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Tamoxifen Induced Endometrial Changes

Thickened endometrium with small cysts
Markedly cystic changes within the thickened endometrium

Findings:

The endometrium in both cases is markedly thickened. In the second case multiple cysts are identified within the endometrium.

Discussion:

In the past decade, tamoxifen has been found to be an efficacious therapeutic agent in the treatment of breast cancer in the postmenopausal patient. It is a nonsteroidal "antiestrogen" that binds to the estrogen receptor. In addition to the above stated properties of the drug, it can also act as an estrogen agonist in a low estradial environment. The agonist properties can affect the endometrium, and does, in a high percentage of patients (50%). Endometrial polyps, carcinoma and hyperplasia have all been described in patients taking this medication. The reader is referred to an excellent recent review of the imaging findings of Tamoxifen treated patients by Ascher et al. (Radiology 214:29-38, 2000). The incidence of endometrial polyps in women treated with tamoxifen is significantly higher than in untreated women (8%-36% vs 0%-10%). Pathologically, endometrial polyps seen in women treated with tamoxifen appear to be different than endometrial polyps in the general population. They tend to be larger (mean diameter 5.0 cm.). Histologically, they are characterized by the combination of proliferative activity (cystic glandular dilatation) aberrant epithelial differentiation (metaplasia) and focal perglandular stromal condensation. This last feature has been postulated to be associated with a form of mullerian adenosarcoma. Likewise, the prevalence of endometrial hyperplasia is higher in tamoxifen treated patients than in those with breast cancer not receiving tamoxifen as well as the general population (1.3%-20% vs 0%-10%). Many investigators believe there is an increase in the relative risk of developing endometrial cancer in patients treated with tamoxifen. In one widely quoted randomized clinical study by Fornander et al, a statistically significant increase in the prevalence of endometrial carcinoma (6.4 fold increase) was found compared with control subjects after five years of treatment. Other investigators have quoted a 1.3-7.5 fold increase in the relative risk of developing endometrial cancer in tamoxifen treated patients. There is no question that tamoxifen affects the endometrium, increasing the risk of endometrial carcinoma and this is undoubtedly related to dosage and duration of treatment. It should be remembered however that patients with breast carcinoma have an increased relative risk of adenocarcinoma of the endometrium (1.72) even with no treatment. Likewise women over the age of 70 have an increased risk of endometrial carcinoma also even without treatment (2.4).

Tamoxifen treated patients are often described at hysteroscopy and pathologically as having cystic atrophy of the endometrium. Rather than the typical pale and thin endometrium seen in atrophy these patients often have scattered protuberances which represent glandulocystic atrophia. The location of the cystic changes is controversial (see Below). Sonographically, the most frequent appearance in patients receiving tamoxifen therapy is that of a thickened endometrium with numerous cystic spaces. This is an appearance frequently seen in patients with endometrial polyps. Transvaginal scanning is an important part of the sonographic evaluation of these patients. Transvaginal probes of 5MHz -10MHz are utililized allowing the endometrium to be seen in detail. The endometrium and its thickness should be assessed. The endometrial measurement is obtained in a sagittal plane of section and the maximal thickness should be reported. The measurement is of the two opposed layers of the endometrium not including the poorly echogenic inner myometrium or any fluid within the endometrial cavity. Normal post-menopausal endometrial thickness should not exceed 5mm in double layer thickness. Patients receiving tamoxifen often have a thicker endometrium than control patients (9-13 mm vs 4.0-5.4mm). In the past several years sonohysterography has greatly added to the diagnostic accuracy of endometrial pathology. Endometrial polyps which frequently occur in these patients can be well delineated with this technique. Endometrial hyperplasia and submucosal myomata will have a different appearnace.

A report describing the sonographic findings in these patients by Hulka et al found the single patient in their series with endometrial carcinoma to have a solid, thickened and heterogeneous endometrium at sonography. Most patients had a multiplicity of findings and thus they were not able to assign a single sonographic feature to a single pathologic entity. An interesting study by Goldstein found that the abnormally thickened tissue at sonography that was suggestive of endometrial polyps or hyperplasia in fact proved to be subendometrial in location. This point is controversial. Technically, endometrial glands that extend into the myometrium under the endometrium represents adenomyosis. A study by Cecchini et al found no increased prevalence of endometrial carcinoma or hyperplasia which could be ascribed to tamoxifen therapy. They and others have postulated that the apparent increase in endometrial thickness observed at sonography might be explained by tamoxifen induced changes of the endometrial stroma and myometrium. A study evaluating the role of Doppler sonography in the evaluation of these patients found that the mean PI and RI were significantly lower in the tamoxifen group than in the non-tamoxifen group. They had no patients with endometrial carcinoma, however.

Thickened endometrium with cystic changes (arrown) in a patient taking Tamoxifen

After instillation of saline into the uterine cavity the cysts (arrows) are clearly seen to be subendometrial in location

A recent study by Hann et al evaluated 91 postmenopausal breast cancer patients being treated with tamoxifen. Approximately 50% of patients had an endometrial thickness of 8 mm or more. Nearly half of the endometrial samples obtained in this group had histologic abnormalities, with endometrial polyps being the most common abnormality (33%). There were two cases of endometrial carcinoma (6%). Both cases were in women treated for at least 6 years with tamoxifen and both presented with postmenopausal bleeding.

 

References:

Hulka CA, Hall DA. Endometrial abnormalities associated with tamoxifen therapy for breast cancer: sonographic and pathologic correlation. Amer J Roentgenol 160:809-812, 1993

Fornander T, Cedermark B, Mattson A et al Adjuvant tamoxifen in early breast cancer: occurence of new primary cancers Lancet 1:117-120, 1989

Goldstein SR. Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 170:447-451, 1994

Exacoustos C, Aupi E, Cangi B, Chiaretti M, Arduini D, Romanini C. Endometrial evaluation in postmenopausal breast cancer patients receiving tamoxifen: an ultrasound, color flow Doppler, hysteroscopic and histological study. Ultrasound Obstet Gynecol 6:435-442, 1995

Cecchini S, Ciatto S, Bonardi R, Mazzotta A, Grazzini G, Pacini P. Screening by ultrasonongraphy for endometrial carcinoma in postmenopausal breast cancer patients under adjuvant tamoxifen. Gynecol Oncol 60:409-411, 1996

Hann LE, Giess CS, Bach AM, Tao Y, Baum HJ, Barakat RR. Endometrial thickness in tamoxifen-treated patients: Correlation with clinical and pathologic findings. Amer J Roentgenol 168:657-661, 1997

Tepper R, Beyth Y, Altaras MM, et al. Value of sonohysterography in asymptomatic post menopausal tamoxifen-treated patients. Gynecol Oncol 1997; 64:386-391

Kedar RP, Bourne TH, Powles TJ, et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomized breast cancer prevention trial. Lancet 1994; 343:1318-1321

Berlière M, Carles A, Galant C, Donnez J. Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol 1998; 91:40-44.

McGonigle KF, Shaw SL, Vasilev SA, Odom-Maryon T, Roy S, Simpson JF. Abnormalities detected on transvaginal ultrasonography in tamoxifen-treated postmenopausal breast cancer patients may represent endometrial cystic atrophy. Am J Obstet Gynecol 1998; 178:1145-1150

Ascher SM, Imaoka I, Lage JM. Tamoxifen-induced uterine abnormalities: The role of imaging. Radiology 214:29-38, 2000

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Peter W. Callen, M.D.
Professor of Radiology, Obstetrics, Gynecology and Reproductive Science
University of California Medical Center, San Francisco, California