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Background: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. It is generally accepted that the occurrence of malignancy in endometrial polyps among healthy women is up to 0.5%. However, no one has yet described the incidence of this malignant transformation among postmenopausal breast cancer tamoxifen-treated patients. Objective. The aim of this study was to study the exact rate of malignant changes in endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients., Methods: We reviewed the pathological results and medical records of all postmenopausal breast cancer patients in whom endometrial polyps were recovered following at least 6 months of tamoxifen treatment in our institute. We also looked for the rate of malignant changes in polyps recovered from all healthy postmenopausal controls with endometrial polyps in our institute during the period of the study., Results: Two (3.0%) of 67 endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients revealed malignant features. None of the clinical variables tested, including risk factors for endometrial cancer, was significantly different between the groups. In the controls only 5 (0.48%) of 1034 polyps were malignant., Conclusion: Up to 3.0% of endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients may show malignant changes. This rate is higher than that found in our controls as well as that reported in the general female population., (Copyright 1999 Academic Press.)

Objective: The aim of this study was to evaluate changes in transvaginal ultrasonographic endometrial thickness with increased duration of tamoxifen treatment in postmenopausal breast cancer patients., Material and Methods: In this prospective study we evaluated the changes (mean +/- SD) of endometrial thickness measured by transvaginal ultrasonography in 181 postmenopausal breast cancer patients, according to the duration of tamoxifen treatment. According to our protocol, the ultrasonographic evaluations were performed every 6 months for the first 2 years of the follow-up and every 12 months thereafter. Two such subsequent ultrasonographic evaluations were performed in 181 patients following 35.1 +/- 41.7 months of tamoxifen treatment, three studies in 127 patients following 44.7 +/- 47.98 months of treatment, four studies in 75 following 54.2 +/- 61.7 months of treatment, five studies in 51 patients following 65.3 +/- 74.4 months of treatment, and six studies in 27 patients following 79.5 +/- 98.8 months of treatment., Results: The measured endometrial thickness detected varied from 8.84 +/- 4.66 to 10.61 +/- 12.35 mm. There were no significant changes in mean +/- SD of endometrial thickness following various durations of tamoxifen treatment., Conclusions: Extension of duration of tamoxifen treatment in postmenopausal breast cancer patients up to 79.48 +/- 98.79 consecutive months does not cause a significant increase in transvaginal ultrasonographic endometrial thickness., (Copyright 1999 Academic Press.)

Aim: Tamoxifen is the antihormonal treatment of choice for premenopausal breast cancer patients with advanced breast disease. Its premenopausal administration has been shown to induce supraphysiological 17beta-estradiol serum levels and to be associated with the presence of persistent, bilateral functional ovarian cysts. However, these abnormalities have not yet been compared to controls. In this study we evaluated the possibility that the above hormonal and/or ovarian abnormalities are more frequent among premenopausal breast cancer patients treated with tamoxifen than among similar nontreated patients, and thus they may be attributed to tamoxifen effect., Methods: We evaluated serum hormone levels of 17beta-estradiol, follicular-stimulating hormone, luteinizing hormone, and progesterone, the presence of ovarian cysts, and various demographic and clinical characteristics in 20 premenopausal breast cancer patients treated with tamoxifen (study group) and compared them to those observed in 12 similar nontreated patients (control group)., Results: Ovarian cysts were found in 80% of the study patients and only in 8.3% of the control patients (P = 0.001). The incidence of oligomenorrhea was nearly significantly higher in the study than in the control group (50 and 16.7%, respectively; P = 0.0651). Various serum hormone levels tested were not found to be significantly different between the two groups, except for 17beta-estradiol serum levels as detected on days 14 and 21 of the menstrual cycle, which were significantly higher among the study than in the control patients. (Day 14 serum estradiol: 757.7 +/- 372.0 pg/mL versus 206.5 +/- 275.0 pg/mL, P = 0.0012. Day 21 serum estradiol: 300.0 +/- 134.5 pg/mL versus 96.5 +/- 71.5 pg/mL, P = 0.0008.), Conclusions: Tamoxifen treatment increases the incidence of ovarian cysts and the significantly higher 17beta-estradiol serum levels in premenopausal breast cancer patients., (Copyright 1999 Academic Press.)

Malignant transformation of benign cystic teratoma of the ovary is rare, with an incidence of 1.8%. The commonest malignant neoplasm to develop is squamous carcinoma (80%). Adenocarcinoma occurs with less frequency, and only one of which has ever been cited to be of gastrointestinal origin. A 38-year-old female underwent TAH-BSO due to a large right ovarian tumor. Microscopically and immunohistochemically, the tumor was defined as mucinous adenocarcinoma originating from gastrointestinal epithelium in benign cystic teratoma., (Copyright 1998 Academic Press.)

Assessment of receptor levels in tamoxifen-exposed endometrial pathologies may indicate endometrial cells potential for interaction with tamoxifen. To assess this assumption, we analyzed estrogen receptor (ER) and progesterone receptor (PR) expression by an immunohistochemical technique in endometrial specimens with benign hyperplasia, benign polyps, and carcinoma obtained from postmenopausal breast cancer patients treated with tamoxifen (study group) and from age-matched healthy postmenopausal women treated with estrogen replacement therapy (control group I) and not treated with estrogen replacement therapy (control group II). Overall gland and stromal ER expression of benign endometrial hyperplasia and of benign endometrial polyps was significantly higher in control groups I and II than that obtained from the study group (endometrial hyperplasia: P = 0.0274 and 0.00093, respectively, and P = 0.00003 and 0.00001, respectively; benign endometrial polyps: P = 0.02889 and 0.00596, respectively; and P = 0.00228 and 0.00005, respectively), while there were no differences between the two control groups. Overall gland and stromal PR expression was nearly similar in all the three groups (P = NS). There was no correlation between the length of tamoxifen treatment and the presence of ER and PR in various endometrial pathologies in the tamoxifen-treated patients. The significantly lower ER expression in most benign endometrial pathologies obtained from postmenopausal tamoxifen treated patients may further support the weak estrogen-like effect of tamoxifen on the endometrium in the menopause.

Postmenopausal breast cancer patients who were treated with tamoxifen and progestogens showed a uniform decidual reaction of the endometrium. It is well established that progestogens antagonize the estrogen effect on the endometrium by reducing its receptors in the endometrium. To assess in vivo such a possible effect of progestogens on endometrium primarily exposed to tamoxifen, we analyzed estrogen and progesterone receptors (ER, PR) on endometrial specimens showing decidualization from nine postmenopausal breast cancer patients on tamoxifen and progestogen treatment and on endometrial polyps with areas of decidualization from two other similar patients. ER was weakly detected in the endometrial glands of four (36.4%) patients and in the endometrial stroma of one (9.1%) patient. PR was detected in the endometrial gland of only one (9.1%) patient. No PR was detected in the endometrial stroma. There was no correlation between the length of tamoxifen treatment, the tamoxifen dosage, or the length of progestogen treatment and the ER or PR content, although progestogens were administered for more than 3 consecutive months in all patients. This relatively very low ER and PR content may be attributed to the antagonistic effect of progestogens on the "priming" estrogen-like effect of tamoxifen on the endometrium.

A prospective study was performed to assess the efficacy of sonohysterography (SHG) in identifying endometrial pathologies among asymptomatic, postmenopausal breast cancer patients treated with tamoxifen. In this study the uterine cavity of 68 such patients with endometrial thickness of > or = 8 mm was prospectively evaluated by SHG. Forty-six (67.6%) patients in whom SHG did not identify any findings in the uterine cavity (negative group) were followed by diagnostic hysteroscopy. Another 22 (32.4%) who were identified by SHG to have abnormal endometrial findings, such as an echogenic or polypoid mass (positive group), were followed by operative hysteroscopy and by postoperative SHG. In the positive group the basal transvaginal sonogram revealed an endometrial echogenic mass in only 10 (45.5%). In the remaining 12 (54.5%) patients, the transvaginal sonogram identified only thick endometrium. In these latter 12 patients, histological assessment confirmed endometrial polyps in 8 (66.7%) and fibroid in 1 (8.3%). Four (18.2%) patients in the positive group had no histological endometrial pathology. Two (50%) of them had a uterine septum as diagnosed during hysteroscopy, in one (25%) operative hysteroscopy failed to resect the endometrial polyp, and in another (25%) there was a false-positive SHG diagnosis. Overall, SHG accurately diagnosed endometrial and/or other intrauterine pathology in 95.5% of these patients. In the 46 patients with "negative" basal SHG features, diagnostic hysteroscopy confirmed this diagnosis. Thus, there was no SHG false-negative diagnosis. Comparing the results of the basal SHG with those of operative hysteroscopy and/or the histopathological findings in the positive group, the sensitivity of SHG was 1.0, the specificity 0.0, positive predictive value 95.5%, and negative predictive value 0.0. It is suggested that SHG is a useful diagnostic tool for the assessment of specific endometrial pathologies in asymptomatic postmenopausal breast cancer patients treated with tamoxifen who were diagnosed by transvaginal sonography to have thick endometrium.

Background: Postmenopausal breast cancer patients treated with tamoxifen have been found to have a high incidence of ovarian tumors. Transvaginal ultrasonography is an accurate and reliable method for measuring ovarian size. The purpose of this study was to establish normal values for basal ovarian volume in postmenopausal tamoxifen-treated patients and compare them with those established for healthy, postmenopausal women in the same population with no exposure to hormone treatment., Methods: In a prospective open pilot study, the ovaries of 65 postmenopausal breast cancer patients treated for at least 6 months with tamoxifen were measured by transvaginal ultrasonography. From the same population, 311 healthy postmenopausal women with no exposure to hormone therapy were examined and served as controls. After matching for menopausal age, ovarian volume was compared between groups., Results: Mean ovarian volume of postmenopausal tamoxifen-treated patients was persistently low through the menopause, whereas the mean ovarian volume of the controls was large, gradually decreasing up to the 10th menopausal year (8.6 +/- 2.3 and 2.8 +/- 2.1 cm3, respectively). Mean ovarian volume of the tamoxifen-treated patients was significantly lower than that of the controls during the initial menopausal years., Conclusions: An ovarian volume that is considered within normal range for a specific menopausal age in a healthy postmenopausal woman is abnormal for a postmenopausal tamoxifen-treated patient.

We present a 46-year-old patient who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy for persistent trophoblastic disease. Single-agent chemotherapy with alternate methotrexate 1 mg/kg/day and leucovorin 0.1 mg/kg for 8 days was instituted on the first postoperative day. Various adverse symptomatology developed, culminating in a unique side effect, polyserositis. To the best of our knowledge, the wide spectrum of side effects, the short time lapse after onset of chemotherapy, and their severity are uncommon in a patient receiving her first chemotherapeutic treatment with MTX.

From September 1, 1989, to November 30, 1994, 175 menopausal breast cancer patients treated with tamoxifen were followed at the authors' institutions. During this period. 16 (9.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, for various indications. Of these, 10 (62.5%) had either uni- or bilateral ovarian tumors. The analysis of surgical findings showed an incidence of 5.7% (10/175) ovarian tumors among all the patients. In 2 (20%), the ovarian masses displayed enlargement over a relatively short period while on treatment. In 5 (50%) patients, the findings were bilateral. All tumors were detectable by ultrasonography, except four serous cystadenomas found in 3 women. The mean duration of tamoxifen treatment was 36.6 +/- 24.9 (range 9-86) months. The rate of 5.7% for ovarian tumors, in this selected group of patients, is four to five times higher than that reported for similar pathologic conditions detected by general screening with ultrasonographic scans among nonselected, asymptomatic, and untreated postmenopausal women. Two possibilities should be considered in the development of ovarian tumors coinciding with tamoxifen treatment; (1) women with breast malignancy are prone to develop benign or malignant ovarian tumors in relation to genetic factors, regardless of tamoxifen treatment; and (2) tamoxifen may stimulate enlargement of such tumors and may even cause them.

Between September 1, 1989 and October 31, 1994, 173 postmenopausal breast cancer women on tamoxifen treatment were followed up in the authors' institutions. During this period, 14 (8.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for various indications. Eight (57.1%) were found to have adenomyosis, of whom one had a large fundal adenomyotic lump and the other seven patients had two to four small microscopic foci of adenomyosis. In this study, the rate of adenomyosis described among those postmenopausal breast cancer patients treated with tamoxifen is nearly three to four times higher than the rate reported in the literature for pre- and postmenopausal women. There is no previous reported increased incidence of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen. Thus, it is suggested that the prolonged and unopposed estrogen-like stimulation by tamoxifen may play a causal role rather than be a casual factor in the development of this pathologic entity.

Adjuvant tamoxifen therapy for breast cancer patients has been found to be associated with various endometrial pathologic conditions, including endometrial cancer. This preliminary case control study evaluated whether prolonged and continuous exposure to tamoxifen in the menopause may aggravate existing endometrial pathologies. Two vaginal ultrasound evaluations of endometrial thickness and histologic findings of two endometrial biopsies, performed 18 months apart, were evaluated for 25 asymptomatic, postmenopausal breast cancer patients who were continuously treated with tamoxifen. In the first endometrial biopsy, 4 patients (16.0%) were found to have endometrial pathologies: 2 patients had proliferative endometrium, 1 had hyperplastic endometrium, and 1 had an endometrial polyp. In the second endometrial biopsy, none of these patients showed any endometrial pathologies. Another patient (4.0%) with no endometrial pathology in the first visit had endometrial hyperplasia in the second visit. None of the patients developed endometrial cancer, and generally there was no increase in ultrasonographically-measured endometrial widths. The results of this preliminary study may suggest that there is no increased risk of development of endometrial pathologies during an additional 18 months of continuous tamoxifen therapy nor is there aggravation of already existing endometrial pathologies.

Endometrial thickness, as evaluated by vaginal ultrasonography, and endometrial histologic findings, as well as demographic characteristics, health habits, and risk factors for endometrial cancer, were compared between 93 asymptomatic postmenopausal breast cancer patients who had been on tamoxifen treatment and 20 patients who had not. The mean ultrasonographic endometrial thickness in the women on tamoxifen treatment was 13.1 +/- 10.4 mm, which was significantly thicker than the 4.0 +/- 3.2 mm found in the nontreated women (P = 0.001). The frequency of endometrial pathological findings was remarkably high (35.5%) among the tamoxifen-treated patients, compared with nontreated patients (20.0%), with a P value of 0.058 and an odd ratio of 4.6. Thus, it is suggested that the remarkably high prevalence of pathological endometrial changes was due to the continuous and unopposed exposure of the endometrium to tamoxifen.

We present the first case of heterologous mixed mesodermal tumor that developed 9 years following tamoxifen therapy in a climacteric woman with no previous pelvic irradiation and was initially treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. She continued tamoxifen therapy for 2 years, following the initial treatment, until the diagnosis of a recurrent tumor by laparotomy. The patient died of the disease 5 months subsequent to the second surgery. The association of prolonged unopposed estrogenic stimulation, with tamoxifen as a possible etiologic factor in the development of endometrial sarcomas, is discussed.

From January 1, 1984 to April 30, 1990, 38 patients were surgically found to have an intraabdominal disease resembling epithelial ovarian cancer. This diagnosis was confirmed in 31 patients; the remaining 7 met the criteria of primary peritoneal papillary serous carcinoma. Five of these were diagnosed retrospectively and two during surgery. The mean age at diagnosis was 61.2 years. Tumor histology revealed papillary serous carcinoma in six and mixed (papillary serous and papillary clear cell carcinoma) in one patient. Optimal debulking was achieved in three of seven cases (42.8%). Cisplatin-based combination chemotherapy was administered to all in the study group. Complete response was obtained in four patients, with one surviving for 76 months. The median survival in these patients was 34.5 months (range 6-76 months). Currently, three patients with complete response are alive with clinically undetectable disease. CA-125 assays were available in three cases and blood levels corroborated the clinically determined status of the disease. Tumor steroid hormone receptor status was determined in one case and revealed low levels of estrogen and progesterone receptors. To the best of our knowledge, the usefulness of CA-125 in the diagnosis, management, follow-up, and determination of tumor steroid hormone receptor status, mixed papillary serous and clear cell subtype histological patterns for primary peritoneal papillary serous carcinoma are first described in this report. It seems that this neoplasm may be treated and followed up as in epithelial ovarian cancer, obtaining long-term survival; however, the biologic behavior and management problems of this relatively new entity deserve further clinical experience.

A case of squamous cell carcinoma of the endometrium which fulfills Fluhmann's criteria is presented. This case is reviewed together with additional 25 cases which had been already reported in various papers in the literature. The pathogenesis and the etiologic factors associated with primary squamous cell carcinoma of the endometrium are discussed. A review of the literature indicates that this rare malignancy is found in older patients, is highly malignant and carries a poor prognosis as myometrial invasion, and local extension or metastasis is found in 80% of the patients.