Introduction
All cases of uterine sarcoma encountered in our gynae-oncology service since 2007 were reviewed. Those who had been previously treated with tamoxifen underwent a comprehensive chart review. In addition a literature search was performed using Medline.
Case Report
The first patient is a fifty-three year old para 0 who was diagnosed with Grade 3 estrogen (ER) and progesterone (PR) positive, invasive ductal carcinoma of the right breast. After treatment with surgery, chemotherapy, radiotherapy tamoxifen was prescribed for five years. Several weeks after completing treatment post-menopausal bleeding developed and an MRI demonstrated a large pelvic mass. Histology proved to be high grade endometrial stromal sarcoma. The second patient was a seventy six year old para 6 who was diagnosed with a Grade 1 low grade cribriform ductal carcinoma with minimal lobular carcinoma in-situ (LCIS) of the left breast and was treated by left breast wide local excision. After adjuvant radiotherapy this lady was commenced on tamoxifen which she received for 5 years.
She presented with post-menopausal bleeding and examination revealed a large pelvic mass. Histology proved this to be carcinosarcoma (Malignant Mixed Mesodermal Tumors), which had metastasized to the lungs. The third patient is a forty-seven year old para 3 who was diagnosed during pregnancy with Grade 2 ER/PR positive invasive ductal carcinoma of right breast with lympho-vascular invasion and ductal carcinoma in-situ (DCIS). She was treated with right mastectomy followed by chemotherapy, radiotherapy and adjuvant hormonal therapy tamoxifen was initiated. This lady subsequently complained of irregular vaginal bleeding and a dry cough. Histology of a large pelvic mass identified a leiomyosarcoma, which was also proven histological to have metastasized to the lungs.
Discussion
Tamoxifen binds to oestrogen receptors and elicits oestrogen agonist or antagonist depending on the target tissues. The efficacy of Tamoxifen in breast cancer is due to its anti-oestrogen properties but it exhibit weak oestrogen effects to endometrium. The literature on histological endometrial changes in patients treated with Tamoxifen reports variable figures on pathologic findings. These include simple and atypical hyperplasia, hyperplasia with polyp formation (single and multiple), polyp-cancer and adenocarcinoma1. From the study, it is indicated that gynaecological symptoms in women with Tamoxifen warrant full investigation. Reports estimate that Tamoxifen increases the risk of endometrial cancer two to threefold3.
Other studies suggest that Tamoxifen enhances the risk of developing more aggressive form of uterine malignancies2,3. Uterine sarcomas are rare form of uterine malignancies occurring in 2% to 5% of all patients with uterine malignancies4. In a review of all National Surgical Adjuvant Breast and Bowel Project (NSABP) trials, the rate of sarcoma in women treated with Tamoxifen was 17 per 100,000 patient years versus none in the placebo group5. Similarly in a separate trial of high risk women without breast cancer taking Tamoxifen as part of breast cancer prevention trial with medial follow up of 6.9 years, there were 4 sarcomas in the Tamoxifen group versus none in placebo group 5. This is compared with the incidence of 1 to 2 per 100,000 patient years in the general population6. Pelvic radiation was risk factor for developing uterine sarcoma. Duration of Tamoxifen administration is crucial for its effectiveness, but this also effects related to the partial oestrogenic activity of the drug. A lot of reports published in recent years have demonstrated a significant association between longer duration of Tamoxifen treatment and the appearance of uterine sarcoma7,8. Most of the Tamoxifen associated sarcomas were MMMT (Malignant Mixed Mesodermal Tumours)9,10.
The purpose of this report is to highlight the association of tamoxifen and uterine sarcoma, and to emphasize the need for formulating a standardized follow-up protocol by multidisciplinary team including breast surgeons, oncologists (Radiation and Medical) and GPs for women receiving tamoxifen. Any women on Tamoxifen who developed gynaecological symptoms should be referred to Gynaecologist for review.
Correspondence: MS Mat Samuji
Department of Radiation Oncology, Cork University Hospital, Wilton, Cork
Email: [email protected]
Acknowledgements
J Coulter, Department of Gynaecology, South Infirmary Victoria University Hospital, Cork
References
1. Ismail S.M. Pathology of endometrium treated with Tamoxifen. J Clin Pathol 1994; 47:827-833.
2. Sesti F, Patrizi L, Ermini B, Palmieri G, Orlandi A, Piccione E. High grade endometrial stromal sarcoma after Tamoxifen therapy for breast cancer. Gynaecol Obstet Invest 2005; 60:117-120.
3. Curtis RE, Freedman DM, Sherman ME, Fraumeni JF Jr. Risk of malignant mixed mullerian tumours after Tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004; 96:70-74.
4. Avarette HE and Nguyen, H. 1995. Gynaecologic cancer. In Murphy G.P, Lawrence W. Jr, Lenhard R.E Jr. American Cancer Society textbook of Clinical oncology. 2nd ed. Atlanta: American Cancer Society, 552-79.
5. Wickerham D.L, Fisher B, Wolmark N, Bryant J, Costantino J, Bernstein L. Association of Tamoxifen and uterine sarcoma. J Clin Oncol, 2002; 20:2758-60.
6. Mouridsen J.E, Palshof T, Patterson J, Battersby L. Tamoxifen in advance breast cancer. Cancer Treat Rev, 1978; 5:131-41.
7. Bergman L, Beelen MLR, Galee MPW, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after Tamoxifen for breast cancer. Lancet 2000; 356:881-7.
8. Lasset C, Bellen MLR, Gallee MPW. Tamoxifen and risk of endometrial cancer. Lancet 2001; 357:410-4.
9. ACOG Committee Opinion. Tamoxifen and endometrial cancer. Int J Gynaecol Obstet. 1996; 53:197-9.
10. Altaras M.M, Aviram R, Cohen I, Cordoba M, Yarkoni S, Beyth Y. Role of prolonged stimulation of Tamoxifen therapy in the aetiology of endometrial sarcomas. Gynaecol Oncol, 1993; 49:255-8