Sonohysterography for Evaluation of the Endometrium in Women Treated with Tamoxifen

Lucy E. Hann 1 Elissa M. Gretz 2,3 Ariadne M. Bach 1 Sonia M. Francis 1 Received September 18, 2000; accepted after revision January 30, 2001. Presented at the annual meeting of the American Roentgen Ray Society, New Orleans, May 1999. 1 Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Address correspondence to L. E. Hann. 2 Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021. 3 Present address: 445 E. 86th St., Apt. 1B, New York, NY 10028. AJR 2001;177:337 342 0361 803X/01/1772 337 American Roentgen Ray Society Sonohysterography for Evaluation of the in Women Treated with Tamoxifen OBJECTIVE. This study was performed to evaluate sonohysterography for the diagnosis of endometrial abnormalities in women treated with tamoxifen. MATERIALS AND METHODS. Fifty sonohysterograms were obtained in 48 consecutive tamoxifen-treated women. All women were postmenopausal and had been undergoing tamoxifen therapy for a mean of 2.6 years. Forty-six sonohysterograms (92%) were completed and four were unsuccessful. Sonohysterogram findings were correlated with prior endometrial biopsy results for 23 sonohysterograms (46%) that were preceded by endometrial biopsy. Sonohysterogram findings were also compared with histopathology results, available for 38 sonohysterograms (76%) that were followed by hysteroscopy with dilatation and curettage. RESULTS. Sonohysterography revealed 31 endometrial polyps (62%), six thickened endometria (12%), five normal endometria (10%), and four subendometrial cysts (8%). Surgery was avoided when seven sonohysterograms (14%) revealed normal endometria or subendometrial cysts. In the group with histopathologic correlation, 23 of 28 polyps were confirmed and two of five thickened endometria were shown to represent endometrial hyperplasia. Twelve (63%) of 19 sonohysterograms with prior normal endometrial biopsy findings had abnormalities on sonohysterography, including 10 polyps and two thickened endometria. CONCLUSION. Sonohysterography aids the diagnosis of endometrial abnormalities in tamoxifen-treated women even if prior endometrial biopsies have negative findings. In 14% of cases, visualization of a normal endometrium on sonohysterography obviated surgery. T amoxifen citrate is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer; it has also been used recently for the prevention of breast cancer in high-risk women [1 4]. Large trials have shown that in women with estrogen receptor positive breast cancer, tamoxifen treatment for 5 years reduces the annual breast cancer recurrence rate by 50%, reduces the annual death rate by 28%, and decreases the risk of contralateral breast cancer by 39% regardless of receptor status [1 4]. Recently, the Breast Cancer Prevention Trial documented a 50% reduction in the rate of breast cancer among high-risk women who received tamoxifen treatment as compared with control subjects [4]. Tamoxifen inhibits estrogen-dependent tumor growth by competing with estrogen at receptor sites. This competition for receptor sites may result in either antiestrogenic or weakly estrogenic effects, depending on tissue site and receptor status. In the uterus, tamoxifen has an estrogenic effect that produces endometrial abnormalities such as endometrial polyps, hyperplasia, and carcinoma [4 11]. The National Surgical Adjuvant Breast and Bowel Project B-14 trial documented a 1.6 in 1000 annual risk of endometrial carcinoma in tamoxifen-treated women and a relative risk of endometrial cancer that is 2.2 times greater than that in control subjects [1, 4]. Because tamoxifen-treated women have an increased frequency of endometrial neoplasia and premalignant conditions such as atypical hyperplasia, there is interest in screening this population for endometrial abnormalities. However, the value of screening has not been established, and the optimum method of surveillance has not been determined [4 15]. Recently, several groups of investigators have shown the usefulness of sonohysterography for the diagnosis of endometrial abnormalities, particularly in women with abnormal uterine bleeding [16 23]. We undertook this study to evaluate sonohysterography for the diagnosis of AJR:177, August 2001 337

Hann et al. endometrial abnormalities in women who are undergoing tamoxifen treatment for breast cancer. Materials and Methods From February 1996 to May 1999, 48 consecutive tamoxifen-treated women were referred for 50 sonohysterograms. Sonohysterography findings were retrospectively reviewed and compared with available histopathology findings from endometrial biopsy or hysteroscopy with dilatation and curettage. All women were postmenopausal for a mean of 10 years (range, 0.5 32 years) and had been undergoing tamoxifen therapy for a mean of 2.6 years (range, 0.2 6 years). The mean patient age was 60 years (range, 39 78 years). Women were referred for sonohysterography because of endometrial thickening greater than 8 mm (n = 30), postmenopausal bleeding (n = 19), and abnormal findings on Pap smear (n = 1). All sonohysterography was preceded by transvaginal sonography. Endometrial thickness measurements were obtained in the anteroposterior dimension on sagittal images, and any endometrial cystic spaces were documented. Sonohysterography was performed by an experienced radiologist using Sequoia or 128 XP machines (Acuson, Mountain View, CA) and endovaginal curved 4-8 MHz transducers. Informed consent was obtained for all studies. Sonohysterography was performed in a standard manner as previously described [16, 21, 23]. Eighteen studies (36%) were performed with a 5.3- French Soule s catheter (L. De Orio, RNC, Oak Brook, IL), and 32 studies (64%) were performed with a 5- French Ackrad H/S catheter with balloon (Ackrad Laboratories, Cranford, NJ). The exocervix was cleansed with povidone-iodine and the cervix was cannulated without the use of a cervical dilator or a tenaculum. The catheter was positioned in the lower uterine segment, and sterile saline was infused during real-time visualization. The amount of saline solution required for adequate distention of the endometrial cavity varied, ranging from approximately 10 to 40 ml. The presence of endometrial thickening, subendometrial cysts, polyps, and other abnormalities was recorded. Endometrial measurements were obtained in the sagittal plane. The anterior and posterior single thickness measurements were added together for double-layer endometrial measurement. For tamoxifen-treated women, a double-layer thickness of 8 mm or less was considered normal [10, 11, 24]. Sonohysterography findings were compared with histopathology findings, which were available in 38 (76%) of the 50 studies that were followed by hysteroscopy, dilatation, and curettage within a mean of 5.7 weeks (range, 1 21 weeks). In addition, transvaginal sonography endometrial findings were compared with sonohysterography results. Correlation was also made with prior endometrial biopsy results for the 23 sonohysterograms (46%) that were preceded by endometrial biopsy within a mean of 3.9 months (range, 1 day 11.5 months). Sonohysterography and transvaginal sonography findings were based on the original report; the correlative histopathology and endometrial biopsy findings were determined from the pathology reports. Results Forty-six sonohysterograms (92%) were completed and four studies (8%) were unsuccessful because of difficulty cannulating the cervix. No complications were observed. Sonohysterography findings are presented in Table 1. Endometrial polyps were the most frequent finding (Fig. 1). Thirty-one sonohysterograms (62%) revealed endometrial polyps, six (12%) showed thickened endometria greater than 8 mm (Fig. 2), four (8%) showed subendometrial cysts, and five (10%) showed normal endometria. The mean maximum dimension of endometrial polyps was 21 mm (range, 2 50 mm). Transvaginal Sonography Findings Compared with Sonohysterography Findings Results of transvaginal sonography are compared with sonohysterography findings in Table 2. Forty (80%) of 50 preliminary transvaginal sonograms revealed cystic endometria. Thirty-one (78%) of 40 cystic endometria on transvaginal sonography were shown to represent endometrial polyps on sonohysterography, and in four cases (10%) the cystic spaces were caused by subendometrial cysts. Hysteroscopically evident endometrial polyps were present in one of three patients with endometrial thickness less than 5 mm, in four (40%) of 10 patients with endometrial thickness less than 8 mm, and in 27 (68%) of 40 patients with endometrial thickness exceeding 8 mm on transvaginal sonography. Sonohysterography Findings Compared with Histopathology Thirty-eight sonohysterograms (76%) were followed by hysteroscopy with dilatation and curettage. Histopathology findings are compared with sonohysterography results in Table 3. Twenty-three (82%) of 28 endometrial polyps shown on sonohysterography were confirmed on histopathology. Two of six patients with thickened endometria on sonohysterography had endometrial hyperplasia, one of which was simple and the other, atypical hyperplasia (Fig. 2). No cases of endometrial carcinoma were seen. Sonohysterography findings differed from hysteroscopy and histopathology diagnoses in nine (24%) of 38 studies that were followed by dilatation, curettage, and hysteroscopy. Five sonohysterograms revealed polyps but normal endometria were found at histopathology. Four of the five cases with discrep- Findings of 50 TABLE 1 Sonohysterograms of 48 Women Treated with Tamoxifen Finding No. % Unsuccessful study 4 8 Polyps 31 62 Thickened endometrium 6 12 Subendometrial cysts 4 8 Normal endometrium 5 10 Total 50 100 Fig. 1. 56-year-old woman undergoing tamoxifen therapy for 3 years who had prior endometrial biopsy with negative findings. Sagittal sonohysterogram reveals 3-cm endometrial polyp (calipers) and normal endometrium. Polyp was confirmed at hysteroscopy. 338 AJR:177, August 2001

Sonohysterography of the A Fig. 2. 55-year-old woman undergoing tamoxifen treatment for 5 years. A, (calipers) is thickened, with cystic areas on sagittal transvaginal sonogram. B, Longitudinal sonohysterogram reveals circumferentially thickened endometrium (solid arrows) measuring 12 mm and containing cystic areas. Catheter (open arrows) is in cervix. Histopathology from hysteroscopy with dilatation and curettage showed endometrial hyperplasia with atypia. TABLE 2 Endometrial Thickness Transvaginal Sonography Findings Compared with Sonohysterography Findings Transvaginal Sonography No. of Studies No. with Cystic Unsuccessful Polyp ancy between sonohysterography and histopathology for the diagnosis of endometrial polyp had a characteristic sonographic appearance for polyps, including feeding vessels on color and power Doppler imaging [25] (Fig. 3). The fifth patient had a suspected 5-mm polyp in the left horn of a septate uterus on sonohysterography, but no Doppler imaging was performed and histopathology revealed atrophic endometrium. The other cases with discordant histopathology and hysteroscopy findings had thickened endometria on sonohysterography. One patient with a thickened endometrium on sonohysterography had an endometrial polyp and a cystic endometrium at hysteroscopy. Histopathologic diagnoses in the remaining three patients with thickened endometria were secretory endometrium, normal endometrium, and normal endometrium with endocervical polyp. Sonohysterography Findings in Patients Without Hysteroscopic Correlation Thirteen sonohysterograms were not followed by hysteroscopy with dilatation and curettage. Seven of these studies had no further evaluation because sonohysterography revealed normal- thickness endometria (n = 4) or Sonohysterography Thickened Subendometrial Cysts 0 5 mm 3 1 0 1 0 1 1 5 7.9 mm 7 6 1 3 1 0 2 8 11.9 mm 14 11 1 11 0 2 0 >12 mm 26 22 2 16 5 1 2 Total 50 40 4 31 6 4 5 Normal subendometrial cysts (n = 3) (Fig. 4). These patients were asymptomatic and had been referred for sonohysterography because of endometrial thickening greater than 8 mm on transvaginal sonography. Two additional patients with normal endometrium or subendometrial cysts on sonohysterography required surgery because of postmenopausal bleeding. One of these symptomatic patients had a normal endometrium confirmed histopathologically, and the other patient had an endocervical polyp. The remaining six patients without hysteroscopic correlation had follow-up endometrial biopsies yielding benign histology. B AJR:177, August 2001 339

Hann et al. TABLE 3 Histopathology a In one patient, histopathology revealed normal endometrium and an endocervical polyp. b One patient had an endometrial polyp and cystic endometrium at hysteroscopy. Findings of Prior Endometrial Biopsy Compared with Sonohysterography Findings Sonohysterography findings were also correlated with findings of endometrial biopsies that preceded 23 (46%) of 50 sonohysterograms, as shown in Table 4. Twelve (63%) of 19 sonohysterograms with prior negative endometrial biopsy findings (Fig. 1) had abnormalities, including 10 endometrial polyps and two thickened endometria. In the group with prior endometrial biopsies positive for polyp fragments, one sonohysterogram revealed an endometrial polyp and one showed a normal endometrium. After endometrial biopsy showed disordered proliferative endometrium, sonohysterography revealed subendometrial cysts and a normal endometrial thickness. A Sonohysterography Findings Compared with Histopathology Results in 38 Patients Who Underwent Hysteroscopy with Dilatation and Curettage Polyp Thickened Sonohysterography Subendometrial Cysts Normal Unsuccessful Polyp 23 1 a 0 0 1 Hyperplasia 0 2 0 0 0 Normal 5 3 b 1 1 1 Total 28 6 1 1 2 B Fig. 3. 77-year-old woman undergoing tamoxifen therapy for 2 years in whom sonohysterography revealed endometrial polyp, but hysteroscopy was negative for polyp and histopathology revealed benign endometrium. A, Transverse sonohysterogram reveals polypoid mass (arrow ) containing cystic areas and projecting into endometrial cavity. B, Longitudinal color power Doppler sonogram reveals feeding vessel (arrow ) that further supports diagnosis of endometrial polyp. Discussion The benefits of tamoxifen for breast cancer treatment far outweigh any potential endometrial abnormalities that may occur [4]. However, because tamoxifen is widely used, it is important to develop adequate methods for diagnosing endometrial complications resulting from tamoxifen. We found that sonohysterography was useful for diagnosing endometrial abnormalities that develop in tamoxifentreated women. Forty-six (92%) of 50 sonohysterograms were successfully obtained, and no complications were observed. Polyps, found in 62% of patients, were the most frequent finding, and polyps were better diagnosed on sonohysterography than on endometrial biopsy. Sonohysterography was also useful for excluding endometrial disorders, and no further intervention was performed in 14% of patients who had a normal endometrium on sonohysterography. Our patient population included tamoxifentreated women with postmenopausal bleeding and tamoxifen-treated women with endometrial thickening detected on transvaginal sonography but who were otherwise asymptomatic. Debate exists regarding the normal range of endometrial thickness for treated with tamoxifen women. An endometrial thickness of less than 5 mm essentially excludes the presence of endometrial abnormalities [26 28]. Karlsson et al. [27] reported results of 1168 women with postmenopausal bleeding and found no malignant endometrium smaller than 5 mm. The risk of other benign endometrial disorders in women with endometrial thickness less than 5 mm was 5.5% [27]. This threshold value of 5 mm has a high negative predictive value ( 99%) and is most useful for the exclusion of significant endometrial disorders in women with bleeding [28]. Most asymptomatic women treated with tamoxifen have endometrial thickness exceeding 5 mm, and endometrial thickness in those women is greater than that in postmenopausal control subjects [6, 10, 13]. The increased endometrial thickness observed in tamoxifentreated women is caused by the estrogen agonist effect of tamoxifen, which is similar to hormone replacement therapy. Lin et al. [24] reported that 91 of 112 asymptomatic postmenopausal women undergoing hormone replacement therapy had endometrial thickness greater than 8 mm, and the authors recommended biopsy for asymptomatic women with endometrial thickness greater than 8 mm. Using the 8-mm cutoff value, approximately half of women treated with tamoxifen will have transvaginal sonography endometrial measurements in the normal range [10, 29]. 340 AJR:177, August 2001

Sonohysterography of the A Fig. 4. 63-year-old woman with tamoxifen who required no further examination after sonohysterography revealed that apparent endometrial thickening on transvaginal sonography was caused by subendometrial cysts. A, (arrows) appeared ill-defined, had cystic areas, and measured 11 mm in thickness on sagittal transvaginal sonogram. B, On longitudinal sonohysterogram, endometrium (open arrows) appears normal and subendometrial cyst (solid arrow ) is seen. Sonohysterography Findings Compared with Prior Endometrial Biopsy TABLE 4 Results in 23 Patients Endometrial Biopsy Sonohysterography Finding No. of Biopsies Unsuccessful Polyp Thickened Subendometrial Cysts Insufficient 1 0 1 0 0 0 Normal 19 2 10 2 3 2 Polyp 2 0 1 0 0 1 Proliferative 1 0 0 0 1 0 Total 23 2 12 2 4 3 Normal Using sonohysterography, we showed endometrial polyps in 62% of women treated with tamoxifen who had a thickened endometrium or postmenopausal bleeding. Our results are similar to those of Timmerman et al. [29], who found endometrial polyps in 26 (49%) of 53 tamoxifentreated women in a study comparing sonohysterography with office hysteroscopy. Hulka and Hall [9] found endometrial polyps in nine of 11 patients treated with tamoxifen who had transvaginal sonography and endometrial sampling. Other investigators have reported a much lower prevalence of polyps, in the range of 33% [6, 10]. This discrepancy may be explained by sampling methods. Kedar et al. [6] suggested that the prevalence of endometrial polyps may be underestimated by reports that use endometrial biopsy as the standard of reference. Endometrial biopsy may obtain tissue from adjacent endometrium and miss a mobile polyp that may be deflected by the biopsy catheter. Sonohysterography findings in women with prior negative findings at endometrial biopsy also indicate an advantage to sonohysterography for the diagnosis of endometrial polyps. We documented endometrial abnormalities on sonohysterography in 12 (63%) of 19 sonohysterograms that had negative correlative endometrial biopsy; 10 of these abnormalities were endometrial polyps. Similar limitations of endometrial biopsy were reported by Dubinsky et al. [17], who performed sonohysterography in 81 women with postmenopausal bleeding and endometrial thickness greater than 5 mm. In that study, 41 of 45 patients with endoluminal masses on sonohysterography had prior negative findings on endometrial biopsies [17]. We found no cases of endometrial carcinoma in our series. Although estimates are that approximately 50% of tamoxifen-treated women will have endometrial abnormalities [11], most of these abnormalities are benign. Surveillance is done to exclude endometrial cancer, but the degree of risk should not be overestimated. The annual risk of endometrial carcinoma in tamoxifen-treated women is in the range of 1.6 in 1,000 individuals [4]. Endometrial carcinoma is more frequent with prolonged tamoxifen use (>5 years), and patients generally present with vaginal bleeding [8, 10]. Numerous studies have shown that 80 88% of tamoxifen-associated endometrial cancers are early tumors (FIGO [International Federation of Gynecology and Obstetrics] stage 1) [4, 5, 7, 8, 30]. Further intervention was avoided when sonohysterography revealed a normal endometrium or subendometrial cysts in 14% of our tamoxifen-treated women who had endometrial thickness greater than 8 mm on transvaginal sonography. Goldstein [31] was the first to describe subendometrial cysts resulting from adenomyosistype changes that occur in women treated with tamoxifen. Both endometrial polyps and subendometrial cysts may present as cystic thickening of the endometrium on transvaginal sonography, but sonohysterography may enable the differentiation between these two entities by correctly identifying the subendometrial location of cystic change. Achiron et al. [14] studied 20 tamoxifen-treated patients who had thickened cystic endometria on transvaginal sonography. In twelve patients (60%), the abnormality was produced by subendometrial cysts, and all patients had normal endometrial histopathology at hysteroscopic sampling [14]. The benefits of sonohysterography for tailoring clinical treatment of tamoxifen-treated women is similar to the experience in women with postmenopausal bleeding reported by Lev-Toaff et al. in 1996 [19] and Bree et al. in 2000 [22]. Five of 31 endometrial polyps diagnosed using sonohysterography were not confirmed by hysteroscopy and histopathology despite their classic appearance. This discrepancy between sonohysterography and hysteroscopy for the diagnosis of endometrial polyps raises the issue of gold standard. Several studies have compared sonohysterography with hysteroscopy [21, 29, 32, 33]. Tepper et al. [32] found no false-negative diagnoses on sonohysterography in a study of sonohysterography and operative hysteroscopy in tamoxifen-treated women who had thickened endometria on transvaginal sonography. Comparisons of sonohysterography and office hysteroscopy have shown a sensitivity of approximately 85% and a specificity of 100% for sonohysterography as compared with 77% B AJR:177, August 2001 341

Hann et al. and 92% for hysteroscopy [21, 29]. Operative hysteroscopy, as used in our study, may offer better visualization of the endometrial cavity than office hysteroscopy, but we still had five suspected endometrial polyps on sonohysterography that were not confirmed hysteroscopically. Similar results were shown by Schwarzler et al. [33], who reported that operative hysteroscopy missed two of 25 polyps detected using sonohysterography in women with postmenopausal bleeding. Possibly, an endometrial polyp may be expelled spontaneously in the interval between sonohysterography and hysteroscopy. Alternatively, the discrepancy may be related to hysteroscopic technique. Although hysteroscopes have a wide field of view, visualization may be limited if the scope is advanced beyond a mobile polyp. Limitations of our study include its retrospective design and its relatively small study group. Also, because correlative endometrial biopsies and hysteroscopy were not available for all sonohysterograms, sensitivity and specificity of sonohysterography could not be determined. In conclusion, we found that sonohysterography was useful for the diagnosis of endometrial abnormalities in tamoxifen-treated women. Polyps, found in 62% of our studies, were the most frequent finding. Sonohysterography aids in the diagnosis of endometrial abnormalities in tamoxifen-treated women even if prior endometrial biopsies have negative findings; and in 14% of our patients, visualization of a normal endometrium on sonohysterography obviated surgery. References 1. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998;339:1609 1618 2. Early Breast Cancer Trialists Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. 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