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Genitourinary Imaging |
1 From the Department of Obstetrics and Gynecology (I.C., C.P.N., R.T.), Gynecological Ultrasound Unit (R.T.), and Medical Oncology Unit, (J.S., D.Y.) Sapir Medical Center, Kfar-Saba 44281, Israel, affiliated with Sackler Faculty of Medicine, Tel Aviv University. Received February 19, 2002; revision requested April 22; final revision received October 6; accepted October 25. Address correspondence to I.C.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Of 332 postmenopausal women with breast cancer who were treated with tamoxifen, 32 (9.6%) had simple ovarian cysts. Long-term follow-up transvaginal ultrasonography (US) was performed in patients who had these simple ovarian cysts, and serum CA 125 samples were taken. Standard linear regression analysis with repeated measurements with irregular time points with the mixed-effects model was used to correlate cyst size at transvaginal US with the time elapsed since the diagnosis of ovarian cysts. Statistical analysis was performed by using the t test for regression slope.
RESULTS: There was a significant decrease in cyst size over time (P = .017). Three (9%) of the 32 patients underwent surgery. Histologic evaluation of the removed ovaries revealed simple ovarian cyst, well-differentiated ovarian carcinoma, and metastatic adenocarcinoma. The remaining 29 (91%) continued with regular follow-up examinations only. In 11 (34%) of the 32 patients there were no changes in cyst size over time. In nine patients (28%) additional cysts appeared. Cysts disappeared, increased in size, disappeared and reappeared, or decreased in size in four (12%) patients each. Serum CA 125 levels were within the normal range.
CONCLUSION: In postmenopausal patients with breast carcinoma who were treated with tamoxifen, long-term follow-up US of simple ovarian cysts demonstrates a significant decrease in cyst size over time.
© RSNA, 2003
Index terms: Breast neoplasms, therapy, 00.32 • Ovary, cysts, 852.3111, 852.3112 • Ovary, US, 852.1298 • Tamoxifen
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Twelve patients violated the study protocol because of poor compliance and delayed follow-up examinations, and they were excluded from the study.
Of the 332 patients investigated, 32 (9.6%) appeared to have benign simple ovarian cysts at ultrasonography (US). These latter patients were evaluated with transvaginal US (R.T.) and measurement of serum CA 125 levels every 3 months. Three (9%) patients underwent surgery. The remaining 29 (91%) continued with regular follow-up examinations only (R.T.). All patients were treated with 20–30 mg of tamoxifen daily (J.S., D.Y.) (ABIC, Chemical and Pharmaceutical Industries, Netanya, Israel) throughout the study period.
Clinical Factors
We compared 10 clinical factors between the 32 postmenopausal tamoxifen-treated patients with benign ovarian cysts (group 1) and the remaining 300 postmenopausal tamoxifen-treated patients without ovarian cysts (group 2): age at onset of study, age at onset of menopause, weight, chemotherapy, radiation therapy, smoking (concurrent to study, smoking of any amount of cigarettes), diabetes mellitus (concurrent clinical disease that requires medical treatment), hypertension (concurrent clinical disease that requires medical treatment), previous hormone replacement therapy (any combination of estrogen and progesterone [sequential or combined] administered up to the time of diagnosis of the breast cancer), and postmenopausal bleeding (any episode of vaginal bleeding reported by the patient since the diagnosis of the breast cancer) (Table 1).
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Transvaginal US was initially performed with a 5.0-MHz US system (Aloka, Tokyo, Japan). For the last 3 years of follow-up, transvaginal US was performed with a 128XP10 ultrasound system (Acuson, Mountain View, Calif) with 5–7 MHz and ATL HDI 5000 with a high-resolution transvaginal transducer.
The follow-up studies were performed to evaluate the size, number, and disappearance of cysts.
Imaging Analysis
One author (R.T.) performed all the initial and follow-up imaging, as well as the interpretation of the US images.
Patients were selected for follow-up when they had benign simple cysts that were anechoic, with thin walls and distal acoustic enhancement with a mean diameter of less than 5 cm.
Cyst size was defined as the mean size of three measurements. A change in size of the cysts was arbitrarily defined as any change in mean diameter of more than 20%.
Statistical Analysis
Standard linear regression analysis with repeated measurements with irregular time points with the mixed-effects model was used to correlate cyst size at transvaginal US with time elapsed since the diagnosis of ovarian cysts. Statistical analysis was performed by using the t test for regression slope. A P value of .05 was regarded as denoting significance.
Statistical analysis for the comparison of the various clinical factors was performed by using the Wilcoxon two-sample test and the Fisher exact test. A P value of less than .05 was considered to show statistical significance. Statistical analysis was performed by consensus.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The time elapsed between the diagnosis of breast carcinoma and the diagnosis of ovarian cysts was 23.5 months ± 28.1, and the time between the initiation of tamoxifen treatment and the diagnosis of ovarian cysts was 16.8 months ± 16. The time elapsed between the diagnosis of breast carcinoma and the performance of the first transvaginal US was 10.23 months ± 7.48, and the time between the initiation of tamoxifen treatment and the first transvaginal US was 7.8 months ± 6.6.
Transvaginal US
Changes in cyst size measured with transvaginal US were obtained by using standard linear regression analysis, as shown in the Figure. The following equation was used: cyst size = 0.09845 (constant) - 17.28558 (b) x months of follow-up (P = .017), where b is the slope regression coefficient.
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Seven (22%) patients each had two cysts, five (16%) each had three cysts, and three (9%) each had four cysts.
Operations
Three patients underwent surgery. One patient underwent laparotomy because of pelvic and abdominal pains that accompanied a cyst with a diameter of 4.6 cm. Histologic evaluation revealed a simple ovarian cyst. In the second patient, there was a sudden increase in cyst size from a mean diameter of 4.0 cm to a mean diameter of 6.0 cm. This was observed at transvaginal US performed within the recommended 4-month interval. Histologic evaluation revealed a small, well-differentiated ovarian carcinoma evaluated as grade IC. This tumor was not related to the original cyst. In the third patient, transvaginal US performed within the recommended 4-month interval revealed a gradual increase in cyst size to a diameter of 3.8 cm, with a concomitant appearance of a semisolid component. Histologic evaluation of the affected ovary revealed metastatic adenocarcinoma of the breast carcinoma. This tumor was related to the cyst. The metastatic lesions were found in the affected ovary and in multiple areas in the pelvis. However, all lesions were very small.
Hormonal and CA 125 Serum Evaluations
All serum CA 125 levels were within the normal range. All patients in the study had serum 17 estradiol levels in the normal menopausal range of less than 20 pg/mL (<73.4 pmol/L).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The research data on the natural history of benign ovarian cysts in postmenopausal patients who are treated with tamoxifen for breast carcinoma are scarce. There are only a few reports, with a relatively small number of patients, concerning ovarian cysts that developed coincidently with postmenopausal tamoxifen exposure (2–6).
We detected simple ovarian cysts in 32 (9.6%) postmenopausal women with breast cancer after 16.8 months ± 18 of tamoxifen treatment. Other investigators have reported similar results. Shushan et al (4) detected ovarian cysts in five (6.3%) similar patients with a mean tamoxifen treatment interval of 19.4 months ± 7.8. Lindahl et al (5) used transvaginal US to follow-up 90 asymptomatic postmenopausal patients with breast cancer. In patients treated with tamoxifen, cysts were present in five of 35 patients before treatment, six of 37 after 3 months, and none of 32 after 1 year of treatment. The corresponding frequencies for those not treated with tamoxifen were two of 20, three of 11, and two of 23, respectively. Kedar et al (6) reported the results of transvaginal and color Doppler US follow-up examinations that were performed on 111 postmenopausal women from the randomized, double-blind controlled Pilot Breast Cancer Prevention Trial. The patients were randomly selected to receive either 20 mg of tamoxifen (61 patients) or a placebo (50 patients). Four (6.6%) ovarian cysts, two simple and two complex, were detected in the group that received tamoxifen (one patient had bilateral cysts), compared with two (4%) simple cysts detected in the control group.
In healthy postmenopausal women, the proportions were found to be slightly different. Conway et al (8) found a similar rate (6.6%) of cysts during US screening of 1,769 healthy postmenopausal women, while Levine et al (7) identified a higher rate (17.3%) with transabdominal and transvaginal US performed on 184 healthy postmenopausal women.
The long-term natural history of simple ovarian cysts in postmenopausal tamoxifen-treated patients has been reported in only one study, to our knowledge (5). In this study, all cysts disappeared within 1 year of follow-up.
In our study, throughout the follow-up period 12% of the cysts disappeared, 12% increased in size, 34% had no change in size, and 12% decreased in size. In 12% of the patients, the cysts disappeared and then reappeared. In another 28%, additional cysts appeared.
In healthy postmenopausal women, again, the proportions were found to be different. Cysts resolved spontaneously in 23.3%–53% of patients, persisted in 28%–59.5% of patients, and increased in size in 3% of patients (7,8,11,12).
To demonstrate long-term changes in transvaginal US-measured cyst size in our study, we used standard linear regression analysis, as shown in the Figure. There was an overall significant decrease in cyst size over time (P = .017). Likewise, in postmenopausal tamoxifen-treated patients we may expect benign simple ovarian cysts to decrease in size over time.
In our study, the ovaries were removed from three (9%) of the 32 patients. Of these three, two patients underwent surgery because of an increase in the size of the cysts, and in one of these patients, a concomitant appearance of a semisolid component was also noticed at transvaginal US performed within the recommended 4-month interval. Histologic evaluation revealed a well-differentiated ovarian carcinoma in the first patient and a metastatic adenocarcinoma in the second. The third patient underwent surgery because of pelvic pains. In this patient, simple ovarian cysts were diagnosed.
Our research revealed no other report in the literature of similar findings among postmenopausal tamoxifen-treated patients.
There have been very few verified cases of malignant involvement with completely anechoic, thin-walled ovarian cysts smaller than 5 cm that have been diagnosed in healthy postmenopausal women (20,21). Thus, malignancy would appear to be very rare in these cysts (12). Kroon and Andolf (12) performed surgery on 43 (51.8%) patients in whom no ovarian cancer was identified. Conway et al (8) performed surgery in 26.1% of women with persistant ovarian cysts. No malignancy was identified. Goldstein et al (9) did not find any malignant lesion among 28 simple ovarian cysts of less than 5 cm in diameter, which includes two that were surgically removed because of symptoms and a change in appearance at transvaginal US. Therefore, in contrast to postmenopausal women who are healthy, in postmenopausal patients who are being treated with tamoxifen there might be some tendency (two of 32 in our study, 6%) toward malignant changes in simple ovarian cysts, which may justify continuous, long-term follow-up of these cysts. Transvaginal US should be performed every 4 months for as long as the cysts persist.
Several studies, however, have shown no significant differences in the incidence of new primary ovarian cancers between postmenopausal patients with breast carcinoma treated with tamoxifen and subjects in control groups (22–24). The relative risk for the development of a new ovarian malignancy was also low in these studies (22–24).
Our study identified seven (22%) patients who each had two cysts, five (16%) patients who each had three cysts, and three (9%) patients who each had four cysts. Overall, nine (28%) patients had additional cysts. Shushan et al (4) detected eight cysts overall in five postmenopausal tamoxifen-treated patients, all of which were simple cysts. To our knowledge, there is no other report in the literature on multiple simple ovarian cysts in similar patients. Kedar et al (6) reported on one patient with bilateral cysts among 61 healthy postmenopausal women who were exposed to preventive tamoxifen treatment. It seems, therefore, that in postmenopausal tamoxifen-treated patients, there is a tendency toward the appearance of multiple simple ovarian cysts.
The incidence of benign ovarian diseases among postmenopausal patients with breast carcinoma treated with tamoxifen was found to be higher than that reported for similar diseases in the control subjects (3). A 5.7% rate of benign ovarian diseases, among 175 postmenopausal patients treated with tamoxifen for breast carcinoma that was diagnosed with histopathologic examination, has previously been reported (3). A high rate (50%) of bilaterality was also noted (3).
We could not find any statistically significant difference in various clinical factors that were compared between postmenopausal tamoxifen-treated patients with simple ovarian cysts and postmenopausal tamoxifen-treated patients patients without cysts, except for a higher rate of hypertension among the former group. Consequently, there is no predictive factor for the appearance of simple ovarian cysts among postmenopausal tamoxifen-treated patients with breast cancer.
In conclusion, the natural history of benign ovarian cysts in postmenopausal patients treated with tamoxifen for breast cancer shows an overall significant decrease in cyst size over time. There is a tendency toward multiple simple ovarian cysts. Two cases of ovarian malignancy were diagnosed in this study. Therefore, long-term US follow-up may be justified.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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