DNA-content in endometrial carcinoma of tamoxifen-treated breast cancer patients

DNA measurements and histopathologic evaluation were performed in 17 patients treated with adjuvant tamoxifen for early breast cancer and who developed endometrial carcinoma during or after the tamoxifen therapy. The tumors were exclusively characterized by euploid DNA content except for two cases, one mixed mesodermal sarcoma, a highly malignant and rare tumor, and one adenocarcinoma. Although the use of adjuvant tamoxifen therapy most likely enhances the risk of developing endometrial carcinoma, the beneficial effects of adjuvant breast cancer treatment is of well-known clinical importance. The hazards of giving long-term tamoxifen seem to be low since the endometrial tumors were associated with low-grade malignancy and euploid DNA pattern.     

Malignant endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients.

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.     

Ovarian cysts in tamoxifen-treated women with breast cancer

OBJECTIVE: The objective of this study was to detect any ovarian changes in tamoxifen-treated breast cancer patients. METHODS: In all, 51 patients with breast cancer were enrolled in the study, which was conducted in the SSK (Social Security Agency) Aegean Maternity Hospital between January 1999 and December 2002. The patients' demographic and medical data were reviewed. All patients taking part in the study received tamoxifen therapy, but the duration was not uniform. Gynecological examination and transvaginal ultrasonography (TVU) were performed in each case. Any ovarian cysts or masses were identified, and serum Ca-125 levels were recorded. RESULTS: Of the 51 tamoxifen-treated patients enrolled in this study, 24 were still premenopausal and 27 were postmenopausal when they were monitored for breast cysts during the tamoxifen treatment started after the diagnosis of breast cancer. Their average age was 53.7 (range 31-64) years. The mean duration of tamoxifen therapy was 23.5 (range 8-49) months. Ovarian cysts were diagnosed in nine (17.6%) patients and required surgery in two of these; pathological examination revealed serous cysts of the ovary in both. CONCLUSION:: In cases with ovarian cyst formation during tamoxifen treatment of breast cancer, discontinuation of tamoxifen followed by monitoring is quite a reasonable way to proceed in most cases. Surgical intervention should be carried out when cysts are >5 cm in diameter.     

Transvaginal ultrasonography and hysterosonography to monitor endometrial effects in tamoxifen-treated patients

PURPOSE OF INVESTIGATION: Our purpose was to evaluate if, during tamoxifen treatment, hysterosonography may increase diagnostic accuracy when compared with transvaginal ultrasonography and to identify, when and in how many cases, further biopsies may be avoided. METHODS: We performed transvaginal utrasound in 310 asymptomatic women under tamoxifen treatment, using 8 mm endometrial thickness as the cut-off. One hundred and seven patients with an endometrium thicker than 8 mm were enrolled for hysterosonography. Parameters to be evaluated by transvaginal ultrasound and hysterosonography were thickness and structural features of the endometrium. It was possible to compare ultrasound examinations with histopathological findings obtained by biopsy in 83 patients. RESULTS: Globally only ten patients from the study cohort had true endometrial pathology. Based on structural features of the endometrium, we found a global accuracy of 95.6%, with 2.8% false negatives and 4.1% false positives. CONCLUSION: Hysterosonography can increase diagnostic accuracy during tamoxifen treatment and may allow further invasive investigations to be avoided in patients with suggestive hysterosonographic features.     

Psychological impact of endometrial monitoring in tamoxifen-treated postmenopausal breast cancer patients

In view of the higher incidence of endometrial pathology in tamoxifen-treated breast cancer patients, it has been recommended that endometrial surveillance be performed on these women by means of transvaginal sonography. Our study investigated how breast cancer patients experience the endometrial surveillance and which personality factors influence this experience. We also studied compliance with the recommended examination. Fifty-three consecutive asymptomatic postmenopausal breast cancer patients who had taken tamoxifen for at least 6 months were included. Our results show that 23% of the women felt very anxious just before the examination. One woman in five evaluated the procedure as annoying, unpleasant, invasive and awkward, but only 3% found it really unacceptable. Difficulties in coping with mastectomy as well as anxiety negatively affected the experience of the examination. One in six women were doubtful about their ability to comply with such an examination in the future. Women who have difficulties in coming to terms with the mastectomy, anxious women, and women with a low tolerance towards common medical procedures are at especial risk of becoming dropouts. Suggestions are made for developing strategies that might improve these women's compliance.     

Endometrial thickness in tamoxifen-treated patients: an independent predictor of endometrial disease.

OBJECTIVE: To assess the independent contribution of transvaginal ultrasound in identifying women at risk for endometrial disorders, and determine whether a cutoff value identifies women who need endometrial histologic assessment. METHODS: Postmenopausal women with breast cancer who were receiving tamoxifen, with ultrasonographic endometrial thickness greater than 4 mm or vaginal bleeding, had hysteroscopy with selective endometrial biopsies. Endometrial thickness, duration of tamoxifen therapy, and endometrial histology were studied. Parametric and nonparametric tests and logistic regression and receiver operating characteristic curves were used for statistical analysis. RESULTS: The study population consisted of 163 women, 46 with vaginal bleeding. The proportion of women with abnormal histologic findings was greater among those with endometrial thicknesses exceeding 9 mm compared with those with endometrial thicknesses 9 mm or less (60% versus 6.1%, P < .001) and among women who received tamoxifen for more than 27 months than those who received it for less time (46% versus 16%, P < .005). Logistic regression showed that endometrial thickness greater than 9 mm and vaginal bleeding were independent predictors of abnormal findings at hysteroscopy. CONCLUSION: In women taking tamoxifen, sonographic endometrial thickness exceeding 9 mm and the presence of vaginal bleeding are independent predictors of endometrial disease. If either exists, hysteroscopy and biopsy should be done.     

Estrogen receptor polymorphisms in tamoxifen-treated women with breast cancer.

In postmenopausal women with estrogen receptor (ER)-positive breast cancer, long-term tamoxifen administration has proved beneficial after surgical treatment and subsequent chemotherapy. One of the major adverse effects of tamoxifen is the development of endometrial pathology (polyps, endometrial hyperplasia and endometrial cancer). PvuII and XbaI polymorphisms of the estrogen receptor-alpha gene (ERalpha) and RsaI and AluI polymorphisms of the estrogen receptor-beta gene (ERbeta) have been associated with breast cancer. Thus the present study aimed to identify whether ER gene polymorphisms are associated with breast cancer stage or endometrial responsiveness to long-term tamoxifen treatment in 87 postmenopausal, tamoxifen-treated women with ER-positive breast cancer. The mean age of the patients was 58.7 +/- 4.7 years and the mean duration of tamoxifen treatment was 3.9 +/- 1.1 years. At diagnosis, the stage of breast cancer was determined as follows: 29 women (32%) at Stage I, 49 (58%) at Stage II and 9 (10%) at Stage III. The frequency distributions of the estrogen receptor polymorphisms in all women with breast cancer were not different from those predicted by the Hardy-Weinberg equilibrium hypothesis (p > 0.10). None of the ER polymorphisms studied was linked to either the presence of endometrial pathology or the stage of breast cancer.     

A randomised controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women

Objective  To study the prophylactic use of levonorgestrel intrauterine system (LNG-IUS) in the prevention of endometrial pathology in women having breast cancer treated with tamoxifen.
Design  Randomised controlled trial.
Setting  A tertiary teaching hospital.
Population  One hundred and thirteen women (66 premenopausal/47 postmenopausal) who required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy.
Methods  Women were randomised to treatment group (prophylactic LNG-IUS insertion before the commencement of tamoxifen) or control group. Uterine cavity was examined by outpatient hysteroscopy and endometrial biopsy before and at 12 months after commencement of tamoxifen.
Main outcome measures  De novo endometrial pathology at 1 year of tamoxifen.
Results  Women in the treatment group had a much lower incidence of endometrial polyp (1.8 versus 15.5%, P = 0.017) (relative risk: 0.12; 95% CI: 0.02–0.91) at 12 months. There was no significant difference in the incidence of submucosal fibroid between the two groups (1.8 versus 3.4%, P = 1.0). LNG-IUS was retained in 95% women in the treatment group at 1 year.
Conclusion  LNG-IUS reduces the occurrence of de novo endometrial polyp in women treated with tamoxifen for breast cancer.     

Ovarian cysts in postmenopausal tamoxifen-treated breast cancer patients with endometrial thickening detected by transvaginal sonography

OBJECTIVE: To investigate the frequency of ovarian cysts in tamoxifen-treated postmenopausal breast cancer patients with endometrial thickening detected by transvaginal sonography. METHODS: Medical records and transvaginal sonographies of 38 postmenopausal women treated for breast cancer with adjuvant tamoxifen therapy who had undergone endometrial sampling due to abnormal endometrial thickness were reviewed retrospectively. RESULTS: During the study period five of 38 tamoxifen-treated postmenopausal patients (13.2%) had ovarian cysts. The mean tamoxifen treatment interval of the patients with an ovarian cyst was 22.4 +/- 18.4 months (p = 0.17). The mean endometrial thickness of the patients with an ovarian cyst was 12.6 +/- 5.9 mm (p = 0.17). Endometrial biopsy detected six cases of abnormal endometria, including endometrial carcinoma (n = 1), endometrial polyp (n = 1) and simple endometrial hyperplasia without atypia (n = 4). Three patients with ovarian cysts underwent laparatomy revealing simple cysts on histopathological examination. Two patients with ovarian cysts declined laparatomy and are currently under follow-up. CONCLUSION: Ovarian cysts a common side-effect of tamoxifen treatment in postmenopausal tamoxifen-treated breast cancer patients. Transvaginal sonography should be performed to detect any concomitant endometrial pathology.     

Cytologic diagnosis of endometrial adenocarcinoma using the Endo-pap sampler

Six hundred ambulatory women were screened with the Endo-pap cytology sampler in two medical centers. None of the women developed complications from the use of the instrument. Their smears were routinely processed together with cervical cytology smears. One hundred fifty-three of these women had a tissue diagnosis by endometrial biopsy, dilatation and curettage, or hysterectomy. Adequate cytology specimens were obtained in 93% of these patients. In these 153 patients, 32 (18%) had a tissue diagnosis of endometrial adenocarcinoma, and 31 patients had a tissue diagnosis of endometrial hyperplasia. The cytology samples obtained with this device were diagnostic of endometrial adenocarcinoma in 30 (94%) of these 32 patients and ten (32%) of the patients with endometrial hyperplasia. Two patients (1.6%) were diagnosed falsely positive. The Endo-pap cytology sampler is considered a safe and effective screening tool for endometrial adenocarcinoma. Its value in diagnosing endometrial hyperplasia remains to be determined.     

Cytologic detection of endometrial carcinoma by the endocyte technique

Ninety-seven patients admitted for diagnostic curettage of peri- and postmenopausal bleeding underwent cytologic evaluation by the endocyte technique in order to test the accuracy of the method. Six patients with endometrial carcinoma were diagnosed by curettage and in five of them the cytologic specimens correctly agreed with histology; the other case was an inadequate sample for cytologic diagnosis. Hyperplastic endometrium was found in 14 cases by curettage; only three of them had been detected by cytology. This cytologic technique proved to be satisfactory in diagnosing endometrial cancer but inadequate for detection of premalignant lesions.     

Comparison of endometrial pathologies collected by hysteroscopy and hysterectomy in postmenopausal breast cancer tamoxifen-treated patients

PURPOSE OF INVESTIGATION: 1) To assess whether endometrial specimens obtained from removed uteri might show an increase in endometrial pathologies which had been previously diagnosed by hysteroscopy in postmenopausal breast cancer tamoxifen-treated patients. 2) To assess whether hysteroscopy is an efficient method of detecting endometrial pathologies in such patients. METHODS: The findings of two consecutive pathological evaluations in 18 postmenopausal breast cancer tamoxifen-treated patients, performed 11.2+/-11.2 months apart, were compared. The first specimen was collected by hysteroscopy and the second was obtained following hysterectomy. RESULTS: The most significant changes observed were three new cancers diagnosed at hysterectomy, one of which was poorly-differentiated. In the first (hysteroscopy) samplings, one patient had atrophic endometrium, a second patient had endometrial proliferation and a third patient had a benign endometrial polyp. Overall, 55.6% of the study patients had various endometrial pathologies in the first sampling, while 83.3% had endometrial pathologies in the second sampling. However, this difference was not statistically significant. CONCLUSION: 1) Endometrial histologic evaluations, performed on removed uteri 11.2+/-11.2 months following previous endometrial samplings of postmenopausal breast cancer tamoxifen-treated patients, showed a non-significant risk of developing overall endometrial pathologies. 2) Hysteroscopy may have missed some endometrial pathologies which were diagnosed later on in specimens obtained by hysterectomy.     

Abnormalities detected on transvaginal ultrasonography in tamoxifen-treated postmenopausal breast cancer patients may represent endometrial cystic atrophy

OBJECTIVE: This study was conducted to examine the histopathologic changes in tamoxifen-treated postmenopausal patients with endometrial thickness ≥5 mm with transvaginal ultrasonography. STUDY DESIGN: Thirty-five tamoxifen-treated postmenopausal breast cancer patients underwent transvaginal pelvic ultrasonography with endometrial thickness ≥5 mm followed by either curettage-hysteroscopy (n = 24), or hysterectomy (n = 11). Endometrial histopathologic findings were examined. RESULTS: Overall, endometrial polyps were the most common histopathologic finding (23 of 35 patients). Endometrial cystic atrophy was uncommonly detected in patients undergoing curettage-hysteroscopy (1 of 24 patients) compared with patients undergoing hysterectomy (9 of 11 patients). No cases of endometrial cancer or hyperplasia were detected. CONCLUSIONS: Endometrial polyps were a frequent finding in tamoxifen-treated postmenopausal women who had endometrial thickness ≥5 mm with the use of transvaginal ultrasonography. Endometrial cystic atrophy may explain “thickened endometrium” on transvaginal ultrasonography in this patient population with no evidence of endometrial polyps, hyperplasia, or adenocarcinoma after surgical evaluation. (Am J Obstet Gynecol 1998;178:1145-50.)     

The value of sonohysterography in the prediction of endometrial pathologies in asymptomatic postmenopausal breast cancer tamoxifen-treated patients

BACKGROUND: The study evaluated the efficacy of sonohysterography in identifying endometrial pathologies in asymptomatic postmenopausal tamoxifen (TAM)-treated patients by evaluating its performance characteristics. MATERIALS AND METHODS: Multiple assessments of sonohysterography evaluations of intrauterine mass diameter were evaluated by logistic regression analysis based on overall 85 patients (who had transvaginal ultrasonographic endometrial thickness of >/=8 mm) followed by hysteroscopy and endometrial histological findings. Performance characteristics were calculated with correlation to the endometrial histological findings. RESULTS: The mean endometrial thickness was 14.6 +/- 6.2 mm, and the mean intrauterine mass diameter detected by SIS was 11.6 +/- 10.4 mm. There was a gradual decrease in sensitivity and gradual increase in specificity of the SIS studies with the increase in intrauterine mass diameter. False-negative and false-positive of SIS were 2.4% and 8.2%, respectively. ROC curve analysis of intrauterine mass revealed 5 mm as the best accurate cutoff value for the diagnosis of endometrial pathologies, with a sensitivity of 74.1%, specificity of 93.0%, and positive predictive value of 88.3% and negative predictive value of 84.2%. The risk of endometrial pathology was elevated by 1.37-fold, with any additional millimeter of diameter of the intrauterine mass. The mean diameter of the intrauterine mass gradually increased the greater the severity of the histological findings. CONCLUSIONS: Sonohysterography improves the accuracy of diagnosis of intrauterine mass in asymptomatic postmenopausal tamoxifen-treated patients. The size of the intrauterine mass correlates with the severity of the endometrial pathology.     

The value of transvaginal ultrasonography in the prediction of endometrial pathologies in asymptomatic postmenopausal breast cancer tamoxifen-treated patients

OBJECTIVE: There is no established ultrasonographic endometrial cutoff value for the diagnosis of endometrial pathologies in asymptomatic postmenopausal tamoxifen (TAM)-treated patients. We attempted to seek the most accurate cutoff value. MATERIALS AND METHODS: Multiple ultrasonographic cutoff points were evaluated by logistic regression analysis based on 279 patients who had transvaginal ultrasonographic examinations followed by endometrial histopathological analysis. Performance characteristics were calculated with correlation to the endometrial histological findings. We also calculated how many endometrial pathologies could have been left undiagnosed and the number of endometrial samplings, with different cutoff values, which could have been avoided. RESULTS: There was a gradual increase in specificity and a gradual decrease in sensitivity of the ultrasonographic studies with the increase of endometrial thickness. More overall and more various endometrial pathologies were identified with the increase in cutoff values. The best cutoff value appeared to be 15 mm (sensitivity 37.9%, specificity 87.2%, positive predictive value 63.0%, and negative predictive value 70.2%). However, by avoiding performance endometrial sampling up to this cutoff value, 62.2% endometrial pathologies including 48 endometrial polyps, one case of endometrial hyperplasia with atypia, and one case of endometrial cancer may have been left undiagnosed. At the same time, endometrial sampling in 78.5% of cases may have been avoided. CONCLUSION: In asymptomatic postmenopausal breast cancer tamoxifen-treated patients, the use of wider ultrasonographic endometrial cutoff values could be associated not only with the performance of fewer endometrial samplings, but also with a higher possibility of endometrial pathologies, including endometrial cancers, being left undiagnosed.     

Comparison of ultrasonography,hysteroscopy, and biopsy in the diagnosis of endometrial lesions in postmenopausal tamoxifen-treated patients

BACKGROUND: At present, no proven recommendations can be made for the surveillance of tamoxifen-treated women. The aim of the present study was to evaluate ultrasonography and hysteroscopy in this setting. METHODS: Three hundred and ten postmenopausal patients using tamoxifen underwent vaginal ultrasonography, hysteroscopy, and endometrial biopsy; 274 were asymptomatic and 49 had abnormal bleeding. Ultrasonographic endometrial thickness and echotexture were recorded. Hysteroscopic endometrial appearance, presence of focal endometrial lesions and polyps were also recorded. General or selective endometrial biopsy was performed. Ultrasonographic and hysteroscopic follow up was provided. RESULTS: At ultrasonography, mean endometrial thickness was 10.8 mm. At hysteroscopy, cystic atrophy and suspect focal lesions were detected in 49.2% and 5.3% of women, respectively. Polyps were present in 44.8% of women; 38.9% of these polyps were missed at ultrasonography, whereas 11.4% were suspected but were not found at hysteroscopy. At biopsy, non-atypical hyperplasia and atypical changes were found in 4.8% and 1.3% of patients, respectively. Three carcinomas were found, all in asymptomatic women. Logistic regression analysis showed that only suspect focal lesions at hysteroscopy were significantly associated with abnormal histology. With a 6-mm cut-off value for endometrial thickness, negative and positive predictive values for ultrasonography in detecting hyperplastic or neoplastic changes were 96% and 8%, respectively; the corresponding values for hysteroscopy were 96% and 65%. No additional carcinoma was found at follow up. CONCLUSIONS: No single ultrasonographic feature (echotexture and borders) is significantly associated with the detection of endometrial hyperplasia or carcinoma; hysteroscopy, although not predictive unless revealing a focal lesion, is more accurate in detecting polyps and hyperplastic changes.