Discrepancy between Ultrasonography and Hysteroscopy and Histology of Endometrium in Postmenopausal Breast Cancer Patients Using Tamoxifen Marian J. E. Mourits,* Ate G. J. Van der Zee,* Pax H. B. Willemse,² Klaske A. Ten Hoor,* Harry Hollema,‡ and Elisabeth G. E. De Vries² *Department of Gynecology, ² Department of Medical Oncology, and ‡Department of Pathology, University Hospital Groningen, 9713 GZ Groningen, The Netherlands Received May 5, 1998 Background. The increased risk of endometrial carcinoma fol- lowing the use of tamoxifen has stimulated studies on endometrial diagnostic screening methods. In tamoxifen users the endometrial thickening observed with transvaginal ultrasonography (TVU) frequently cannot be confirmed by hysteroscopy orhistology. Objective. The aim was to investigate the relationship between TVU and hysteroscopic and histologic endometrial findings in postmenopausal patients using tamoxifen. Methods. Fifty-three asymptomatic postmenopausal tamoxifen- using breast cancer patients underwent a gynecological examina- tion combined with TVU. Patients with an endometrial thickness of > 5 mm were offered hysteroscopy and endometrial biopsy. Findings. Thirty-one patients (58%) had an endometrial thick- ness of > 5 mm with enhanced, inhomogeneous echogenicity. Hys- teroscopy was performed in 22 patients and 3 underwent hyster- ectomy. Seven of 22 patients had endometrial polyps, histologically characterized by cystically dilated glands lined with atrophic epithelium and periglandular stromal condensation. His- tology of the three hysterectomy specimens showed a similar picture of atrophic luminal epithelium, covering dilated glands lined with atrophic epithelium and surrounded by dense stroma, which resembled the histology of the endometrial polyps. In all three specimens the histologically measured endometrial thickness corresponded with that on TVU. Interpretation. Tamoxifen can induce specific endometrial changes consisting of cystically dilated glands with periglandular stromal condensation while the overlying epithelium remains atro- phic. The changes occur either in the endometrium itself or as a protrusion of the endometrium, i.e., as endometrial polyps. These findings explain the discrepancy between ultrasound, hysteros- copy, and histology. Due to the high number of false-positive findings, TVU is not an effective screening instrument in these patients. © 1999 Academic Press INTRODUCTION Tamoxifen, a nonsteroidal antiestrogen, is the preferred en- docrine treatment for women with metastatic breast cancer and is used as an adjuvant therapy. Tamoxifen is not a pure estro- gen antagonist. Tamoxifen exerts a weak estrogenic effect on vaginal epithelium [1], myometrium [2], and endometrium [3] in postmenopausal women. An increased risk of endometrial carcinoma associated with tamoxifen use was observed for the first time in 1989 in a prospective randomized controlled trial [4]. Several reports have been published since then which show a 1.3 to 7.5-fold increased risk in postmenopausal tamoxifen- using compared to nonusing breast cancer patients [5–9]. The IARC [10] concluded in 1996 that tamoxifen is carcinogenic in humans. In the same year DNA-adduct formation in the human endometrium induced by tamoxifen was described [11]. This has stimulated the development of screening strategies for endometrial carcinoma in postmenopausal tamoxifen users. Transvaginal ultrasonography (TVU) is a well-established method for measuring endometrial thickness in otherwise healthy women with postmenopausal bleeding [12–14]. Most authors recommend a cutoff value for the thickness of the endometrial double layer of 4 –5 mm. Below this value, the risk of endometrial carcinoma is negligible [13, 14]. In asymptom- atic postmenopausal women TVU has been evaluated less frequently as a screening tool for endometrial cancer [15]. In postmenopausal patients with breast cancer, tamoxifen treatment is frequently associated with the presence of an increased endometrial thickness on TVU, often with an abnor- mal sonographic appearance of irregular echogenicity suspect of polyps, hyperplasia, or carcinoma [16 –20]. Investigators have, however, noted a discordance between sonographic and hysteroscopic and histologic endometrial findings in 45–90% of these patients [3, 16, 17, 19 –21]. The previously described cutoff value for endometrial thickness in postmenopausal women does not seem to apply to this group. Several authors have, nevertheless, recommended annual screening for endo- metrial pathology in tamoxifen-treated breast cancer patients with TVU using the standard cutoff criteria [18, 21–23]. The present study was performed to analyze the relationship between TVU and hysteroscopy and endometrial histology in postmenopausal breast patients on tamoxifen. Gynecologic Oncology 73, 21–26 (1999) Article ID gyno.1998.5316, available online at http://www.idealibrary.com on 21 0090-8258/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.