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(Radiology. 2000;214:29-38.)
© RSNA, 2000

State of the Art

Tamoxifen-induced Uterine Abnormalities: The Role of Imaging1

Susan M. Ascher, MD, Izumi Imaoka, MD and Janice M. Lage, MD

1 From the Departments of Radiology (S.M.A., I.I.) and Pathology (J.M.L.), Georgetown University Medical Center, 3800 Reservoir Rd, NW, Washington, DC 20007-2197 (S.M.A., I.I.), and the Department of Radiology, Shimane Medical University, Japan (I.I.). Received September 22, 1998; revision requested, November 4; revision received, March 2, 1999; accepted July 28. Address reprint requests to S.M.A. (e-mail: aschers@gunet.georgetown.edu).

Abstract

Tamoxifen citrate is an orally administered, nonsteroidal antiestrogen agent that is widely used for the treatment of breast cancer and that has recently been found to prevent breast cancer in some high-risk populations. Tamoxifen may, however, cause adverse effects at the uterine level. In this article, the authors review (a) the histopathologic uterine changes associated with tamoxifen therapy, (b) the spectrum of uterine imaging findings in women treated with tamoxifen, and (c) the recommendations of the American College of Obstetrics and Gynecology for women treated with tamoxifen. An algorithm for imaging evaluation of the uterus in women treated with tamoxifen is presented.

Index terms: Leiomyoma, 854.315 • Magnetic resonance (MR), comparative studies, 854.121411, 854.121412, 854.12143 • State of the Art • Tamoxifen • Ultrasound (US), comparative studies, 854.12981, 854.12983, 854.12988, 854.12989 • Uterine neoplasms, 854.32 • Uterus, abnormalities, 854.1495, 854.64 • Uterus, cysts, 854.311 • Uterus, MR, 854.121411, 854.121412, 854.12143 • Uterus, US, 854.12981, 854.12983, 854.12988, 854.12989

Tamoxifen citrate is an antiestrogen agent that binds to estrogen receptors. Large clinical trials in which tamoxifen was evaluated as adjuvant chemotherapy in women with breast carcinoma found (a) a statistically significant increase in disease-free survival in estrogen receptor–positive postmenopausal women, (b) an increase in overall survival in estrogen receptor–positive postmenopausal women, (c) a statistically significant decrease in the incidence of contralateral breast cancer in estrogen receptor–positive postmenopausal women, and (d) beneficial effects in both estrogen receptor–negative and premenopausal women (1–4).

In April 1998, the Breast Cancer Prevention Trial halted a double-blind, randomized clinical trial 14 months ahead of schedule when initial results showed a 45% reduction in the rate of developing breast cancer in women at high risk who were randomly assigned to receive tamoxifen (20 mg/d), as compared with the rate in women at high risk who received a placebo (5). On September 2, 1998, a Food and Drug Administration advisory committee unanimously voted to recommend approval of tamoxifen to reduce women's risk of developing breast cancer (6). The implications of the Breast Cancer Prevention Trial and Food and Drug Administration decisions are underscored by the fact that women aged 60 years and older are at high risk. According to Dr Robert Justice, acting director of the Food and Drug Administration Division of Oncology Drug Products, " ‘potentially tens of millions of women’ could be candidates for tamoxifen" (6).

In addition to an antiestrogen action on breast tissue, tamoxifen is a weak estrogen agonist in postmenopausal endometrial tissue, and a spectrum of endometrial abnormalities are associated with its use, including polyps, hyperplasia, and carcinoma (7–26). Although there are more than 4.5 x 106 woman-years experience with this drug, and up to 50% of women receiving tamoxifen develop endometrial abnormalities within 6–36 months of treatment, there is no consensus regarding endometrial surveillance in these patients (9,27,28). Various investigators (13,17,21,28,29) have advocated an annual gynecologic examination plus endometrial biopsy (EMB), endovaginal ultrasonography (US), hysterosonography, dilation and curettage, and/or hysteroscopy.

HISTOPATHOLOGIC REVIEW

To our knowledge, only one large prospective study (28) has been reported in which the effect of tamoxifen on the uterus was evaluated in women with breast cancer. In that study, 264 postmenopausal women underwent transvaginal US and EMB both before and after undergoing tamoxifen treatment. After 3 years of follow-up, the investigators observed an increase in the incidence of uterine lesions. These included polyps, hyperplasia (with and without atypia), endometrial carcinoma, leiomyomas, and adenomyosis. A brief discussion of these tamoxifen-related uterine changes follows.

Endometrial Polyps
The incidence of endometrial polyps is higher in women treated with tamoxifen than in untreated women: 8%–36% versus 0%–10% (12–15,23,25,26). Although these polyps may cause abnormal uterine bleeding, most women are asymptomatic. In the general population, endometrial polyps typically measure 0.5–3.0 cm in diameter, and, microscopically, contain a mixture of three elements in varying degrees: (a) stroma of dense fibrous tissue, (b) thick-walled vascular channels, and (c) endometrial glands (25,26).

"Tamoxifen" (tamoxifen-related) polyps are different. They are unusually large (mean diameter, 5 cm) and, microscopically, are distinguished from typical polyps by their combination of proliferative activity (cystic glandular dilatation), aberrant epithelial differentiation (metaplasia), and focal periglandular stromal condensation (22,25,26) (Fig 1). The importance of the periglandular stromal condensation is unknown, but it has been postulated (22) that it may be associated with a form of müllerian adenosarcoma. In addition, extensive stromal reaction (ie, fibrosis) may account for difficulties in resecting tamoxifen-related polyps at hysteroscopy (Fig 2) (Sanz LB, oral communication, 1998).



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  		Figure 1a. Tamoxifen-related polyps. (a) Bivalved hysterectomy specimen demonstrates a large, benign tamoxifen-related polyp distending the endometrial canal. Note the posterior stalk (arrow) and superior and inferior rami (*) that circumscribe cystic spaces (C). (Reprinted, with permission, from reference 30.) (b) Low-power light photomicrograph from a different patient shows a benign tamoxifen-related polyp with cystic dilatation (C) and superficial stromal hemorrhage (arrow). (Hematoxylin-eosin stain; original magnification, x4.)

 


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  		Figure 1b. Tamoxifen-related polyps. (a) Bivalved hysterectomy specimen demonstrates a large, benign tamoxifen-related polyp distending the endometrial canal. Note the posterior stalk (arrow) and superior and inferior rami (*) that circumscribe cystic spaces (C). (Reprinted, with permission, from reference 30.) (b) Low-power light photomicrograph from a different patient shows a benign tamoxifen-related polyp with cystic dilatation (C) and superficial stromal hemorrhage (arrow). (Hematoxylin-eosin stain; original magnification, x4.)

 


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  		Figure 2. Four-on-one image obtained at hysteroscopic removal of a tamoxifen-related polyp (P). Extensive microscopic stromal reaction, common to tamoxifen-related polyps, may account for difficulties during resection.

 
Endometrial Hyperplasia
There is a significant increase in the incidence of endometrial hyperplasia in postmenopausal patients with breast cancer treated with tamoxifen. The incidence is 1.3%–20.0% in such patients, as compared with the 0%–10% incidence in postmenopausal patients with breast cancer who are not receiving tamoxifen and the general (symptomatic and asymptomatic) female population (10,12–15,23,25,28,31,32) (Fig 3). The diagnosis of endometrial hyperplasia is established on the basis of microscopic findings of a morphologically abnormal proliferative-type endometrium; some authors (32) insist that, in addition, there must be an abnormal increase in endometrial volume.



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  		Figure 3. Low-power light photomicrograph shows simple hyperplasia in a tamoxifen-related polyp. Note the densely fibrotic stroma surrounding the glandular structures, suggestive of an adenomyomatous polyp. (Hematoxylin-eosin stain; original magnification, x10.)

 
Endometrial hyperplasia can be divided into two broad categories: hyperplasia without cytologic atypia and hyperplasia with cytologic atypia. These categories are further subdivided into simple or complex according to the extent of glandular complexity and crowding. This nomenclature has prognostic importance: In up to 23% of patients with atypical hyperplasia, the hyperplasia progresses to carcinoma, whereas in only 2% of patients with hyperplasia without atypia, the hyperplasia progresses to carcinoma (32).

Endometrial Carcinoma
Tamoxifen chemotherapy or prophylaxis increases the relative risk of developing endometrial cancer (4,5,17–21). Specifically, there is a 1.3–7.5-fold increase in the relative risk of developing endometrial cancer, and the risk increases with duration of treatment and cumulative tamoxifen dose (4,5,17,19,22,23). The authors of one tumor registry analysis (33) suggested that tamoxifen-related endometrial cancers are more aggressive than endometrial cancers in the general population. In subsequent studies (17,19,23), however, no statistically significant differences were found in the histologic type, International Federation of Gynecology and Obstetrics stage, and prognosis of endometrial cancers in women treated with tamoxifen (Fig 4).



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  		Figure 4. Light photomicrograph reveals a well-differentiated International Federation of Gynecology and Obstetrics grade I endometrial carcinoma arising in a tamoxifen-related polyp. Note the cribriform gland formation (arrow). (Hematoxylin-eosin stain; original magnification, x10.)

 
Although tamoxifen has been classified as a human endometrial carcinogen by the International Agency for Research on Cancer (its carcinogenic status is currently being debated by the National Toxicology Program Board of Scientific Counselors) (34), many investigators (24,29,35) have questioned the clinical importance of its weak carcinogenic effect, given that endometrial cancer has a relatively low incidence in the general female population to begin with (approximately 33,000 new cases per year). According to Jaiyesimi et al (36), the cumulative incidence of endometrial cancers in all women who received tamoxifen in the major trials is 0.9%, as compared with 0.2% in control groups; therefore, this may not represent a substantial health risk in light of the beneficial effects of tamoxifen in women with breast cancer. The risk-benefit analysis of prophylactic tamoxifen treatment for the subset of women at high risk is more controversial, although preliminary data from the Breast Cancer Prevention Trial suggest that the benefits of tamoxifen therapy outweigh the real, but small (2.5-fold), increased risk of developing endometrial cancer (5).

Other Uterine Changes
Other uterine changes reported in association with tamoxifen treatment include "tamoxifen" mucosa, cysts, adenomyosis, and leiomyomas, although studies with age-matched control groups for these conditions are scant or lacking (16,37–40).

At hysteroscopy, "tamoxifen" mucosa is described as smooth, white, hypervascularized, and atrophic, with scattered protuberances that represent glandulocystic atrophia (cystic atrophy; Fig 5) (16). This "tamoxifen" mucosa with its protuberances differs macroscopically from the atrophic mucosa seen in postmenopausal women who are not receiving tamoxifen. That is, in the latter women, the mucosa is characterized as pale and thin, without protuberances (41).



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  		Figure 5. "Tamoxifen" mucosa. Low-power light photomicrograph shows cystic atrophy and dilated glands below the mucosal surface (arrows). At hysteroscopy, "tamoxifen" mucosa (ie, the endometrium) is white and hypervascularized and has scattered protuberances (glandulocytic atrophia). (Hematoxylin-eosin stain; original magnification, x4.) (Reprinted, with permission, from reference 30.)

 
Endometrial cystic atrophy is diagnosed histologically when multiple cystic spaces lined by atrophic endometrium are present within a dense fibrous stroma (42). In the case of patients treated with tamoxifen, the exact location of the cysts is controversial. Some investigators report that the cysts extend to the endometrial-myometrial junction but clearly reside within the endometrium; others have placed the cysts in the proximal portion of the myometrium (also called the subendometrial location) (42–44). This is further complicated by the fact that endometrial glands that extend into the myometrium may also be called adenomyosis—with the recognition that "the definition of adenomyosis is arbitrary" (41). Whether the apparent increased incidence of adenomyosis in women treated with tamoxifen is a true phenomenon or represents a spectrum of tamoxifen-associated cysts ("adenomyosis-like changes") is unknown (38). Regardless of their location, the cysts seen in women treated with tamoxifen do not appear to be premalignant (42).

The leiomyomas observed in women treated with tamoxifen do not differ histologically from those found in untreated women (45,46). However, leiomyoma and adenomyosis, in addition to polyps, may contribute to the larger uterine volume reported (11–13,38) in women treated with tamoxifen.

Paradoxical Effects
Interestingly, tamoxifen has apparent paradoxical effects at the uterine level: Some portions of the endometrium may be stimulated by tamoxifen, while others undergo the effects of a more accelerated menopause. As a result, coexistent atrophy and adenomyosis have been described (37,38) in postmenopausal women treated with tamoxifen. These seemingly contradictory findings can be explained, in part, by the existence of more than one population of uterine receptors responding to tamoxifen and/or the possibility that growth sites may lose their sensitivity to the antiestrogenic effects of tamoxifen after an initial stimulatory response. Alternatively, these effects may reflect the spectrum of cyst locations in women undergoing tamoxifen treatment, as discussed in the preceding section (42).

IMAGING REVIEW

Many investigators, noting the high prevalence of histopathologic changes in the endometrium, including atypical hyperplasia in both symptomatic and asymptomatic patients treated with tamoxifen, have advocated endometrial screening, although they have not agreed on the exact method and schedule for screening. The following is a description of the imaging appearance(s) of the uterus in women receiving tamoxifen.

Endovaginal US
US is the first-line imaging modality for evaluation of the endometrium (Table). The normal postmenopausal endometrium appears as a single echogenic line and should not exceed 5 mm as a bilayer thickness (47,48). In postmenopausal women undergoing estrogen replacement therapy, the normal endometrium may measure up to 8 mm in thickness. The thickness of normal endometrium in women receiving tamoxifen, however, is controversial (49). In general, women undergoing tamoxifen treatment have a thicker endometrium as compared with that in control subjects (9–13 mm vs 4.0–5.4 mm) (12–15). In addition, regardless of the cutoff value (4–8-mm thickness) for detecting endometrial abnormalities, the most common endometrial transvaginal US pattern seen in women treated with tamoxifen is a thickened endometrium with cystic spaces (12–14,21,28,35,50–52) (Fig 6). The following paragraphs will summarize the US appearance of the uterus in patients with breast cancer who are receiving tamoxifen.


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  		Major Endometrial Imaging Findings in Women Undergoing Tamoxifen Treatment
 


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  		Figure 6. Sagittal endovaginal US image shows the most common endometrial finding in women undergoing tamoxifen treatment: a thickened endometrium (arrows) punctuated by cysts (*). A benign polyp was found at sampling.

 
Hulka and Hall (50), in one of the initial investigations, analyzed the US studies in 14 women treated with tamoxifen. Of these, 11 underwent a diagnostic sampling procedure (dilation and curettage or EMB), and a total of 18 abnormalities were reported. The sagittal US images (transabdominal and transvaginal) in each of the 11 patients showed an abnormally thickened (>7-mm) endometrium. The US findings included hyperechoic tissue with multiple small cystic spaces (seven patients); hyperechoic, homogeneous tissue (two patients); heterogeneous tissue with small cystic spaces (one patient); and heterogeneous solid tissue (one patient) (Fig 7). The corresponding histopathologic results included uterine polyps (nine patients), hyperplasia (four patients), endometritis (two patients), proliferative endometrium (one patient), inactive endometrium (one patient), and carcinoma (one patient). In addition, six of nine cases of polyps were associated with other endometrial abnormalities. The authors concluded that (a) tamoxifen therapy is associated with several US findings, and (b) US is of limited use in the diagnosis of specific abnormalities because multiple pathologic findings frequently coexist.



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  		Figure 7a. Spectrum of endovaginal US findings. (a) Transverse image demonstrates a thickened echogenic endometrium (arrows) with small cystic spaces. (b) Transverse image in another patient demonstrates heterogeneous endometrial tissue (arrows) with small cystic spaces. (c) Sagittal image in a third patient shows heterogeneous solid endometrial tissue (arrows). At sampling, histopathologic findings included proliferation (a) and benign polyps (b, c).

 


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  		Figure 7b. Spectrum of endovaginal US findings. (a) Transverse image demonstrates a thickened echogenic endometrium (arrows) with small cystic spaces. (b) Transverse image in another patient demonstrates heterogeneous endometrial tissue (arrows) with small cystic spaces. (c) Sagittal image in a third patient shows heterogeneous solid endometrial tissue (arrows). At sampling, histopathologic findings included proliferation (a) and benign polyps (b, c).

 


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  		Figure 7c. Spectrum of endovaginal US findings. (a) Transverse image demonstrates a thickened echogenic endometrium (arrows) with small cystic spaces. (b) Transverse image in another patient demonstrates heterogeneous endometrial tissue (arrows) with small cystic spaces. (c) Sagittal image in a third patient shows heterogeneous solid endometrial tissue (arrows). At sampling, histopathologic findings included proliferation (a) and benign polyps (b, c).

 
In another study, Uziely et al (21) reported their findings in 95 patients with breast cancer treated with tamoxifen who underwent endovaginal US followed by EMB. Histopathologic changes were observed in 14 patients, 13 of whom had been treated for more than 12 months and all of whom had an endometrial thickness of more than 5 mm. Histopathologic results included polyps (four patients), hyperplasia (three patients), dysplasia (three patients), and carcinoma (three patients). The authors concluded that there is a statistically significant correlation between long-term tamoxifen administration and endometrial proliferation; however, they did not find a significant correlation between endometrial thickness and endometrial biopsy results. They recommended that women treated with tamoxifen for more than 12 months undergo annual endovaginal US and EMB.

In a subsequent prospective study, Cohen et al (54) performed endovaginal US followed by EMB to evaluate 72 asymptomatic postmenopausal women treated with tamoxifen for breast cancer. Seventy-one patients had an endometrial thickness of more than 5 mm, and in 22 of these women, adequate tissue was obtained at endometrial sampling. Histopathologic examination revealed proliferative endometrium (18 patients), polyp (three patients), and carcinoma (one patient). By using an endometrial thickness of 5 mm as the upper limit of the normal range, the sensitivity of endovaginal US in relation to positive histologic findings was 91%, and the specificity was 96%. These statistics, however, should be interpreted with caution: Positive histologic findings (eg, endometrial proliferation and simple hyperplasia) may be clinically unimportant. Moreover, there was no obvious correlation between the various histopathologic endometrial findings and endometrial thickness; that is, a "thicker" endometrium on the US image did not necessarily correlate with specific pathologic endometrial findings (54). Finally, the inability to acquire sufficient tissue at EMB in more than half of patients with a "thick" endometrium was worrisome. Other investigators (55,56) also have reported difficulty in obtaining adequate histologic specimens, coupled with a low sensitivity of EMB for detection of endometrial abnormalities.

In a follow-up study, Cohen et al (15) performed endovaginal US in 93 asymptomatic postmenopausal patients with breast cancer treated with tamoxifen and a control group of 20 untreated postmenopausal patients with breast cancer. Endometrial thickness and frequency of endometrial histopathologic findings were significantly greater in the treated group than in the control group (thickness, 13.1 mm vs 4.0 mm; frequency, 35.5% vs 20.0%). The authors concluded that the remarkably high prevalence of pathologic endometrial changes is a function of continuous and unopposed exposure of the endometrium to tamoxifen.

Hann et al (51), in a recent retrospective analysis with 91 postmenopausal patients with breast cancer treated with tamoxifen, found that 48% of US images revealed an endometrial thickness of 8 mm or more. Adequate endometrial samples were obtained in 36 of these patients, of whom 12, or one-third, had endometrial polyps. Other pathologic conditions encountered included endocervical polyps (four patients), hyperplasia (three patients), carcinoma (two patients), papillary syncytial metaplasia (one patient), cystic change (one patient), and inflammatory debris (one patient). Moreover, several patients had more than one endometrial abnormality. The authors concluded that endometrial thickness increases with duration of tamoxifen treatment but does not correlate with symptoms.

To our knowledge, there has been only one large study in which the uterus was evaluated in a randomized cohort of postmenopausal women receiving either tamoxifen or a placebo. Kedar et al (14) evaluated 111 women with transvaginal US followed by EMB. There were no significant differences between the tamoxifen and placebo groups in terms of age and time of US and EMB. Women undergoing treatment with tamoxifen had a significantly larger uterus (mean, 34 cm3), thicker endometrium (mean, 9.1 mm), and lower impedance to flow in the uterine arteries (mean resistive index, 0.81) than did women in the placebo group (mean uterine size, 22 cm3; mean endometrial thickness, 4.8 mm; and mean resistive index, 0.92) (Fig 8). Twenty-four women receiving tamoxifen had endometrial abnormalities at sampling, including proliferation (eight patients), atypical hyperplasia (10 patients), polyp (five patients), and mitotic cells (one patient). By using an endometrial thickness of greater than or equal to 8 mm, the predictive value for atypical hyperplasia or polyp was 100%. Five patients in the placebo group had an endometrial abnormality, including proliferation (three patients), polyp (one patient), and mitotic cells (one patient). There was no correlation between the presence of uterine abnormalities and the age of the women, the concentration of tamoxifen, or the level of tamoxifen metabolites in peripheral blood. The authors concluded that their results confirm the increased risk of endometrial abnormalities in women receiving tamoxifen at a dose of 20 mg/day, as reported by other investigators (1,12–14).



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  		Figure 8a. US images of polyps. (a) Transverse endovaginal US image demonstrates typical features of a tamoxifen-related polyp: a heterogeneous, widened endometrial echo complex (arrows) with small cystic spaces. (b) Endovaginal Doppler US interrogation within the polyp shows a low-impedance arterial trace. The waveform of uterine arteries also has low impedance. Hysterectomy specimen (not shown) confirmed the presence of a large endometrial polyp. There was no evidence of coexistent carcinoma. Left arrow = peak systolic velocity, right arrow = peak diastolic velocity.

 


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  		Figure 8b. US images of polyps. (a) Transverse endovaginal US image demonstrates typical features of a tamoxifen-related polyp: a heterogeneous, widened endometrial echo complex (arrows) with small cystic spaces. (b) Endovaginal Doppler US interrogation within the polyp shows a low-impedance arterial trace. The waveform of uterine arteries also has low impedance. Hysterectomy specimen (not shown) confirmed the presence of a large endometrial polyp. There was no evidence of coexistent carcinoma. Left arrow = peak systolic velocity, right arrow = peak diastolic velocity.

 
Hysterosonography
Hysterosonography has increasingly been used to improve the ability to diagnose intrauterine pathologic conditions and to resolve discrepancies between endometrial thickening on endovaginal US images and insufficient material or nondiagnostic results at EMB (53–59). Specifically, hysterosonography is an attractive adjunct to endovaginal US because it more clearly defines endoluminal lesions that are pedunculated or sessile and can be used to better determine whether an abnormality is endometrial or subendometrial (Fig 9).



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  		Figure 9a. Hysterosonography as adjunct to endovaginal US. (a) Sagittal endovaginal US image shows a thickened heterogeneous endometrial echo complex (arrows). (b) Transverse hysterosonogram shows improved delineation of an endometrial polyp (arrows). Correlative histopathologic results revealed endometrial carcinoma. (Fig 9a and 9b courtesy of Arthur C. Fleischer, MD, Department of Radiology, Vanderbilt University Medical Center, Nashville, Tenn.) (c) Sagittal endovaginal color Doppler US image in another patient demonstrates a thickened, hyperechoic, solid endometrium (solid arrows) with color flow centrally (open arrows). (d) Sagittal hysterosonogram corresponding to c shows saline solution outlining the intracavitary mass (*), allowing confident diagnosis of a polyp (P). At sampling, this polyp was found to be benign. (Fig 9c and 9d courtesy of Robert L. Bree, MD, Department of Radiology, University of Michigan Medical Center, Ann Arbor.)

 


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  		Figure 9b. Hysterosonography as adjunct to endovaginal US. (a) Sagittal endovaginal US image shows a thickened heterogeneous endometrial echo complex (arrows). (b) Transverse hysterosonogram shows improved delineation of an endometrial polyp (arrows). Correlative histopathologic results revealed endometrial carcinoma. (Fig 9a and 9b courtesy of Arthur C. Fleischer, MD, Department of Radiology, Vanderbilt University Medical Center, Nashville, Tenn.) (c) Sagittal endovaginal color Doppler US image in another patient demonstrates a thickened, hyperechoic, solid endometrium (solid arrows) with color flow centrally (open arrows). (d) Sagittal hysterosonogram corresponding to c shows saline solution outlining the intracavitary mass (*), allowing confident diagnosis of a polyp (P). At sampling, this polyp was found to be benign. (Fig 9c and 9d courtesy of Robert L. Bree, MD, Department of Radiology, University of Michigan Medical Center, Ann Arbor.)

 


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  		Figure 9c. Hysterosonography as adjunct to endovaginal US. (a) Sagittal endovaginal US image shows a thickened heterogeneous endometrial echo complex (arrows). (b) Transverse hysterosonogram shows improved delineation of an endometrial polyp (arrows). Correlative histopathologic results revealed endometrial carcinoma. (Fig 9a and 9b courtesy of Arthur C. Fleischer, MD, Department of Radiology, Vanderbilt University Medical Center, Nashville, Tenn.) (c) Sagittal endovaginal color Doppler US image in another patient demonstrates a thickened, hyperechoic, solid endometrium (solid arrows) with color flow centrally (open arrows). (d) Sagittal hysterosonogram corresponding to c shows saline solution outlining the intracavitary mass (*), allowing confident diagnosis of a polyp (P). At sampling, this polyp was found to be benign. (Fig 9c and 9d courtesy of Robert L. Bree, MD, Department of Radiology, University of Michigan Medical Center, Ann Arbor.)

 


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  		Figure 9d. Hysterosonography as adjunct to endovaginal US. (a) Sagittal endovaginal US image shows a thickened heterogeneous endometrial echo complex (arrows). (b) Transverse hysterosonogram shows improved delineation of an endometrial polyp (arrows). Correlative histopathologic results revealed endometrial carcinoma. (Fig 9a and 9b courtesy of Arthur C. Fleischer, MD, Department of Radiology, Vanderbilt University Medical Center, Nashville, Tenn.) (c) Sagittal endovaginal color Doppler US image in another patient demonstrates a thickened, hyperechoic, solid endometrium (solid arrows) with color flow centrally (open arrows). (d) Sagittal hysterosonogram corresponding to c shows saline solution outlining the intracavitary mass (*), allowing confident diagnosis of a polyp (P). At sampling, this polyp was found to be benign. (Fig 9c and 9d courtesy of Robert L. Bree, MD, Department of Radiology, University of Michigan Medical Center, Ann Arbor.)

 
The potential utility of hysterosonography in imaging of tamoxifen-related changes was noted in a 1994 case report (60) in which a patient treated with tamoxifen was described as having an atrophic endometrium at EMB despite a thickened endometrium (1.9 cm) on endovaginal US images. Hysterosonography demonstrated a large polyp, which was confirmed and excised at hysteroscopy. Later, Goldstein (43) described five women with a thick, "irregular, bizarre, heterogeneous" endometrium on endovaginal US images. At hysterosonography, anechoic areas were noted in the subendometrial proximal myometrium, not in the endometrium as originally interpreted on the basis of endovaginal US images. At EMB, all patients had an inactive endometrium. On the basis of these findings, albeit from a small sample, the author cautioned against over-interpreting a "thickened" endometrium on endovaginal US images that have not been enhanced with fluid.

Achiron et al (44) also investigated the discrepancy between a thickened endometrium at endovaginal US and benign results at sampling in patients with breast cancer treated with tamoxifen. They evaluated 20 women with cystic thickening (>5 mm) of the endometrium at endovaginal US who underwent hysterosonography followed by hysteroscopy and endometrial curettage. In eight patients, hysterosonography delineated free-floating echogenic masses (polyps); the remaining 12 patients had endometrial or subendometrial cysts. At inspection and sampling, polyps were confirmed in the first group, whereas 11 of the 12 women in the second group had scanty, senile cystic atrophy. The remaining patient had benign proliferative endometrial changes. The authors concluded that to increase specificity, postmenopausal women treated with tamoxifen who demonstrate thickening of the endometrium on endovaginal US images should undergo hysterosonography.

To our knowledge, there has been one prospective study in which endovaginal US, hysterosonography, and hysteroscopy were compared. Tepper et al (61) used transvaginal US and found that 68 of 114 patients with breast cancer treated with tamoxifen had an endometrial thickness of more than 8 mm. In 46 of the 68 patients, hysterosonography did not reveal any intracavity pathologic conditions. Correlative hysteroscopy and biopsy revealed complex hyperplasia (two patients), simple hyperplasia (five patients), and atrophic endometrium or no tissue (39 patients). In the remaining 22 patients, hysterosonography revealed hyperechoic or polypoid masses, and histologic results confirmed the presence of endometrial polyps (13 patients), polyps with simple or complex hyperplasia (four patients), and leiomyomas (two patients). Two patients were found to have a uterine septum. The authors concluded that hysterosonography has high sensitivity (100%) and a high positive predictive value (95.5%) in patients receiving tamoxifen who have an endometrial thickness of more than 8 mm at endovaginal US.

MR Imaging
Despite the proven effectiveness of MR imaging for demonstrating endometrial abnormalities (62,63), little has been written in the MR imaging literature about uterine findings in women undergoing treatment with tamoxifen (64). In the largest series to date of which we are aware, Ascher et al (30) reported on the MR imaging appearance of the uterus in 35 postmenopausal patients with breast cancer who were undergoing tamoxifen treatment, and they correlated the imaging findings with histopathologic results. The authors noted two imaging patterns: (a) an endometrium with homogeneously high signal intensity on T2-weighted MR images (mean thickness, 0.5 cm) associated with contrast material enhancement of the endometrial-myometrial interface and a signal void lumen on gadolinium-enhanced images in 18 patients (Fig 10) and (b) an endometrium with heterogeneous signal intensity on T2-weighted MR images (mean thickness, 1.8 cm) associated with enhancement of the endometrial-myometrial interface and latticelike enhancement traversing the endometrial canal on gadolinium-enhanced images in 17 patients (Fig 11). Other imaging findings included endometrial-myometrial and subendometrial cysts, nabothian cysts, leiomyomas, and adenomyosis. Ten patients with the former pattern of findings had an atrophic or proliferative endometrium at histopathologic analysis. Twelve of 17 patients with the latter pattern had polyps, one of which had a focus of endometrial carcinoma.



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  		Figure 10a. (a) Sagittal T2-weighted fast spin-echo MR image (3,850/120 [repetition time msec/effective echo time msec]) shows a thin, high-signal-intensity endometrium (arrowheads) and cysts (arrows). (b) On the corresponding sagittal gadolinium-enhanced spoiled gradient-echo MR image (140/4 [repetition time msec/echo time msec]), there is enhancement of the endometrial-myometrial interface (open arrow), and the lumen is a signal void. Endometrial-myometrial cysts (solid arrows) are visible. Cystic atrophy was diagnosed at sampling. The corresponding light micrograph is shown in Figure 5. (Reprinted, with permission, from reference 30.)

 


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  		Figure 10b. (a) Sagittal T2-weighted fast spin-echo MR image (3,850/120 [repetition time msec/effective echo time msec]) shows a thin, high-signal-intensity endometrium (arrowheads) and cysts (arrows). (b) On the corresponding sagittal gadolinium-enhanced spoiled gradient-echo MR image (140/4 [repetition time msec/echo time msec]), there is enhancement of the endometrial-myometrial interface (open arrow), and the lumen is a signal void. Endometrial-myometrial cysts (solid arrows) are visible. Cystic atrophy was diagnosed at sampling. The corresponding light micrograph is shown in Figure 5. (Reprinted, with permission, from reference 30.)

 


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  		Figure 11a. (a) Coronal T2-weighted fast spin-echo MR image (3,850/120 [effective]) demonstrates many of the uterine manifestations in women undergoing tamoxifen therapy: a heterogeneous widened endometrial canal (black arrows), adenomyosis (open arrow), and leiomyomas (curved arrows). (Reprinted, with permission, from reference 30.) (b) Sagittal fat-suppressed gadolinium-enhanced T1-weighted spoiled gradient-echo MR image (140/4) highlights the stalk (white arrow) of a polyp originating from the anterior endometrium and an area of adenomyosis (open arrow). Note the subtle, latticelike enhancement (black arrows) traversing the endometrial canal, a feature common to polyps. (c, d) Sagittal gadolinium-enhanced T1-weighted spoiled gradient-echo MR images (140/4) in two other patients emphasize the widened endometria with latticelike enhancement (arrows). The latticelike enhancement in d circumscribes well-defined cystic spaces (*). The US scans shown in Figure 8 correspond to d. In c, note the leiomyoma (L) with lower signal intensity and the cysts (arrowheads). At sampling, all had benign endometrial polyps.

 


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  		Figure 11b. (a) Coronal T2-weighted fast spin-echo MR image (3,850/120 [effective]) demonstrates many of the uterine manifestations in women undergoing tamoxifen therapy: a heterogeneous widened endometrial canal (black arrows), adenomyosis (open arrow), and leiomyomas (curved arrows). (Reprinted, with permission, from reference 30.) (b) Sagittal fat-suppressed gadolinium-enhanced T1-weighted spoiled gradient-echo MR image (140/4) highlights the stalk (white arrow) of a polyp originating from the anterior endometrium and an area of adenomyosis (open arrow). Note the subtle, latticelike enhancement (black arrows) traversing the endometrial canal, a feature common to polyps. (c, d) Sagittal gadolinium-enhanced T1-weighted spoiled gradient-echo MR images (140/4) in two other patients emphasize the widened endometria with latticelike enhancement (arrows). The latticelike enhancement in d circumscribes well-defined cystic spaces (*). The US scans shown in Figure 8 correspond to d. In c, note the leiomyoma (L) with lower signal intensity and the cysts (arrowheads). At sampling, all had benign endometrial polyps.

 


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  		Figure 11c. (a) Coronal T2-weighted fast spin-echo MR image (3,850/120 [effective]) demonstrates many of the uterine manifestations in women undergoing tamoxifen therapy: a heterogeneous widened endometrial canal (black arrows), adenomyosis (open arrow), and leiomyomas (curved arrows). (Reprinted, with permission, from reference 30.) (b) Sagittal fat-suppressed gadolinium-enhanced T1-weighted spoiled gradient-echo MR image (140/4) highlights the stalk (white arrow) of a polyp originating from the anterior endometrium and an area of adenomyosis (open arrow). Note the subtle, latticelike enhancement (black arrows) traversing the endometrial canal, a feature common to polyps. (c, d) Sagittal gadolinium-enhanced T1-weighted spoiled gradient-echo MR images (140/4) in two other patients emphasize the widened endometria with latticelike enhancement (arrows). The latticelike enhancement in d circumscribes well-defined cystic spaces (*). The US scans shown in Figure 8 correspond to d. In c, note the leiomyoma (L) with lower signal intensity and the cysts (arrowheads). At sampling, all had benign endometrial polyps.

 


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  		Figure 11d. (a) Coronal T2-weighted fast spin-echo MR image (3,850/120 [effective]) demonstrates many of the uterine manifestations in women undergoing tamoxifen therapy: a heterogeneous widened endometrial canal (black arrows), adenomyosis (open arrow), and leiomyomas (curved arrows). (Reprinted, with permission, from reference 30.) (b) Sagittal fat-suppressed gadolinium-enhanced T1-weighted spoiled gradient-echo MR image (140/4) highlights the stalk (white arrow) of a polyp originating from the anterior endometrium and an area of adenomyosis (open arrow). Note the subtle, latticelike enhancement (black arrows) traversing the endometrial canal, a feature common to polyps. (c, d) Sagittal gadolinium-enhanced T1-weighted spoiled gradient-echo MR images (140/4) in two other patients emphasize the widened endometria with latticelike enhancement (arrows). The latticelike enhancement in d circumscribes well-defined cystic spaces (*). The US scans shown in Figure 8 correspond to d. In c, note the leiomyoma (L) with lower signal intensity and the cysts (arrowheads). At sampling, all had benign endometrial polyps.

 
Gadolinium enhancement improved the definition of the endometrial process. Specifically, with gadolinium enhancement, an enhancing stalk was seen in many of the polyps, allowing the diagnosis to be established with confidence (Fig 12). In the one polyp that was malignant, MR imaging allowed accurate exclusion of a deep myometrial invasion. The ability of MR imaging to help accurately predict myometrial invasion has been established in the general (untreated) postmenopausal population, and these findings should hold true for women receiving tamoxifen (65–68) (Fig 13). Although larger studies are needed to determine if MR imaging can help reliably distinguish the various endometrial pathologic conditions associated with tamoxifen use, Ascher et al (30) concluded that MR imaging may (a) help identify those patients who should undergo a sampling procedure versus those who can be followed up noninvasively with MR imaging and (b) lead to a more aggressive intervention (dilation and curettage vs EMB) if a nondiagnostic or normal result is obtained in a patient with abnormal MR imaging findings.



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  		Figure 12. MR imaging evaluation of a polyp. Sagittal gadolinium-enhanced fat-suppressed T1-weighted spoiled gradient-echo MR image (140/4) shows enhancing tissue traversing the endometrial canal. Moreover, an enhancing stalk (arrow) originating from the posterior myometrium is well depicted, allowing the diagnosis of polyp to be established with confidence. Note the enhancing superior and inferior branches of the polyp (arrowheads), which encircle cysts (*) within the polyp. The corresponding hysterectomy specimen is shown in Figure 1a. (Reprinted, with permission, from reference 30.)

 


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  		Figure 13. MR imaging assessment of the myometrium. Sagittal T2-weighted fast spin-echo MR image (3,850/120 [effective]) shows a heterogeneous mass suggestive of a polyp (*) distending the endometrial canal. In all cases of polyp, a focus of carcinoma is assumed, and the possibility of myometrial invasion is assessed. The finding of an intact junctional zone (arrows) allows exclusion of deep myometrial invasion. At hysterectomy, a focus of endometrial carcinoma was found, without evidence of myometrial invasion. (Reprinted, with permission, from reference 69.)

 
In a subsequent study (70), MR imaging was compared with endovaginal US for uterine evaluation in 28 women with breast cancer treated with tamoxifen. Histopathologic correlation was obtained in 21 patients. Histopathologic results included polyps (eight patients, one with superficial carcinoma), cystic atrophy (10 patients), and proliferative change (three patients). For the correlation of imaging findings with histopathologic results, MR imaging had 100% sensitivity, 61.5% specificity, 76.2% accuracy, 61.5% positive predictive value, and 100% negative predictive value, whereas endovaginal US had 87.5% sensitivity, 7.7% specificity, 38.1% accuracy, 36.8% positive predictive value, and 50% negative predictive value. There was no statistically significant difference between the two modalities in terms of mean endometrial thickness. Of interest, tamoxifen-associated cysts were noted on MR images in eight of 12 patients with a false-positive endovaginal US diagnosis, including seven of 10 patients with cystic atrophy. These cysts may be responsible for spurious endometrial thickening on transvaginal US scans (Fig 14). The authors (70) concluded that both modalities are sensitive for the detection of endometrial abnormalities, although neither is very specific. To date, to our knowledge, there have been no published large studies in which MR imaging, endovaginal US, and hysterosonography were compared.



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  		Figure 14a. Endovaginal US and MR imaging evaluation of endometrial-myometrial cysts. (a) Transverse endovaginal US image shows small cysts (short arrows) flanking the endometrial echo complex (long arrow). This appearance may lead to a spuriously widened endometrial measurement. (b) Sagittal gadolinium-enhanced T1-weighted spoiled gradient-echo MR image (140/4) demonstrates the actual locations of the cysts (arrows) at the endometrial-myometrial junction, consistent with cystic atrophy—a finding common in women undergoing tamoxifen treatment. In cases of equivocal widening of the endometrium at endovaginal US, there may be a benefit to performing hysterosonography or MR imaging.

 


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  		Figure 14b. Endovaginal US and MR imaging evaluation of endometrial-myometrial cysts. (a) Transverse endovaginal US image shows small cysts (short arrows) flanking the endometrial echo complex (long arrow). This appearance may lead to a spuriously widened endometrial measurement. (b) Sagittal gadolinium-enhanced T1-weighted spoiled gradient-echo MR image (140/4) demonstrates the actual locations of the cysts (arrows) at the endometrial-myometrial junction, consistent with cystic atrophy—a finding common in women undergoing tamoxifen treatment. In cases of equivocal widening of the endometrium at endovaginal US, there may be a benefit to performing hysterosonography or MR imaging.

 
RECOMMENDATIONS

The most recent American College of Obstetricians and Gynecologists opinion article (71) set forth the following recommendations for women with breast cancer who are being treated with tamoxifen:

1. Women with breast cancer should undergo annual gynecologic examinations, including pap smear and bimanual and rectovaginal examinations.

2. Any abnormal bleeding, including bloody discharge, spotting, or any other gynecologic symptoms, should be evaluated thoroughly. Any bleeding or spotting should be investigated by means of biopsy.

3. Practitioners should be alert to the increased incidence of endometrial malignancy. Screening procedures or diagnostic tests should be performed at the discretion of the individual gynecologist.

4. If atypical hyperplasia develops, use of tamoxifen should be discontinued, and dilation and curettage or other appropriate management should be instituted within an appropriate interval.

5. If tamoxifen therapy must be continued, hysterectomy should be considered in women with atypical endometrial hyperplasia.

6. Tamoxifen treatment may be reinstituted after hysterectomy for endometrial carcinoma, in consultation with the physician responsible for the woman's breast care.

The committee also suggested that women enrolled in chemoprevention trials (including the Breast Cancer Prevention Trial that was ongoing at the time) may warrant closer observation to ensure prompt treatment of any endometrial lesions that develop during tamoxifen therapy.

CONCLUSION

Given the sobering fact that one in eight American women will develop breast cancer, the use of adjuvant tamoxifen treatment will continue to increase. In addition, prophylactic tamoxifen treatment in high-risk women (including women older than 60 years) is on the horizon. Many of these women will need to be evaluated for potential uterine abnormalities. To be sure, the American College of Obstetricians and Gynecologists has reported (71) that "no cost-benefit analysis has demonstrated any particular method of [uterine] screening to be superior . . . [and] current data do not seem to support routine annual [endometrial] biopsies for all women taking tamoxifen." But that does not lessen the need for a close working relationship among oncologist, gynecologist, radiologist, and women undergoing tamoxifen therapy. To the contrary, radiologists must become familiar with the appearances of the uterus in women receiving tamoxifen and the relative strengths and weaknesses of the various imaging modalities used for evaluation of the uterus.

To aid in that process, we offer an imaging algorithm (Fig 15) based on the American College of Radiology's appropriateness criteria (72) and results in published reports. Specifically, transvaginal US is the first-line imaging modality for evaluation of the uterus in women undergoing tamoxifen therapy. The strength of transvaginal US is in the assessment of endometrial thickness, and, in some instances, it may provide information about endometrial texture or focal masses. In cases where the transvaginal US image is nondiagnostic or is suggestive of an abnormality, hysterosonography can provide additional information. That is, hysterosonography can be used to image polyps and endometrial-myometrial and subendometrial cysts with confidence and can help direct sampling procedures when necessary. Although the role of MR imaging in this patient population is less clear, MR imaging can demonstrate both endometrial and myometrial pathologic conditions. MR imaging may be appropriate (a) in patients with an equivocal or abnormal endovaginal US scan who are unable to undergo hysterosonography due to cervical stenosis and (b) at centers that do not offer hysterosonography.



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  		Figure 15. Imaging algorithm for postmenopausal patients undergoing tamoxifen treatment. The normal endovaginal US (TVUS) appearance of endometrial thickness (double layer) in women undergoing tamoxifen treatment is controversial. Some authors (11-14) have reported the mean endometrial thickness in these women to be greater (9-13-mm) than that in untreated postmenopausal women (4.0-5.4-mm). Moreover, up to 50% of women receiving tamoxifen develop endometrial abnormalities within 6-36 months of treatment (26). Therefore, we have conservatively chosen 4 mm as the upper limit for the normal endometrial thickness in these patients. This cutoff value may need to be modified on the basis of the patient's symptoms (eg, bleeding). The role of MR imaging in women undergoing tamoxifen treatment is unproved. MR imaging may be appropriate in the following settings: (a) in patients with factors that preclude satisfactory hysterosonography (SHG), such as cervical stenosis, and/or (b) at centers that do not offer hysterosonography. DSR = diagnostic sampling result.

 

Acknowledgments

The authors acknowledge Arthur C. Fleischer, MD, for contributing case material and editing the manuscript and Robert L. Bree, MD, for contributing case material.

Footnotes

Abbreviation: EMB = endometrial biopsy

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