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International Journal of Gynecological Cancer:
doi: 10.1111/IGC.0b013e3181a83fbf
Ovarian Cancer

Ovarian Carcinosarcomas Associated With Prolonged Use of Tamoxifen: Case Reports

Lavie, Ofer MD*; Longacre, Teri MD†; Segev, Yakir MD, MSc*; Husain, Amreen MD‡

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*Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Carmel Medical Center, Haifa, Israel; and †Department of Pathology, and ‡Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA.

Address correspondence and reprint requests to Yakir Segev, MD, MSc, Department of Obstetrics and Gynecology, Carmel Medical Center, 7 Michal St, Haifa, Israel. E-mail: segevyakir@yahoo.com.

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Abstract

Background: Recent studies have indicated that the risk associated with tamoxifen may be substantially higher for uterine malignant mixed müllerian tumors and uterine sarcomas.

Case: We present 2 cases of ovarian carcinosarcomas in patients with a personal history of breast carcinoma who were treated for a prolonged period with tamoxifen.

Conclusions: To our knowledge, these 2 cases are the first to describe the possible association between ovarian carcinosarcomas and previous personal and familial history of breast carcinoma and\or prolonged use of tamoxifen. These cases may suggest that like in the uterus, tamoxifen has a possible delayed effect, which might be responsible for the formation of aggressive tumors of unclear pathogenesis in the ovaries.

Ovarian carcinosarcomas (OCSs), also called malignant mixed müllerian tumors (MMMTs) of the ovaries, are rare, accounting for less than 2% of ovarian malignancies.1,2 Histologically, carcinosarcomas of the ovary are composed of both epithelial malignant and sarcomatous components, which may be either homologous or heterologous.

Clinically, they are aggressive neoplasms that have poor overall survivals.3,4

Because of the rarity of OCSs, most published series detailing this neoplasm consist of small numbers of patients. As a result, it is difficult to draw conclusions regarding the risks factors, etiologies, and optimal treatment regimen for OCSs.

Tamoxifen (TAM) has been shown to be effective in improving survival for women with breast cancer and seems to decrease the risk of estrogen receptor-positive breast cancer in high-risk populations of healthy women.5-7

Despite its benefits, TAM has weak estrogenic effects that can produce endometrial cell proliferation and consequently increase the risk of endometrial cancer by approximately 3- to 7-fold.7,8 Recent studies have indicated that the risk associated with TAM may be substantially higher for rare, aggressive forms of uterine tumors, notably MMMTs and uterine sarcomas.6-9

A PubMed search of the English literature using the terms ovarian carcinosarcoma, MMMTs of the ovary, breast carcinoma, and TAM revealed no previous published cases of OCSs associated with the use of TAM. We present here the 2 first cases of OCSs associated with prolonged use of TAM. These cases may highlight one of the possible risk factors for this rare ovarian neoplasm.

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CASE 1

A 53-year-old white woman presented with low abdominal pressure, bloating, lower extremity edema, and urinary frequency. Her medical history was significant for breast carcinoma, diagnosed first 12 years ago, for which she went through a right lumpectomy followed by a repeated lumpectomy and right modified radical mastectomy because of recurrences 2 years after her primary diagnosis. The patient had been taking adjuvant TAM (20 mg/d) for the past 8 years. This patient also had a strong family history of breast carcinoma, including a mother diagnosed with breast carcinoma at the age of 50 years and 2 second-degree relatives diagnosed with breast carcinoma.

Pelvic examination revealed ascites and palpable abdominal pelvic mass measuring 15 cm. Pelvic ultrasound and magnetic resonance imaging suggested large pelvic mixed solid-cystic masses and diffused peritoneal thickening suggestive of metastatic implants and ascites.

The patient underwent an exploratory laparotomy that revealed 2.5 L of ascites, an omental cake, bilateral ovarian cystic and solid masses measuring 15 × 15 and 7 × 10 cm, respectively, and peritoneal implants in the pelvis and upper abdomen.

The patient underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and tumor debulking with a pelvic residual tumor of less than 1 cm at the end of the surgical procedure.

Sections of the bilateral ovaries and the fallopian tubes demonstrated OCSs with malignant epithelial glands and stromal components. Sections show malignant epithelial elements with serous and mucinous features. The heterologous elements included a liposarcoma with evidence of lipoblasts (Fig. 1). The histopathologic section of the uterus revealed an atrophic endometrium with myometrial atypia, suggesting a carcinosarcoma originating from the ovary. The tumor was staged as IIIC OCS.

Figure 1
Figure 1
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The patient refused any further adjuvant chemotherapy initially but, several months later, presented to an outside emergency department and was treated by the oncology service with paclitaxol and carboplatin chemotherapy. This patient's treatment is ongoing.

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CASE 2

A 65-year-old Hispanic woman presented with abdominal pain, bloating, and pelvic discomfort. Her oncologic history began at the age of 55 years when she was treated for stage I breast carcinoma. At that time, she underwent a lumpectomy and axillary lymph nodes dissection, followed by adjuvant radiotherapy and TAM treatment (20 mg/d) for 10 years. The patient had a family history of a sister with breast carcinoma in her 50s and a brother with a history of prostate cancer.

Pelvic examination revealed moderate ascites and a palpable pelvic mass. Pelvic ultrasound and computed tomography suggested large pelvic solid masses, diffuse peritoneal thickening suspected for metastatic implants, and 3 enhancing lesions within her right hepatic lobe invading through the liver capsule.

The patient underwent an exploratory laparotomy that revealed an omental cake (10 × 12 cm) extensively involving the transverse colon and the bilateral ovarian solid masses (17 × 11 and 9.5 × 7 cm) with peritoneal implants in the pelvis and in the abdomen involving the appendix and the small bowel. Metastatic tumor was noted in the liver.

Total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy transverse colon resection, appendectomy, and small bowel biopsies were performed with residual tumors of 1 to 2 cm in the liver.

Pathologic sections of the bilateral ovaries and fallopian tubes demonstrated high-grade surface epithelial neoplasm with varying growth patterns, including serous and focal areas of clear cell and dedifferentiation to carcinosarcoma. Prominent mitotic figures were scattered throughout the parenchyma, and necrosis was abundant. Areas suggestive of lymphvascular invasion were identified. Multiple areas of this neoplasm demonstrated spindle cells with very pleomorphic nuclei and variably prominent nucleoli growing in sheets with no neoplastic bone or cartilage formation suggestive of OCSs of the ovary (Fig. 2). To better characterize the different areas of this neoplasm, we have performed immunohistochemical stains on a slide that exhibit both epithelial and sarcomatoid regions. Both the cytokeratin mix and S100 (stains positive in Langerhans cells; melanoma) strongly stained the more-differentiated (epithelial) part of the neoplasm, whereas the sarcomatoid regions were only faintly positive with the cytokeratin mix. Cytokeratin 7 strongly highlighted the epithelial component that were faintly positive in the sarcomatoid regions. Wilms tumor 1 was positive in the sarcomatoid regions and in the epithelial areas and negative in the spindled areas, confirming that this neoplasm is of ovarian origin. Furthermore, estrogen receptor was positive in the epithelial component but negative in the sarcomatoid areas. To exclude the possibility of metastatic breast carcinoma, we have performed an anti-gross cystic disease fluid protein 15 (BRST-2) immunostain and found it to be negative in both ovaries. The histopathologic section of the uterus revealed an atrophic endometrium with myometrial atypia, suggesting a carcinosarcoma originating from the ovary. The tumor was staged as IV OCS.

Figure 2
Figure 2
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The patient went through 6 cycles of adjuvant chemotherapy including paclitaxol, ifosfamide, and mesna with a partial response and decrease in size of the hepatic lesions.

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DISCUSSION

Ovarian carcinosarcomas are rare neoplasms associated with an aggressive clinical course and overall poor prognosis. Previous studies of this rare malignancy describe primarily the presentation of these patients with advanced disease and, consequently, the poor response to chemotherapy of this histopathologic subtype.1-4

Most of the small published series of OCSs focus on potential protocols of treatments and prognosis of these tumors; however, none of the published series elaborate on the family and personal history of prior breast cancer and the possible history of TAM exposure in this unique group of patients.

Previous retrospective studies have suggested that the use of TAM is associated with an overall 3- to 4-fold relative risk for carcinosarcoma of the uterus, which can rise to 7-fold among long-term breast cancer survivors.5-8 These findings indicate that TAM may have delayed effects, such as the increased risk of rare but aggressive tumors of unclear pathogenesis like the carcinosarcomas.

Influences of TAM on the ovaries have been previously described; these include induction of ovulation and cyst formation.10

The PubMed search of the English literature using the terms ovarian carcinosarcoma, MMMTs of the ovary, breast carcinoma, and TAM revealed no previous published cases of OCSs associated with the use of TAM.

Our 2 cases are the first to describe the possible association between OCSs and familial history and\or previous personal history of breast carcinoma and\or prolonged use of TAM. These cases may suggest that like in the uterus, TAM has a possible delayed effect, which might be responsible for the formation of aggressive tumors of unclear pathogenesis in the ovaries of this unique group of patients with both personal and family histories of cancers suggestive of a hereditary breast-ovarian cancer phenotype.

Although the mechanisms underlying TAM-related carcinosarcoma of the uterus are unknown, the potential mechanism may be that TAM exerts a variety of activities including regulation of cytokines such as transforming growth factor beta 1. Because transforming growth factor beta 1 is a potent inhibitor of epithelial cell growth and a stimulator of stromal cells and angiogenesis, this cytokine might be involved in the development of the ovarian stromal tumors induced by TAM.11

Immunohistochemical and molecular analyses have suggested that these tumors may originate as adenocarcinomas of the uterus that acquire sarcomatous differentiation over time.7-9 This mechanism may also be relevant in the OCSs formation.

Despite limited epidemiologic evidences that OCSs are related to TAM treatment,5-7 our 2 cases in this report should stimulate clinicians to investigate every OCS patient regarding prior breast malignancy and the use of TAM. In addition, we believe that molecular genetic examination for BRCA1, BRCA2, and other genes should be considered in OCSs patients.

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REFERENCES

1. Leiser AL, Chi DS, Ishill NM, et al. Carcinosarcoma of the ovary treated with platinum and taxane: the memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol. 2007;105:657-661.

2. Bicher A, Levenback C, Silva EG, et al. Ovarian malignant mixed müllerian tumors treated with platinum-based chemotherapy. Obstet Gynecol. 1995;85:735-739.

3. Crotzer DR, Wolf JK, Gano JB, et al. A pilot study of cisplatin, ifosfamide and mesna in the treatment of malignant mixed mesodermal tumors of the ovary. Gynecol Oncol. 2007;105:399-403.

4. Brown E, Stewart M, Rye T, et al. Carcinosarcoma of the ovary: 19 years of prospective data from a single center. Cancer. 2004;100:2148-2153.

5. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-1662.

6. Mourits MJ, De Vries EG, Willemse PH, et al. Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol. 2001;97:855-866.

7. Curtis RE, Freedman DM, Sherman ME, et al. Risk of malignant mixed müllerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst. 2004;96:70-74.

8. Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol. 2002;20:2758-2760.

9. Wysowski DK, Honig SF, Beitz J. Uterine sarcoma associated with tamoxifen use. N Engl J Med. 2002;346:1832-1833.

10. Shushan A, Peretz T, Mor-Yosef S. Therapeutic approach to ovarian cysts in tamoxifen-treated women with breast cancer. Int J Gynaecol Obstet. 1996;52:249-253.

11. Butta A, Maclennan K, Flanders KC, et al. Induction of transforming growth factor beta 1(TGFH1),in human breast cancer in vivo following tamoxifen. Cancer Res. 1992;52:4261-4264.

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Keywords:

Ovarian carcinosarcoma; Tamoxifen; Breast carcinoma

Copyright © 2009 by IGCS and ESGO

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