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Malignant mixed mesodermal tumor after tamoxifen therapy for breast cancer
Gynecologic Oncology 95 (2004) 264 – 266 www.elsevier.com/locate/ygyno
Case Report
Malignant mixed mesodermal tumor after tamoxifen therapy for breast cancer Michael Hubalek*, Angela Ramoni, Elisabeth Mueller-Holzner, Christian Marth Department of Obstetrics and Gynecology, Innsbruck Medical University, A-6020 Innsbruck, Austria Received 26 March 2004 Available online 12 August 2004
Abstract Background. The risk of tamoxifen related endometrial neoplasm has been confirmed by multiple studies. Especially rare endometrial tumors seem to develop more frequently under tamoxifen therapy. A recent analysis showed a substantially higher risk for malignant mixed mesodermal tumor (MMMT; designated in the WHO classification of female genital tract neoplasms as carcinosarcoma) in association with tamoxifen intake. Case. We are reporting a case of a 40-year-old multiparous premenopausal woman who received tamoxifen 20 mg daily for 2 years after the surgical treatment of breast cancer and subsequent adjuvant chemotherapy. Two years after initiation of tamoxifen treatment, the patient developed an MMMT of the uterus. More than 64 months after radical hysterectomy, salpingo-oophorectomy, and pelvic lymphadenectomy, she remains recurrence-free for MMMT. Unfortunately, she developed a local recurrence of her breast cancer in 2003. After surgical treatment, she is currently being treated with anastrozole. Conclusion. We are reporting a rare case of a premenopausal patient who developed a MMMT within short time of tamoxifen exposure for stage I breast cancer. D 2004 Elsevier Inc. All rights reserved. Keywords: Malignant mixed mesodermal tumor (MMMT); Tamoxifen; Premenopausal
Introduction Carcinosarcomas and other uterine sarcomas are rare, histologically diverse tumors accounting for fewer than 4% of all cancers of the uterine corpus. Malignant mixed mesodermal tumors (MMMTs), the most common uterine sarcomas, are derived from the endometrium and demonstrate both epithelial and stromal differentiation. These neoplasms have an annual worldwide incidence between 0.5 and 3.3 cases per 100.000 women and comprise between 2% and 4% of uterine cancers [1]. MMMTs arise almost exclusively in postmenopausal women and have a poor prognosis. In addition to myometrial invasion, parity has been shown to affect survival * Corresponding author. Department of Obstetrics and Gynecology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Fax: +43 512 504 3112. E-mail address: [email protected] (M. Hubalek). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.06.039
[2]. In the year 2000, a Dutch case-control study showed for the first time a significantly increased risk for MMMTs in patients receiving long-term tamoxifen [3]. In a recent analysis of nine population-based cancer registries comprising 39,451 breast cancer patients, Curtis et al. [4] demonstrated that patients under tamoxifen therapy have a more than twofold absolute risk of developing subsequent cancer of the uterine corpus. The relative risk was substantially higher for MMMTs among these patients. Here we present a premenopausal patient who developed a subsequent uterine malignant mixed mullerian tumor after 2 years of treatment with tamoxifen for breast cancer.
Case In 1996, a 40-year-old multiparous woman presented with multifocal invasive ductal breast cancer. A mastectomy
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and axillary dissection was performed and the tumor was staged pT1c, N1biii, M0. Immunohistochemical staining of the tumor was positive for estrogen receptor. Postoperative treatment consisted of three cycles chemotherapy courses using 5-fluorouracil 600 mg/m2, cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 (CMF). No external radiation therapy was applied to the thoracic wall or lymph nodes. After completing chemotherapy, the patient received tamoxifen 20 mg daily. She came to oncological follow-up examinations every 3 months over 2 years. During this time, she had regular menstrual cycles under tamoxifen therapy. In September 1998, the patient developed an episode of hypermenorrhea. Transvaginal ultrasound showed an endometrium 20 mm in thickness and a cavitary polyp (34 15 mm) with pathological vascularization (Fig. 1). Curettage was performed and histological diagnosis revealed an endometrial polyp with hyperplasia of stromal cells. The stroma showed high cellularity and many cells with polymorphic nuclei. The number of mitotic figures was, however, under 2 in 10 high power fields and therefore still in the normal range. To rule out a low grade stromal sarcoma, a hysterectomy was recommended. In a subsequent radical hysterectomy, the intraoperative frozen section revealed a malignant mixed mesodermal tumor of the uterus. Consequently, a bilateral salpingo-oophorectomy Fig. 2. Histological image showing carcinomatous as well as sarcomatous features of endometrial tissue.
Fig. 1. Ultrasound image of the uterus. Doppler ultrasound reveals pathological vascularization of an endometrial polyp.
and pelvic lymphadenectomy followed hysterectomy. Final pathological examination proved a malignant mixed mullerian tumor of the endometrium with no lymph node metastasis. Histologically, the tumor was 12 10 mm in size and had infiltrated 9 mm into the myometrial wall of the uterus. There was no venous or lymphatic invasion. Resection margins were free of tumor. Immunohistochemically, various tumor cells were positive for cytokeratin (AE1/AE3 and CAM 5.2). The tumor showed portions of stromal sarcoma, adenocarcinoma, and squamous carcinoma and was therefore classified as homologous (Fig. 2). The patient received no chemotherapy or irradiation therapy after surgery. Tamoxifen therapy had been discontinued shortly before surgery. In August 2003, the patient presented with profuse pain around the area of the former mastectomy. CA15-3 had risen from 21 to 46 U/ml within 8 months, whereas CA 125 had been stable within the normal range. A CT scan showed a 3.3 2.7 cm tumorous lesion of the right thoracic wall infiltrating intercostal muscles. No pleural infiltration, intrapulmonal lesions, or involvement of mediastinal or hilus lymph nodes could be detected. A core biopsy of the tumor revealed a local recurrence of the known breast cancer. Immunohistochemistry was positive for estrogen receptor and negative for HER-2/neu. A partial resection of the thoracic wall was performed in 9/2003. After surgery, the patient received 1 mg anastrozole daily. The patient is
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currently disease-free for breast cancer. She has shown no recurrence of the MMMT in more than 64 months.
Discussion Tamoxifen, a selective estrogen receptor modulator, is a standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen will continue to be an important drug for the treatment of hormone-dependent breast cancer despite results suggesting that aromatase inhibitors will play an increasing role in the treatment of breast cancer for postmenopausal women [5,6]. Millions of breast cancer patients will continue to be treated with tamoxifen. The clinician must, however, keep in mind that tamoxifen may have serious side effects. Besides thromboembolic events, in particular, endometrial proliferation and subsequent endometrial cancer are a well documented risk in long-time tamoxifen users. We are reporting a case of a premenopausal, multiparous patient who developed MMMTs within 2 years of tamoxifen exposure for stage I breast cancer. Fortunately, the time of detection was short and the surgical intervention was sufficient for the treatment of the MMMT of the uterus. Interestingly, our patient presented none of the known predisposing factors for uterine neoplasms like hypertension, diabetes, or obesity. She had no history of endometrial polyps or mucosal hyperplasia and she was premenopausal when she was diagnosed with MMMT. The only known risk associated with endometrial cancer in this patient was tamoxifen therapy over a period of 2 years. Curtis et al. [4] provided evidence that the use of tamoxifen is associated with an overall fourfold relative risk for MMMT. This risk rises to eightfold if patients took tamoxifen for more than 5 years. It is important to mention that the age of MMMT occurrence in the patient described was unusual young. MMMTs are extraordinarily rare in premenopausal women. The biological behavior of tamoxifen on the endometrium is not fully understood. Despite its benefits, tamoxifen has been shown to have important proliferative effects on the endometrium. Use of this anti-estrogen may lead to various conditions of endometrial cells [7]. Relatively few articles have focused on the descriptive morphology of the effect of tamoxifen on the endometrium. In a review of 102 cases using hormone replacement therapy-related endometrial specimens and conventional polyps as the control group, the most characteristic findings of tamoxifenassociated lesions included polarized glands along the long axis of polyps (40%), a cambium layer (72%), staghorn glands (36%), myxoid degeneration (12%), small glands (36%) and frequent and diverse metaplasias [8]. Evidence shows that the majority of MMMTs is rather of monoclonal origin than true uterine collision tumors. These neoplasms are proposed to be metaplastic carcinomas, the sarcomatous component being a manifestation of increased aggressive-
ness [9]. In the case we have presented, the patient developed a sonographically visible endometrial polyp under tamoxifen therapy within 2 years of exposure to tamoxifen 20 mg daily. A relationship between the occurrence of MMMT and the daily doses of tamoxifen could not be suggested by any analysis [3,4,10]. However, prolonged tamoxifen therapy substantially increases the risk of developing a uterine neoplasm [4,8]. The molecular mechanisms behind the development of uterine neoplasm of different histologies under tamoxifen therapy remain unexplained. Further investigations concerning the effect of tamoxifen on the premenopausal and on the postmenopausal endometrium are needed to understand the increased risk for MMMT among tamoxifen users. In conclusion, tamoxifen remains the golden standard in the adjuvant treatment of breast cancer. Nevertheless, the results of various studies on tamoxifen and endometrial cancer show that tamoxifen is no longer recommended beyond 5 years [10]. Surveillance for uterine cancer is indicated for women who are being treated with tamoxifen, especially if they are long-term users.
References [1] Geraci P, Maggio S, Adragna F, Corrao G, Guarino S, D’Anna MR, et al. Uterine sarcomas. A retrospective study of 17 cases. Eur J Gynaecol Oncol 1988;9(6):497 – 501. [2] Marth C, Windbichler G, Petru E, Dirschlmayer W, Obermair A, Czerwenka K, et al. Parity as an independent prognostic factor in malignant mixed mesodermal tumors of the endometrium. Gynecol Oncol 1997 Jan;64(1):121 – 5. [3] Bergman L, Beelen MLR, Gallee MPW, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;20:2015 – 20. [4] Curtis RE, Freedman MD, Sherman ME, Fraumeni Jr JFR. Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004 (Jan. 7);96(1):70 – 4. [5] Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998;351:1451 – 67. [6] Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131 – 9 [published erratum appears in Lancet 2002;360:1520]. [7] Cohen I, Altaras MM, Shapira J, Tepper R, Beuth Y. Postmenopausal tamoxifen treatment and endometrial pathology. Obstet Gynecol Surv 1994;49:823 – 9. [8] Kennedy MM, Baigrie CF, Manek S. Tamoxifen and the endometrium: review of 102 cases and comparison with HRT-related and nonHRT-related endometrial pathology. Int J Gynecol Pathol 1999;18: 130 – 137. [9] Mccluggage WG. Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas. Int J Gynecol Cancer 2002; 12:687 – 90. [10] Kloos I, Delaloge S, Pautier P, Di Palma M, Goupil A, Duvillard P, et al. Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature. Int J Gynecol Cancer 2002;12:496 – 500.
Case Report
Malignant mixed mesodermal tumor after tamoxifen therapy for breast cancer Michael Hubalek*, Angela Ramoni, Elisabeth Mueller-Holzner, Christian Marth Department of Obstetrics and Gynecology, Innsbruck Medical University, A-6020 Innsbruck, Austria Received 26 March 2004 Available online 12 August 2004
Abstract Background. The risk of tamoxifen related endometrial neoplasm has been confirmed by multiple studies. Especially rare endometrial tumors seem to develop more frequently under tamoxifen therapy. A recent analysis showed a substantially higher risk for malignant mixed mesodermal tumor (MMMT; designated in the WHO classification of female genital tract neoplasms as carcinosarcoma) in association with tamoxifen intake. Case. We are reporting a case of a 40-year-old multiparous premenopausal woman who received tamoxifen 20 mg daily for 2 years after the surgical treatment of breast cancer and subsequent adjuvant chemotherapy. Two years after initiation of tamoxifen treatment, the patient developed an MMMT of the uterus. More than 64 months after radical hysterectomy, salpingo-oophorectomy, and pelvic lymphadenectomy, she remains recurrence-free for MMMT. Unfortunately, she developed a local recurrence of her breast cancer in 2003. After surgical treatment, she is currently being treated with anastrozole. Conclusion. We are reporting a rare case of a premenopausal patient who developed a MMMT within short time of tamoxifen exposure for stage I breast cancer. D 2004 Elsevier Inc. All rights reserved. Keywords: Malignant mixed mesodermal tumor (MMMT); Tamoxifen; Premenopausal
Introduction Carcinosarcomas and other uterine sarcomas are rare, histologically diverse tumors accounting for fewer than 4% of all cancers of the uterine corpus. Malignant mixed mesodermal tumors (MMMTs), the most common uterine sarcomas, are derived from the endometrium and demonstrate both epithelial and stromal differentiation. These neoplasms have an annual worldwide incidence between 0.5 and 3.3 cases per 100.000 women and comprise between 2% and 4% of uterine cancers [1]. MMMTs arise almost exclusively in postmenopausal women and have a poor prognosis. In addition to myometrial invasion, parity has been shown to affect survival * Corresponding author. Department of Obstetrics and Gynecology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Fax: +43 512 504 3112. E-mail address: [email protected] (M. Hubalek). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.06.039
[2]. In the year 2000, a Dutch case-control study showed for the first time a significantly increased risk for MMMTs in patients receiving long-term tamoxifen [3]. In a recent analysis of nine population-based cancer registries comprising 39,451 breast cancer patients, Curtis et al. [4] demonstrated that patients under tamoxifen therapy have a more than twofold absolute risk of developing subsequent cancer of the uterine corpus. The relative risk was substantially higher for MMMTs among these patients. Here we present a premenopausal patient who developed a subsequent uterine malignant mixed mullerian tumor after 2 years of treatment with tamoxifen for breast cancer.
Case In 1996, a 40-year-old multiparous woman presented with multifocal invasive ductal breast cancer. A mastectomy
M. Hubalek et al. / Gynecologic Oncology 95 (2004) 264–266
265
and axillary dissection was performed and the tumor was staged pT1c, N1biii, M0. Immunohistochemical staining of the tumor was positive for estrogen receptor. Postoperative treatment consisted of three cycles chemotherapy courses using 5-fluorouracil 600 mg/m2, cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 (CMF). No external radiation therapy was applied to the thoracic wall or lymph nodes. After completing chemotherapy, the patient received tamoxifen 20 mg daily. She came to oncological follow-up examinations every 3 months over 2 years. During this time, she had regular menstrual cycles under tamoxifen therapy. In September 1998, the patient developed an episode of hypermenorrhea. Transvaginal ultrasound showed an endometrium 20 mm in thickness and a cavitary polyp (34 15 mm) with pathological vascularization (Fig. 1). Curettage was performed and histological diagnosis revealed an endometrial polyp with hyperplasia of stromal cells. The stroma showed high cellularity and many cells with polymorphic nuclei. The number of mitotic figures was, however, under 2 in 10 high power fields and therefore still in the normal range. To rule out a low grade stromal sarcoma, a hysterectomy was recommended. In a subsequent radical hysterectomy, the intraoperative frozen section revealed a malignant mixed mesodermal tumor of the uterus. Consequently, a bilateral salpingo-oophorectomy Fig. 2. Histological image showing carcinomatous as well as sarcomatous features of endometrial tissue.
Fig. 1. Ultrasound image of the uterus. Doppler ultrasound reveals pathological vascularization of an endometrial polyp.
and pelvic lymphadenectomy followed hysterectomy. Final pathological examination proved a malignant mixed mullerian tumor of the endometrium with no lymph node metastasis. Histologically, the tumor was 12 10 mm in size and had infiltrated 9 mm into the myometrial wall of the uterus. There was no venous or lymphatic invasion. Resection margins were free of tumor. Immunohistochemically, various tumor cells were positive for cytokeratin (AE1/AE3 and CAM 5.2). The tumor showed portions of stromal sarcoma, adenocarcinoma, and squamous carcinoma and was therefore classified as homologous (Fig. 2). The patient received no chemotherapy or irradiation therapy after surgery. Tamoxifen therapy had been discontinued shortly before surgery. In August 2003, the patient presented with profuse pain around the area of the former mastectomy. CA15-3 had risen from 21 to 46 U/ml within 8 months, whereas CA 125 had been stable within the normal range. A CT scan showed a 3.3 2.7 cm tumorous lesion of the right thoracic wall infiltrating intercostal muscles. No pleural infiltration, intrapulmonal lesions, or involvement of mediastinal or hilus lymph nodes could be detected. A core biopsy of the tumor revealed a local recurrence of the known breast cancer. Immunohistochemistry was positive for estrogen receptor and negative for HER-2/neu. A partial resection of the thoracic wall was performed in 9/2003. After surgery, the patient received 1 mg anastrozole daily. The patient is
266
M. Hubalek et al. / Gynecologic Oncology 95 (2004) 264–266
currently disease-free for breast cancer. She has shown no recurrence of the MMMT in more than 64 months.
Discussion Tamoxifen, a selective estrogen receptor modulator, is a standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen will continue to be an important drug for the treatment of hormone-dependent breast cancer despite results suggesting that aromatase inhibitors will play an increasing role in the treatment of breast cancer for postmenopausal women [5,6]. Millions of breast cancer patients will continue to be treated with tamoxifen. The clinician must, however, keep in mind that tamoxifen may have serious side effects. Besides thromboembolic events, in particular, endometrial proliferation and subsequent endometrial cancer are a well documented risk in long-time tamoxifen users. We are reporting a case of a premenopausal, multiparous patient who developed MMMTs within 2 years of tamoxifen exposure for stage I breast cancer. Fortunately, the time of detection was short and the surgical intervention was sufficient for the treatment of the MMMT of the uterus. Interestingly, our patient presented none of the known predisposing factors for uterine neoplasms like hypertension, diabetes, or obesity. She had no history of endometrial polyps or mucosal hyperplasia and she was premenopausal when she was diagnosed with MMMT. The only known risk associated with endometrial cancer in this patient was tamoxifen therapy over a period of 2 years. Curtis et al. [4] provided evidence that the use of tamoxifen is associated with an overall fourfold relative risk for MMMT. This risk rises to eightfold if patients took tamoxifen for more than 5 years. It is important to mention that the age of MMMT occurrence in the patient described was unusual young. MMMTs are extraordinarily rare in premenopausal women. The biological behavior of tamoxifen on the endometrium is not fully understood. Despite its benefits, tamoxifen has been shown to have important proliferative effects on the endometrium. Use of this anti-estrogen may lead to various conditions of endometrial cells [7]. Relatively few articles have focused on the descriptive morphology of the effect of tamoxifen on the endometrium. In a review of 102 cases using hormone replacement therapy-related endometrial specimens and conventional polyps as the control group, the most characteristic findings of tamoxifenassociated lesions included polarized glands along the long axis of polyps (40%), a cambium layer (72%), staghorn glands (36%), myxoid degeneration (12%), small glands (36%) and frequent and diverse metaplasias [8]. Evidence shows that the majority of MMMTs is rather of monoclonal origin than true uterine collision tumors. These neoplasms are proposed to be metaplastic carcinomas, the sarcomatous component being a manifestation of increased aggressive-
ness [9]. In the case we have presented, the patient developed a sonographically visible endometrial polyp under tamoxifen therapy within 2 years of exposure to tamoxifen 20 mg daily. A relationship between the occurrence of MMMT and the daily doses of tamoxifen could not be suggested by any analysis [3,4,10]. However, prolonged tamoxifen therapy substantially increases the risk of developing a uterine neoplasm [4,8]. The molecular mechanisms behind the development of uterine neoplasm of different histologies under tamoxifen therapy remain unexplained. Further investigations concerning the effect of tamoxifen on the premenopausal and on the postmenopausal endometrium are needed to understand the increased risk for MMMT among tamoxifen users. In conclusion, tamoxifen remains the golden standard in the adjuvant treatment of breast cancer. Nevertheless, the results of various studies on tamoxifen and endometrial cancer show that tamoxifen is no longer recommended beyond 5 years [10]. Surveillance for uterine cancer is indicated for women who are being treated with tamoxifen, especially if they are long-term users.
References [1] Geraci P, Maggio S, Adragna F, Corrao G, Guarino S, D’Anna MR, et al. Uterine sarcomas. A retrospective study of 17 cases. Eur J Gynaecol Oncol 1988;9(6):497 – 501. [2] Marth C, Windbichler G, Petru E, Dirschlmayer W, Obermair A, Czerwenka K, et al. Parity as an independent prognostic factor in malignant mixed mesodermal tumors of the endometrium. Gynecol Oncol 1997 Jan;64(1):121 – 5. [3] Bergman L, Beelen MLR, Gallee MPW, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;20:2015 – 20. [4] Curtis RE, Freedman MD, Sherman ME, Fraumeni Jr JFR. Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004 (Jan. 7);96(1):70 – 4. [5] Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998;351:1451 – 67. [6] Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131 – 9 [published erratum appears in Lancet 2002;360:1520]. [7] Cohen I, Altaras MM, Shapira J, Tepper R, Beuth Y. Postmenopausal tamoxifen treatment and endometrial pathology. Obstet Gynecol Surv 1994;49:823 – 9. [8] Kennedy MM, Baigrie CF, Manek S. Tamoxifen and the endometrium: review of 102 cases and comparison with HRT-related and nonHRT-related endometrial pathology. Int J Gynecol Pathol 1999;18: 130 – 137. [9] Mccluggage WG. Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas. Int J Gynecol Cancer 2002; 12:687 – 90. [10] Kloos I, Delaloge S, Pautier P, Di Palma M, Goupil A, Duvillard P, et al. Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature. Int J Gynecol Cancer 2002;12:496 – 500.