive predictive value of 45% for nodal spread. However, the negative predictive value in the literature ranges from 77% to 94%. In other words, nodal spread is unlikely in the presence of normal cervical cytology. DuBeshter makes a convincing argument that this knowledge is good enough that Ultrasound, MRI and frozen section, all expensive tests, to determine myometrial invasion are probably not that helpful.
A Zelmanowicz, A Hildresheim, et al (Natl Cancer Inst, Bethesda, Md; Johns Hopkins Med Institutions, Baltimore, Md; Bowman Gray School of Medicine, Winston-Salem, NC et al)
Evidence for a Common Etiology for Endometrial Carcinomas and Malignant Mixed Mullerian Tumors.
Gynecol Oncol 69: 253-257, 1998.
There are 3 categories of uterine malignant tumors: carcinomas, sarcomas and carcinosarcomas or malignant mixed mullerian tumors (MMMTs).
The authors found that obesity, exogenous estrogen use and nulliparity were associated with increased risk of both tumor types. MMMT patients were more likely to be black. Oral contraceptive use was protective for both types of tumors. Current smokers had a reduced risk of endometrial carcinoma, but former smokers had an increased risk of MMMT.
Conclusion: This study indicates that the risk factors for endometrial carcinoma and malignant mixed mullerian tumors are similar. This suggests that the pathogenesis of these 2 types of endometrial tumors may be similar. MMMTs may represent carcinomas that have secondarily developed sarcomatous differentiation. Confirmation of these findings in larger studies is required.
KM Greven, RB D”Agostino Jr, et al (Wake forest Univ Winston-Salem, NC; Delaware County Regional Cancer Ctr, Drexel Hill Pa; Thomas Jefferson Univ, Philadelphia)
Is there a role for a Brachytherapy Vaginal Cuff Boost in the Adjuvant Management of Patients with Uterine-confined Endometrial Cancer ?
Int J Radiat Oncol Biol Phys 42: 101-104, 1998.
Adjuvant pelvic radiation is often the treatment used for women with uterine-confined endometrial cancer with prognostic factors predictive of recurrence. For these women, the addition of a brachytherapy vaginal cuff boost is controversial. A comparison was made of patients receiving external beam radiation therapy alone and women receiving this therapy with brachytherapy vaginal cuff boost.
The authors have come to the conclusion that for pelvic control or disease-free survival in patients with stage I or II endometrial cancer, there is no suggestion that the addition of a vaginal cuff brachytherapy boost to pelvic radiation is beneficial. A positive result is unlikely to be seen by prospective randomized trials designed to study external irradiation alone versus external beam radiation plus vaginal brachytherapy. To improve disease-free survival in patients at risk for recurrence, protocol development for uterine-confined corpus cancer should focus on identifying patients at risk as well as other means of augmenting external beam irradiation therapy, such as the addition of chemotherapy, because this therapy alone provides excellent pelvic control.
MF Weiss, PP Connell, et al (Univ of Chicago)
External Pelvic Radiation Therapy in Stage IC Endometrial Carcinoma
Obstet Gynecol 93: 599-602, 1999
Patients with endometrial carcinoma who have deep myometrial invasion without extrauterine disease (stage IC) usually receive postoperative radiation therapy, consisting of external beam whole pelvic irradiation and vaginal brachytherapy.
The study group consisted of 61 women, aged 44 to 87 years, with a diagnosis of stage IC endometrial carcinoma who were treated with postoperative pelvic radiation alone between June 1986 and June 1995.
Findings: the 5-year actuarial disease-free survival rate was 86.7% and overall survival was 97.6% in this patient group. There were no local recurrences. Ten patients had distant metastases.
Conclusions: the results of this retrospective study suggest that women with stage IC endometrial carcinoma treated with surgery and adjuvant pelvic radiation, without vaginal brachytherapy, achieve excellent local cancer control. More research is needed on methods to control distant metastases in this patient group.
Editorial comment: As emphasized by the authors such additional treatment like vaginal brachytherapy leads to more vaginal stenosis, runs the risk of increased radiation complications, and most importantly provides no therapeutic advantage.
One patient did get a lateral pelvic wall recurrence, but the main problem is recurrent distal disease, which was observed in 10 (16%) of the patients.
MA Quinn, for the COSA-NZ-UK Endometrial Cancer Study Groups (anti-Cancer Council of Victoria, Melbourne, Australia)
Adjuvant Medroxyprogesterone Acetate in High-Risk Endometrial Cancer.
Int J Gynecol Cancer 8: 387-391, 1998.
One thousand twelve patients with grade 3 endometrioid, adenosquamous, clear-cell, or papillary serous cancer, or with any tumor that was more than one-third invasive or involved the cervix or adnexa, were enrolled in the study. The patients were given adjuvant MPA, 200 mg twice a day, or no hormonal treatment after surgery for 3 or more years.
Findings: Survival rates did not differ between groups. However, MPA recipients had a significantly longer disease-free intervals and survival then patients who did not receive MPA.
Conclusion: Although the MPA-treated patients had a significant reduction in disease recurrence, they did not have improved survival compared with the untreated patients. The use of adjuvant MPA at the dose tested and for the length of time used in the current study appears to have little place in the management of patients with high-risk endometrial cancer.
A L Herbst comments on article of Transvaginal Ultrasonography Compared with Endometrial Biopsy for the Detection of Endometrial Disease (Langer RD, for the Postmenopasual Estrogen/Progestin Interventions Trial Univ of California, San Diego; et al. N Engl J Med 337:1792-1798, 1997), saying that for patients with endometrial thickness less than 5mm there is little chance of endometrial pathology.
Thus transvaginal sonographic measurement of endometrial thickness in the asymptomatic postmenopausal woman appears to have poor positive predicted value and a very high negative predicted value for a cut-off of less than 5mm. It appears that there is no reason to do a biopsy in this group if they are without symptoms. However, the bleeding patient should be sampled, even with an endometrial a thickness of 5mm, since it was noted that carcinoma can be detected in such a patient.
Endometrial Thickness in Tamoxifen-treated Patients: An Independent Predictor of Endometrial Disease.
M Franchi, F Ghezzi, et al (Univ of Insubria, Varese, Italy)
Obstet Gynecol 93:1004-1008, 1999
Several studies have suggested that tamoxifen results in estrogenic changes in the endometrium, ranging from hyperplasia, polyps to invasive carcinoma.
Methods : One hundred sixty-three postmenopausal women with breast cancer who were receiving tamoxifen were studied.
Among women receiving tamoxifen, sonographic endometrial thickness exceeding 9mm and vaginal bleeding independently predict endometrial disease. Either one of these abnormalities should prompt hysteroscopy and biopsy.
The author has used endometrial thickness of more than 9mm and tamoxifen therapy for more than 27 months. Other studies have stressed a cutoff of 8mm and 24 months of treatment.
Endometrial Cancer in Polyps Associated with Tamoxifen Use.
LM Ramondetta, JB Sherwood, et al (Thomas Jefferson Univ, Philadelphia)
Am J Obstet Gynecol 180:340-341, 1999.
Five patients were reported and these patients ranged in age from 51 to 69 . Tamoxifen dosage was 20mg per day. Median duration of treatment was 3.8 years. Three women had postmenopausal bleeding, but 2 had no symptoms.
It was concluded that five cases of carcinoma arising within endometrial polyps were reported 4 of which were unassociated with other endometrial changes. Thus, the sonohystographic differentiation between a polypoid structure and a thickened or unusual endometrium does not obviate the need for histologic sampling and a full assessment of the uterine cavity.
Editorial comments – For patients taking tamoxifen for more than 2 years, there is a risk of endometrial cancer arising in polyps.
Parslov Michael, Lidegaard Ojvind, Klintorp Soren, et al, Copenhagen, Denmark
Risk factors among young women with endometrial cancer: A Danish case-control study.
Am J Obstet Gynecol 2000; 182: 23-29
This study was undertaken to identify and quantify risk factors for endometrial cancer among young women.
Endometrial cancer is a rare disease among premenopausal women. Seven percent of endometrial cancer occurs in women <50 years old. In the same age group about 300 curettage procedures and an equal number of endometrial biopsies are performed for every single diagnosis of endometrial cancer. When the physical complications attendant with these invasive procedures and the socioeconomic consequences of curettage as a screening procedure are considered, the question arises as to whether it is appropriate to carry out this number of intrauterine procedures in fertile women to find so few cases of endometrial malignancy.
Several studies have identified risk factors of endometrial cancer among older women, such as overweight status, estrogen replacement therapy, nulliparity, infertility, diabetes mellitus, and hypertension. However, these risk factors are not necessarily relevant for endometrial cancer among young women.
Hence this study was undertaken and findings were controlling for confounding influence from the other determinants revealed the following variables to be independent risk factors: family history of endometrial cancer, parity, age at first birth, number of induced abortions, use of oral contraceptives, and use of hormone replacement therapy.
Women with a family history of endometrial cancer (mother or sister) had an odd ratio of endometrial cancer of 2.1 (95% confidence interval).
Family predisposition: Family history of endometrial cancer in a first-degree relative (mother or sister) is a well-documented risk factor for endometrial cancer among both premenopausal and postmenopausal women, with odds ratios between 1.5 and 2.8. This relationship was confirmed by our data. It should be noted that the estimated odds ratio of 2.1 represents the impact of family predisposition after body mass index is controlled for. Thus the increased risk was caused by genetic circumstances other than adiposity.
Diabetes and hypertension: In this study no significant association emerged between endometrial cancer and diabetes. Hypertension was not an independent risk factor.
Cigarette smoking : In this study authors were not able to demonstrate an independent effect of smoking and anti-estrogenic effect of smoking.
All studies have demonstrated a protective effect of cigarette smoking on the risk of development of endometrial cancer among postmenopausal women. It is remarkable that the protective influence of cigarette smoking has not been apparent in several studies on premenopausal women with endometrial cancer.
Education : After adjustment for all variables, authors could not retrieve an association with years of schooling, which is a reliable indicator of social class.
Etiologic fraction : With a mother or sister who had endometrial cancer the risk of development of endometrial cancer was increased by a factor of 2. Hormone replacement therapy increased risk by a factor of 3 but only about 2% of premenopausal women receive hormone replacement therapy. Consequently, the etiologic fraction of hormone replacement therapy was 4%. Oral contraceptive use of >1year; ³ 2 term pregnancies, age ³ 30 years when giving birth at first time, and a history of incomplete pregnancies are all conditions that decreased the risk of development of endometrial cancer.
In conclusion, a number of risk factors for endometrial cancer are common to premenopausal and postmenopausal women. These are family history of endometrial cancer, reproductive history, hormone replacement therapy, and the use of oral contraceptives.
Increasing number of births reduced the risk of endometrial cancer. If all women gave birth ³ 2 times, about 40% of endometrial cancer in the premenopausal age group could be eliminated.
O’Regan RM, Cisneros A, England GM, et al [Northwestern Univ, Chicago; Univ of Wisconsin, Madison]
Effects of the Antiestrogens Tamoxifen, Toremifene, and ICI 182, 780 on Endometrial Cancer Growth
J Natl Cancer Inst 90: 1552-1558, 1998
Tamoxifen plays an important role in adjuvant therapy of breast cancer patients. Chronic use of tamoxifen has shown an increase in endometrial cancer. This is due to its estrogen and antiestrogen action.
This study on athymic mice demonstrated the toremifene a chlorinated derivative of tamoxifen has identical effects to tamoxifen for the development of endometrial cancer whereas ICI 182,780 pure antiestrogen. seems to be superior and may not adversely affect the endometrium.
Deborah J Dotters ( Eugene, Oregon)
Preoperative CA 125 in endometrial cancer: Is it useful ?
Am J Obstet Gynecol 2000; 182:1328-34
Objective : The authors sought to determine the clinical utility of preoperative CA 125 measurement in determining the need for lymphadenectomy in patients with endometrial carcinoma.
Study Design : A prospective nonrandomized study was performed over a 2-year period. Patients referred with the diagnosis of endometrial carcinoma had CA 125 levels determined before surgical staging. Operative findings were then correlated with preoperative CA 125 values. Standard statistical calculations were used to determine sensitivity, specificity, positive predictive value, and false-positive and false negative rates. The student t test was used to determine differences between mean values.
Results : Either a CA 125 level of >20 U/ml or a grade3 tumor or both of these correctly predicted 87% of patients requiring surgical staging. In patients with a preoperative diagnosis of stage 1, grade 1 or 2 tumors, a CA 125 level of >20 U/mL correctly identified 75% (9/12) of patients requiring lymphadenectomy compared with only 50% (6/12) identified when a CA 125 level of >35 U/mL had occult extrauterine disease at surgery.
Conclusion: Measurement of preoperative CA 125 is a clinically useful test in endometrial cancer. CA 125 levels of >35 U/mL strongly predicted extrauterine disease but lacked sensitivity in identifying patients needing staging. Either a CA 125 level of >20U/mL or a grade 3 tumor or both of these correctly identified 75% to 87% of patients requiring lymphadenectomy. Until more data are collected, abdominal hysterectomy should be the procedure of choice for patients with grade 1 tumors and CA 125 levels of <20 U/mL.