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© 2000 American Society for Clinical Oncology Effects of Adjuvant Tamoxifen on the Endometrium in Postmenopausal Women With Breast Cancer: A Prospective Long-Term Study Using Transvaginal UltrasoundFrom the Department of Obstetrics and Gynecology, Department of Pathology, and Institute of Medical Informatics and Biometry, University of Rostock, Rostock, Germany. Address reprint requests to Bernd Gerber, MD, PhD, Department of Obstetrics and Gynecology, PO Box 10 08 88, 18055 Rostock, Germany; email bernd.gerber{at}med.uni-rostock.de
PURPOSE: To study the value of transvaginal ultrasound (TVS) in endometrial screening of postmenopausal breast cancer patients treated with tamoxifen.
PATIENTS AND METHODS: In 247 tamoxifen-treated (20 to 30 mg/d for RESULTS: The mean endometrial thickness was 3.5 ± 1.1 mm before treatment and increased to a maximum of 9.2 ± 5.1 mm after 3 years of tamoxifen application (P < .0001), which was significantly (P < .0001) thicker compared with controls. Fifty-two asymptomatic patients with thickened or morphologically suspect endometrium underwent hysteroscopy and dilatation and curettage (D&C), resulting in four uterine perforations. Histopathologically, atrophy was found in 38 patients (73.1%), polyps in nine, hyperplasia in four, and endometrial cancer in one case. In 20 screened patients who reported vaginal bleeding, five atrophies (25%), five polyps, four hyperplasias, and two endometrial cancers were found. Before hysteroscopy and D&C were performed, 36 (69.2%) of 52 asymptomatic and four (20%) of 20 symptomatic patients were scanned by repeated TVS over 2 to 30 months. Invasive diagnostic procedures were significantly (P < .05) more frequent in younger and obese patients. In the controls, one asymptomatic polyp and one symptomatic hyperplasia were found. CONCLUSION: In tamoxifen-treated patients, TVS offered a high false-positive rate, even with a cutoff value of 10 mm for endometrial thickness and repeated TVS scans. Increased iatrogenic morbidity and only one asymptomatic endometrial carcinoma do not warrant endometrial screening by TVS in tamoxifen-treated patients.
RECENTLY, THE nonsteroidal antiestrogen tamoxifen was strongly confirmed as a very effective drug in the adjuvant treatment of hormone-sensitive invasive1-6 and noninvasive7 breast cancer. Moreover, data from the National Surgical Adjuvant Breast and Bowel Project P1 study8 support the effectiveness of tamoxifen in the reduction of risk of breast cancer in high-risk individuals. In October 1998, tamoxifen was approved for this indication in the United States. Consideration must also be given, however, to the fact that tamoxifen exerts estrogenic side effects in different organs. One of these estrogen-like side effects results in endometrial proliferation together with the possibility of development of polyps, hyperplasia, and a two- to four-times higher risk of endometrial cancer than for postmenopausal women not taking tamoxifen.8-17 Because an increasing number of women are being treated with tamoxifen, a strategy for gynecologic surveillance may be warranted. Although patients need to undergo annual gynecologic examinations, routine gynecologic ultrasound screening of tamoxifen patients is not common and requires further study.18,19 Some researchers advocate routine transvaginal sonography (TVS) as a useful tool for endometrial screening in asymptomatic women who are being treated with tamoxifen.20-22 A well-known problem of TVS in tamoxifen-treated patients is the high rate of false-positive findings and an associated increase in invasive procedures, which are mostly not indicated. The aim of the present study was to evaluate TVS in the early detection of tamoxifen-induced endometrial pathology. By means of an elevated cutoff value for endometrial thickness and a wait-and-see attitude with repeated TVS scanning, we attempted to decrease the number of false-positive TVS findings.
Between June 1991 and June 1997, 528 postmenopausal patients with primary breast cancer were treated at the department of obstetrics and gynecology at the University of Rostock in Rostock, Germany. Postmenopausal women were defined as those who had been amenorrheic for more than 1 year. Depending on their hormone receptor status, 381 patients (72.2%) received tamoxifen (20 to 30 mg/d for at least 2 years and a maximum of 5 years), whereas 147 patients (27.8%) received no tamoxifen. One hundred twenty-seven patients (24.1%) were excluded from the study because of previous hysterectomy, hormonal replacement therapy during the last year, higher age and comorbidity, a thickened endometrium (> 5 mm) before the start of tamoxifen therapy, and refusal to participate in the study. Thus 401 postmenopausal patients with previously operated breast cancer and an intact uterus with endometrial thickness  5 mm before tamoxifen treatment (n = 280) started and who felt fit enough to undergo all of the procedures to be performed were recruited. Informed consent was obtained from each patient after the nature of the study was explained. Of the 401 patients who were initially included, 247 (88.2%) of 280 patients receiving tamoxifen and 98 (80.1%) of 121 patients not receiving tamoxifen (controls) were ultrasonographically screened for a minimum of approximately 24 months. Fifty-six patients were lost within the first 2 years because of a breast cancer recurrence or because of missing ultrasound data. We defined endometrial thickness as the width of the combined thickness of the anterior and posterior sides of the endometrium taken on a longitudinal plane using an ultrasound machine with a transvaginal probe of 5.0 MHz. In addition to endometrial thickness, the morphology was also evaluated. Ultrasound evaluation was consistent; ie, initial TVS and follow-up were performed by the same gynecologist. In all patients, routine TVS examination of the endometrium was performed every 6 months. Continuous endometrial evaluations by TVS were performed over a period of 2 years in 247, 3 years in 201, 4 years in 135, and 5 years in 98 patients receiving tamoxifen, and, respectively in 98, 94, 87, and 60 patients not receiving tamoxifen. Ninety patients were also screened 6 to 12 months after termination of tamoxifen therapy, either because of completed 5-year treatment or because of breast cancer recurrence at an earlier time point. The mean ± SD of the endometrial thickness measured by TVS was estimated at different durations of tamoxifen treatment and compared with that of the baseline (before treatment started) and with that of a control group. Because of our own experience of a high rate of false-positive TVS findings, we chose a cutoff of 10-mm endometrial thickness in the study protocol. In patients with an endometrium thicker than 10 mm and morphology not suggestive of abnormality, the protocol required repeated TVS after 3 months. If there was any further increase in endometrial thickness or if the endometrium showed any suspicious morphology (nonhomogeneous endometrium with different density, cysts, or no clear boundary between endometrium and myometrium), hysteroscopy and D&C (dilatation and curettage) were performed. Patients with abnormal vaginal bleeding were subjected to hysteroscopy and D&C immediately.
The histopathologic findings were divided into endometrial polyps, hyperplasia, atrophy, and endometrial carcinoma. Three patients with endometrial carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage Ib) underwent abdominal hysterectomy with bilateral salpingo-oophorectomy, excision of 1 to 2 cm of the upper vagina, and pelvic lymphadenectomy. Tamoxifen-induced glandulocystic atrophy is hysteroscopically characterized by a smooth and white but hypervascular atrophic endometrial layer with scattered protrusions and represents an atrophic epithelium overlying stromal edema. In glandulocystic atrophy, it is sometimes difficult to distinguish between endometrium and myometrium by TVS. Body mass index (BMI) was calculated using the following formula: weight (in kilograms)/height2 (in meters). The BMI was divided into The Wilcoxon test was applied to evaluate differences in endometrial thickness over time. The Mann-Whitney U test was used to compare mean values of two independent samples. Correlation between two numerical parameters was checked by means of the Spearman correlation. All tests were two-sided. The level of significance was set at P < .05.
The mean ± SD patient age at first ultrasonographic assessment was 60.3 ± 7.0 years (median, 59 years; range, 35 to 76 years) in the tamoxifen and 60.1 ± 6.8 years (median, 61 years; range, 46 to 73 years) in the control group. According to BMI, patients treated with tamoxifen (27.3 ± 5.2; median, 26.2; range, 17.9 to 57.6) and controls (27.1 ± 4.0; median, 26.8; range, 17.6 to 36.2) were comparable. The mean endometrial thickness before starting tamoxifen treatment was 3.5 ± 1.1 mm for the group of patients who received tamoxifen (median, 4 mm; range, 1 to 5 mm) and 3.6 ± 1.1 mm for patients in the control group (median, 4 mm; range, 1 to 5 mm; Table 1). Under treatment with tamoxifen, endometrial thickness increased during the first 12 months to 8.7 ± 4.1 mm (median, 8 mm; P < .0001) and changed (not significant) between 9.2 ± 5.1 mm (median, 7 mm) and 8.8 ± 5.6 mm (median, 6 mm) during the 5 treatment years. The mean endometrial thickness of the patients in the control group was unchanged throughout the duration of the study period. The endometrium of women who received tamoxifen (median thickness, 7 mm; range, 1 to 34 mm) was significantly thicker than that of controls (median thickness, 3 mm; range, 1 to 18 mm; P < .0001 [two-sided Mann-Whitney U test]) and was also thicker in relation to the baseline thickness (P < .0001, two-sided Wilcoxon Test). Six to 12 months after stopping tamoxifen application, the mean endometrial thickness decreased to 5.0 ± 2.8 mm (median, 4 mm), but was still significantly (P < .0001, two-sided Wilcoxon Test) thicker than the baseline value.
Fifty-two asymptomatic patients with a suspected endometrial thickness greater than 10 mm (n = 38) or an endometrium that was morphologically suggestive of abnormality with a thickness of 5 to 10 mm (n = 14), in addition to 20 patients with abnormal vaginal bleeding, were subjected to hysteroscopy and D&C. The other 175 patients remained asymptomatic so that an invasive diagnostic procedure with histologic evaluation was not indicated. Before hysteroscopy and D&C were performed, 36 (69.2%) of the 52 asymptomatic patients with thickened endometrium were repeatedly checked with TVS for approximately 2 to 30 months. Four of the 20 patients who presented with abnormal bleeding were also checked initially with repeated TVS but had started to bleed in the meantime. In the 52 asymptomatic patients with ultrasonographically suspect endometrium, histopathologic atrophy was found in 38 (73.1%), endometrial polyps in nine (17.3%), and hyperplasia in four patients (7.7%), as well as one endometrial cancer in FIGO stage Ib. Although regularly screened, 20 patients reported abnormal vaginal bleeding. Nine (45%) of these 20 patients had atrophy, five (25%) had endometrial polyps, four (20%) had hyperplasias, and two (10%) had endometrial cancers. Taken together, 33 of the 47 atrophy cases showed a tamoxifen-like glandulocystic atrophy. There was no obvious relation between occurrence of histopathologic findings and time (Table 2). All three endometrial cancers were diagnosed in FIGO tumor stage Ib during the fourth and fifth years of treatment. One endometrial cancer with bleeding showed an endometrial thickness of 8 mm. Histopathologically, the carcinomas were moderately differentiated (G2) and each case had an endometrioid phenotype (tubular and mucinous adenocarcinoma). One of four patients who were asymptomatic and two of four patients with bleeding that resulted from hyperplasia showed a complex atypical hyperplasia. In an obese patient (BMI 34) in the control group, vaginal bleeding after 44 months was caused by a simple hyperplasia (endometrium of 9-mm thickness), and in a second patient, an asymptomatic polyp (endometrium of 18-mm thickness) was detected by TVS.
The endometrial thickness before and during adjuvant tamoxifen treatment was correlated with age, BMI, and cumulative tamoxifen doses. Before and during the first 3 years of tamoxifen treatment, age was a significant factor (P < .01, two-sided Spearman correlation test) that was found to be negatively correlated with the endometrial thickness. An increased BMI resulted before and during the entire duration of tamoxifen treatment in cases of a significantly (P < .01) thicker endometrium. Although the cumulative tamoxifen dose was not significantly correlated with the endometrial thickness, a trend after 24 (P = .07) and 36 (P = .08) months could be detected (Table 3).
A possible influence of BMI, age, and cumulative dose of tamoxifen on the occurrence of polyps, hyperplasia, and carcinomas was investigated (Table 4). Irrespective of symptoms, patients receiving tamoxifen who had polyps, hyperplasia, and carcinomas (n = 25; BMI, 30.6 ± 6.0) as well as patients with atrophy (n = 47; BMI, 30.4 ± 6.1), showed a significantly (P = .0001, two-sided Mann-Whitney U test) elevated mean BMI compared with asymptomatic patients for whom the endometrium was not suggestive of abnormality (n = 176; 26.0 ± 4.0). Patients with polyps, hyperplasia, and carcinomas (age of 58.0 ± 6.4 years) and with atrophic endometrium (58.4 ± 7.1 years) were significantly (P < .03) younger than asymptomatic patients (61.1 ± 7.2 years). The cumulative tamoxifen doses in these three groups (30.3 ± 6.7, 29.7 ± 7.3, and 29.2 ± 7.5 g, respectively) was not significantly different.
In four (7.1%) of 52 patients with asymptomatic findings, uterine perforation occurred after hysteroscopy and D&C without damage to neighbouring organs. All four patients were monitored over several days without any subsequent complications. In three patients, hysteroscopy and D&C was unsuccessfully completed because of cervical stenosis. In 20 symptomatic patients, one perforation occurred.
When we started this investigation in 1991, we believed, like other investigators, that TVS as a noninvasive method was suitable for endometrial screening. Discussions about endometrial screening in patients receiving tamoxifen are still controversial today; most investigators16,20,21,23-28 consider TVS screening appropriate even in high-risk patients who receive tamoxifen, whereas other investigators29-34 do not consider it necessary in any tamoxifen-treated patients. The reported mean endometrial thickness in tamoxifen-treated patients ranged from 7.2 ± 8.5 to 12.1 ± 12.4 mm, compared with 1.5 ± 4.3 to 5.4 ± 2.7 mm in controls.20,21,31,35,36 Similar to Nahari et al,37 we were unable to find a significant effect of the duration of tamoxifen exposure on the endometrial thickness, whereas other investigators have reported such a correlation.33,38 It should be noted, however, that 6 to 12 months after termination of tamoxifen treatment, the endometrial thickness had obviously decreased but was still significantly thicker than before treatment.
It is almost uniformly accepted that a cutoff of 5 mm for endometrial thickness is suitable for patients without hormonal treatment but not in those who receive tamoxifen.39 An endometrium thicker than 5 mm has been reported in 41%33 to 54%31 of patients receiving tamoxifen. However, recommended cutoffs of 6 to 10 mm19,21,27,30,33 also pose a problem, because many patients with harmless glandulocystic atrophy would be further subjected to unnecessary invasive procedures. To avoid unnecessary endometrial biopsies, we chose, even in 1991, a cutoff value of 10 mm. Moreover, the study design also allowed repeated TVS examinations in asymptomatic patients with an endometrium thicker than 10 mm and endometrial morphology that was not suggestive of abnormality. From our results, we must recommend an endometrial thickness cutoff value for invasive hysteroscopy and D&C in asymptomatic patients treated with tamoxifen of less than 10 mm if a TVS is performed at all. Recently, Franchi et al36 computed a cutoff value of 9 mm by means of receiver operating characteristics. In 117 asymptomatic and 46 symptomatic patients receiving tamoxifen and endometrial biopsies, an abnormal histopathologic finding was found in 60% of those with an endometrial thickness greater than 9 mm, compared with 6.1% of those with an endometrial thickness of As we have shown, a wait-and-see attitude with repeated TVS also does not seem suitable in asymptomatic tamoxifen-treated patients with a thickened endometrium, because most of these patients (69.1% of our own study group) will later be subjected to hysteroscopy and D&C or will experience bleeding (20%). Also, with our conservative management, an invasive procedure was not indicated in at least 65.3% of the screened patients because of the presence of an atrophic endometrium. Tamoxifen can produce a sonographic image of the endometrium that resembles endometrial neoplasia. This apparent increase in endometrial thickness might be explained by tamoxifen-induced edema of cystically dilated endometrial glands with periglandular stromal and myometrial condensation while the overlying epithelium remains atrophic.38 These changes are misinterpreted as hyperplasia with TVS, even though there is no real epithelial disease. The changes occur either in the endometrium itself or as a protrusion of the endometrium, ie, as endometrial polyps.32 As yet, there is no exact pathologic correlation for these findings, which are also known as glandulocystic atrophy. We have seen an increased rate of uterine perforations during D&C. Chiefly, these may be caused by the edematous but atrophic endometrium. On the other hand, the gynecologist knows that there is a thickened endometrium, and he or she will direct appropriate effort at obtaining sufficient endometrial tissue. Other authors have also reported difficulties in sampling endometrium in tamoxifen-treated patients.31,33 Recently, Barakat et al40 presented the results of a prospective endometrial screening study in 111 tamoxifen-treated patients who underwent a total of 635 endometrial biopsies. Fourteen patients required D&C for abnormal biopsy findings. Although three patients required hysterectomy, only one had pathology (complex hyperplasia) detected by endometrial biopsy. The authors concluded that endometrial screening by biopsies led to an increase in operative procedures, whereas the utility of such biopsies in terms of cancer detection seems limited. The results of Neven et al41 and Neven and Vergote41 and our own results suggested a trend to an increase in endometrial lesions with time or cumulative dose of tamoxifen exposure, but these effects did not reach statistical significance, in contrast with results from other authors. The proportion of abnormal histologic findings was higher in women who received tamoxifen for more than 60,43 48,44 or 2736 months compared with those receiving tamoxifen for shorter periods of time. However, these data are from patients who demonstrated endometrial pathology even before tamoxifen treatment.36 Schlesinger et al45 found that endometrial carcinomas that develop after relatively short times or low cumulative doses of tamoxifen may be at least partially attributable to other risk factors. The correlation found between BMI and endometrial thickness could be the result of additional estrogen stimulation owing to a higher aromatase activity in the fatty tissue. The negative correlation between age and endometrial thickness may be due to an ongoing atrophy of endometrial cells with increasing age. These findings would explain why younger, postmenopausal patients with an increased BMI more frequently develop a thickened endometrium, which will lead to an invasive procedure.38,46 Our rates of asymptomatic polyps (2.8%) and of hyperplasia (1.9%) were low. Other authors have reported polyps in 5% to 77%21,24-26,32,35,47 and hyperplasia in 8% to 16%20,21,25,35 in considerably smaller groups of patients and mostly after shorter periods of tamoxifen treatment. It is unlikely that our low rates were caused by the fact that we did not perform operations in cases with homogeneous endometrium of less than 10 mm; rather, they were probably caused by exclusion of patients with endometrium suggestive of abnormality before tamoxifen was given. Although polyps sometimes will be the cause of abnormal bleeding, the risk of malignant transformation is low according to our experience. Only three publications involving small case numbers describe malignant transformation in endometrial polyps removed from postmenopausal tamoxifen-treated patients.39,45,47,48 In our opinion, the aim of sonographic endometrial screening should not be the detection of benign changes. To detect only one asymptomatic endometrial cancer (FIGO stage Ib), we performed 1,265 vaginal ultrasounds, whereas two other carcinomas were detected by bleeding in the same stage. In other studies17,20,21,30,34,35,48 as well, significantly more symptomatic than asymptomatic carcinomas were observed. Vaginal bleeding represents an early symptom of endometrial cancer, which has a good prognosis, but it will not always receive the necessary urgent attention.49 Tamoxifen-treated patients should be informed about their risk and told to contact their gynecologist immediately in cases of bleeding. In a cost-benefit analysis of endometrial screening in tamoxifen-treated patients, Barakat18 reported a decrease in mortality of 0.03%, whereas the cost of undertaking screening in this population may be prohibitively high. Our results suggest that TVS is a poor screening tool in the whole population of tamoxifen-treated patients, even with a cutoff value of 10 mm for endometrial thickness and a wait-and-see attitude, and that endometrial screening by TVS is not warranted in these patients.
Supported by the FORUN project, Rostock, Germany. We thank Ian Jackson, MD, for reviewing the manuscript.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 years) women and 98 controls, the endometrium was prospectively followed-up by means of TVS every 6 months for up to 5 years. Patients with homogeneous endometrium of more than 10-mm thickness were then scanned repeatedly every 3 months. 
