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Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole
Gynecologic Oncology 95 (2004) 769 – 771 www.elsevier.com/locate/ygyno
Case Report
Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole M. Leunena,*, M. Breugelmansa, Ph. De Suttera, C. Bourgainb, J.J. Amya a
Department of Gynecology, Andrology and Obstetrics, Vrije Universiteit Brussel, Brussels, Belgium b Department of Pathology, Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussels, Belgium Received 2 June 2004 Available online 6 October 2004
Abstract Background. Low-grade endometrial stromal sarcoma is an indolent steroid responsive tumor. Successful hormonal treatment, most commonly with megestrol acetate, has been reported. Case. A 76-year-old woman underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy 25 years earlier allegedly for a benign condition. She presented to us with postrenal kidney failure and a huge pelvic mass compressing both ureters. After transvaginal trough-cut biopsy of the mass, the diagnosis of low-grade endometrial stromal sarcoma with a high expression of a-estrogen receptor was made. The patient was treated with letrozole only with a spectacular response. Conclusion. To the best of our knowledge, this is the first case for which letrozole was used on long-term basis as first-line hormonal treatment for a recurrent low-grade stromal sarcoma. D 2004 Elsevier Inc. All rights reserved. Keywords: Endometrial stromal sarcoma; Aromatase inhibitor; Letrozole
Introduction Uterine sarcomas represent 2–3% of all uterine malignancies [1]. Tumors in this category are, in order of decreasing incidence, carcinosarcoma (malignant-mixed mesodermal tumor or malignant-mixed mullerian tumor), leiomyosarcoma, endometrial stromal sarcoma, and adenosarcoma. Endometrial stromal sarcomas are rare tumors, accounting for only 0.1% of all genital tract malignancies, and are characterized by a proliferation of cells with endometrial stromal cell differentiation. Total abdominal hysterectomy and bilateral salpingooophorectomy is recommended as primary treatment for endometrial stromal sarcoma. The role of adjuvant therapy
in the form of chemotherapy, radiation, or hormonal treatment is still not established. Studies have consistently shown the presence of estrogen and progesterone receptors in low-grade endometrial stromal sarcomas [2]. Furthermore, clinical response to hormonal therapy, particularly megestrol acetate, has been reported [3]. One case of low-grade endometrial stromal sarcoma, which progressed under treatment with tamoxifen and subsequently megestrol acetate, achieved an objective response to letrozole [4]. We report a case of recurrent low-grade endometrial stromal sarcoma, treated with letrozole as first line treatment, with excellent response.
Case report * Corresponding author. Department of Gynecology, Andrology and Obstetrics, AZ-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium. Fax: +32 2 477 65 46. E-mail address: [email protected] (M. Leunen). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.07.063
A 76-year-old woman with a body mass index of 19 was admitted to the hospital for postrenal kidney failure. She had had a total abdominal hysterectomy with bilateral salpingo-
770
M. Leunen et al. / Gynecologic Oncology 95 (2004) 769–771
oophorectomy 25 years earlier. Since then, she had been seen on a yearly basis by her gynecologist. Only 1 year before, for unclear reasons, hormonal replacement therapy (HRT) was started. Bimanual examination revealed the presence of a very large bilobated pelvic mass causing a bulging of the vaginal vault without signs of invasion of this latter and extension to the rectum and the pelvic wall. Both the ultrasound and the CT scan of the lower abdomen confirmed the existence of a pelvic mass of 11 8 9 cm. Moreover, hydronephrosis grade III due to external compression of both ureters was visualized. Cystoscopy revealed submucosal penetration of the bladder trigonum by tumor. No biopsy was taken from the bladder wall. Stents were placed in both ureters to bypass the obstruction. Renal function normalized gradually thereafter. Transvaginal trough-cut biopsy was carried out. Histologic examination showed a low-grade stromal tumor with virtually absent mitotic activity, no cell pleimorphism, and no necrosis (Fig. 1a). Ancillary, immunohistochemical stainings revealed a positivity for CD10 and vimentin and
negative stainings for cytokeratin and smooth muscle markers. Moreover, a strong staining intensity for estrogen and progesterone receptors (ER and PR, respectively) was present, consistent with the diagnosis of endometrial stromal sarcoma (Fig. 1b). Review of the slides of the uterus removed 25 years earlier revealed that it was affected by the same tumor. The patient at that time had not been informed of the malignant nature of her uterine tumor, which had been diagnosed as an dendolymphatic stromal myosisT. During her diagnostic workup, the patient developed a thrombosis of the vena cava inferior. Anticoagulant therapy was started. Taking into account the age of the patient, her compromised cardiovascular condition, and the characteristics of the tumor, it was decided not to perform immediately radical surgery but to treat her with letrozole 2.5 mg/day (FemaraR), an aromatase inhibitor. After 9 months of treatment during which the patient experienced no appreciable side effects, the tumor had undergone a spectacular decrease in size. As confirmed by CT scan, it was reduced to 1/3 of its initial volume. In view of this excellent response, the patient chose to continue the therapy with letrozole instead of undergoing an anterior exenteration. The ureter stents had been removed 18 months after initiation of therapy. After 36 months of follow-up, the patient was still asymptomatic and in excellent general condition. The diameter of the pelvic mass has decreased to 3 cm and now remains stable. Vaginal cytology is still compatible with residual stromal sarcoma, meaning that the tumor is present but suppressed, and that lifelong treatment with letrozole must be pursued.
Discussion
Fig. 1. (a) Microscopically, the neoplasm is composed of cells that resemble the stromal cells of proliferative endometrium arranged around small arterioles. (b) Immunohistochemically, the tumor cells are positive for estrogen-receptor protein.
Endometrial stromal sarcomas are divided in low- and high-grade tumors according to cell morphology and mitotic rate. Low-grade endometrial stromal sarcomas are histologically similar to the endometrial stroma in its proliferative phase but typically lack glands. Invasion into myometrium and vascular structures is characteristic for this neoplasm. The lesion typically has an indolent growth with tendency for late recurrence, occurring up to 20–30 years after resection of the primary tumor. The high-grade stromal sarcomas, on the other hand, differ from low-grade lesions in a high mitotic index (exceeding 10 mitoses per 10 highpower fields), corresponding to a more aggressive clinical course and a worse prognosis. The standard treatment for localized endometrial stromal sarcomas is a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Efficacy of adjuvant chemotherapy or hormonal therapy in endometrial stromal sarcomas is not established [5,6]. Adjuvant radiation, however, has been reported to reduce the incidence of pelvic recurrence [5]. Biochemical and immunohistochemical studies have shown the presence of estrogen and progesterone receptors in most low-grade endometrial stromal sarcomas [2]. The
M. Leunen et al. / Gynecologic Oncology 95 (2004) 769–771
principal source of circulating estrogen in postmenopausal women is conversion of adrenal androstenedione to estrone by the enzyme aromatase in peripheral adipose tissue with further conversion to estradiol. The benefit of letrozole, an orally administered, selective, nonsteroidal triazole derivative, derives from its potent inhibition of aromatase; it does not interfere with the steroid pathways. At a daily dose of 2.5 mg letrozole, estradiol and estrone levels fall by 68% and 81%, respectively, and letrozole inhibits aromatization by about 99% [7]. Because of its mechanism of action, letrozole has been evaluated in breast cancer. Two separate phase III trials of patients with locally advanced or metastatic breast cancer showed superior results of letrozole over megestrol acetate in terms of response rates, overall survival, and toxicity [8]. Another source of estrogen in postmenopausal women is HRT. Regarding the role of these exogenous hormones in sarcoma development, no definitive conclusions can be drawn. Only case reports have suggested that exogenous estrogens might have such a carcinogenic action in the uterus. Nevertheless, a potential relationship, particularly for ER- and PR-positive endometrial stromal sarcoma, must be taken into consideration. For instance, long-term HRT may influence disease evolution. A recent report on the effect of exogenous estrogen therapy or HRT on the occurrence of leiomyosarcoma and hormone dependent sarcomas did not conclude to a clear relationship [9]. In our case, peripheral aromatization might have been the major cause of tumor recurrence. However, it cannot be excluded that the 1-year HRT also caused an acceleration of the tumor growth. Based on the superior response rates and outcomes observed in breast cancer patients, and the lower incidence of drug-related side effects, we selected letrozole as a reasonable treatment option in our patient. This is the first
771
report on the use of letrozole as sole and first-line long-term therapeutic agent for a recurrent low-grade endometrial stromal sarcoma. Because of the good tolerance and the potential superiority over progestins, further studies are warranted to evaluate the efficacy of aromatase inhibitors as first-line hormonal therapy in these tumors.
References [1] Koss LG, Spiro RH, Brunschwig A. Endometrial stromal sarcoma. Surg Gynecol Obstet 1965;121:531 – 7. [2] Sabini G, Chumas JC, Mann WJ. Steroid hormones receptors in endometrial stromal sarcomas: a biochemical and immunohistochemical study. Am J Clin Pathol 1992;97:381 – 6. [3] Gloor E, Schnyder P, Cikes M, Hofstetter J, Cordey R, Burnier K, et al. Endolymphatic stromal myosis: surgical and hormonal treatment of extensive abdominal recurrence 20 years after hysterectomy. Cancer 1982;50:1888 – 93. [4] Maluf FC, Sabbatini P, Schwartz L, Xia J, Aghajanian C. Endometrial stromal sarcoma: objective response to letrozole. Gynecol Oncol 2001;82:384 – 8. [5] Piver MS, Rutledge MJ, Copeland L, Webster K, Blumenson L, Suh O. Uterine endolymphatic myosis: a collaborative study. Obstet Gynecol 1984;64:173 – 8. [6] Mansi J, Ramachandra S, Wiltshaw E, Fisher C. Endometrial stromal sarcoma. Gynecol Oncol 1990;36:113 – 8. [7] Dowsett M, Jones A, Johnston SRD. In vivo measurement of aromatase inhibition by letrozole (CGS20267) in postmenopausal women with breast cancer. Clin Cancer Res 1995;1:1511 – 5. [8] Dombernowsky P, Smith I, Falkson G. Letrozole (Femara), a new oral aromatase inhibitor for advanced breast cancer: double-blind randomised trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998;16:453 – 61. [9] Spano JP, Soria J-C, Kambouchner M, Piperno-Neuman S, Morin F, Morere J-F, Martin A, Breau J-L. Long term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol 2003;20:87 – 93.
Case Report
Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole M. Leunena,*, M. Breugelmansa, Ph. De Suttera, C. Bourgainb, J.J. Amya a
Department of Gynecology, Andrology and Obstetrics, Vrije Universiteit Brussel, Brussels, Belgium b Department of Pathology, Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussels, Belgium Received 2 June 2004 Available online 6 October 2004
Abstract Background. Low-grade endometrial stromal sarcoma is an indolent steroid responsive tumor. Successful hormonal treatment, most commonly with megestrol acetate, has been reported. Case. A 76-year-old woman underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy 25 years earlier allegedly for a benign condition. She presented to us with postrenal kidney failure and a huge pelvic mass compressing both ureters. After transvaginal trough-cut biopsy of the mass, the diagnosis of low-grade endometrial stromal sarcoma with a high expression of a-estrogen receptor was made. The patient was treated with letrozole only with a spectacular response. Conclusion. To the best of our knowledge, this is the first case for which letrozole was used on long-term basis as first-line hormonal treatment for a recurrent low-grade stromal sarcoma. D 2004 Elsevier Inc. All rights reserved. Keywords: Endometrial stromal sarcoma; Aromatase inhibitor; Letrozole
Introduction Uterine sarcomas represent 2–3% of all uterine malignancies [1]. Tumors in this category are, in order of decreasing incidence, carcinosarcoma (malignant-mixed mesodermal tumor or malignant-mixed mullerian tumor), leiomyosarcoma, endometrial stromal sarcoma, and adenosarcoma. Endometrial stromal sarcomas are rare tumors, accounting for only 0.1% of all genital tract malignancies, and are characterized by a proliferation of cells with endometrial stromal cell differentiation. Total abdominal hysterectomy and bilateral salpingooophorectomy is recommended as primary treatment for endometrial stromal sarcoma. The role of adjuvant therapy
in the form of chemotherapy, radiation, or hormonal treatment is still not established. Studies have consistently shown the presence of estrogen and progesterone receptors in low-grade endometrial stromal sarcomas [2]. Furthermore, clinical response to hormonal therapy, particularly megestrol acetate, has been reported [3]. One case of low-grade endometrial stromal sarcoma, which progressed under treatment with tamoxifen and subsequently megestrol acetate, achieved an objective response to letrozole [4]. We report a case of recurrent low-grade endometrial stromal sarcoma, treated with letrozole as first line treatment, with excellent response.
Case report * Corresponding author. Department of Gynecology, Andrology and Obstetrics, AZ-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium. Fax: +32 2 477 65 46. E-mail address: [email protected] (M. Leunen). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.07.063
A 76-year-old woman with a body mass index of 19 was admitted to the hospital for postrenal kidney failure. She had had a total abdominal hysterectomy with bilateral salpingo-
770
M. Leunen et al. / Gynecologic Oncology 95 (2004) 769–771
oophorectomy 25 years earlier. Since then, she had been seen on a yearly basis by her gynecologist. Only 1 year before, for unclear reasons, hormonal replacement therapy (HRT) was started. Bimanual examination revealed the presence of a very large bilobated pelvic mass causing a bulging of the vaginal vault without signs of invasion of this latter and extension to the rectum and the pelvic wall. Both the ultrasound and the CT scan of the lower abdomen confirmed the existence of a pelvic mass of 11 8 9 cm. Moreover, hydronephrosis grade III due to external compression of both ureters was visualized. Cystoscopy revealed submucosal penetration of the bladder trigonum by tumor. No biopsy was taken from the bladder wall. Stents were placed in both ureters to bypass the obstruction. Renal function normalized gradually thereafter. Transvaginal trough-cut biopsy was carried out. Histologic examination showed a low-grade stromal tumor with virtually absent mitotic activity, no cell pleimorphism, and no necrosis (Fig. 1a). Ancillary, immunohistochemical stainings revealed a positivity for CD10 and vimentin and
negative stainings for cytokeratin and smooth muscle markers. Moreover, a strong staining intensity for estrogen and progesterone receptors (ER and PR, respectively) was present, consistent with the diagnosis of endometrial stromal sarcoma (Fig. 1b). Review of the slides of the uterus removed 25 years earlier revealed that it was affected by the same tumor. The patient at that time had not been informed of the malignant nature of her uterine tumor, which had been diagnosed as an dendolymphatic stromal myosisT. During her diagnostic workup, the patient developed a thrombosis of the vena cava inferior. Anticoagulant therapy was started. Taking into account the age of the patient, her compromised cardiovascular condition, and the characteristics of the tumor, it was decided not to perform immediately radical surgery but to treat her with letrozole 2.5 mg/day (FemaraR), an aromatase inhibitor. After 9 months of treatment during which the patient experienced no appreciable side effects, the tumor had undergone a spectacular decrease in size. As confirmed by CT scan, it was reduced to 1/3 of its initial volume. In view of this excellent response, the patient chose to continue the therapy with letrozole instead of undergoing an anterior exenteration. The ureter stents had been removed 18 months after initiation of therapy. After 36 months of follow-up, the patient was still asymptomatic and in excellent general condition. The diameter of the pelvic mass has decreased to 3 cm and now remains stable. Vaginal cytology is still compatible with residual stromal sarcoma, meaning that the tumor is present but suppressed, and that lifelong treatment with letrozole must be pursued.
Discussion
Fig. 1. (a) Microscopically, the neoplasm is composed of cells that resemble the stromal cells of proliferative endometrium arranged around small arterioles. (b) Immunohistochemically, the tumor cells are positive for estrogen-receptor protein.
Endometrial stromal sarcomas are divided in low- and high-grade tumors according to cell morphology and mitotic rate. Low-grade endometrial stromal sarcomas are histologically similar to the endometrial stroma in its proliferative phase but typically lack glands. Invasion into myometrium and vascular structures is characteristic for this neoplasm. The lesion typically has an indolent growth with tendency for late recurrence, occurring up to 20–30 years after resection of the primary tumor. The high-grade stromal sarcomas, on the other hand, differ from low-grade lesions in a high mitotic index (exceeding 10 mitoses per 10 highpower fields), corresponding to a more aggressive clinical course and a worse prognosis. The standard treatment for localized endometrial stromal sarcomas is a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Efficacy of adjuvant chemotherapy or hormonal therapy in endometrial stromal sarcomas is not established [5,6]. Adjuvant radiation, however, has been reported to reduce the incidence of pelvic recurrence [5]. Biochemical and immunohistochemical studies have shown the presence of estrogen and progesterone receptors in most low-grade endometrial stromal sarcomas [2]. The
M. Leunen et al. / Gynecologic Oncology 95 (2004) 769–771
principal source of circulating estrogen in postmenopausal women is conversion of adrenal androstenedione to estrone by the enzyme aromatase in peripheral adipose tissue with further conversion to estradiol. The benefit of letrozole, an orally administered, selective, nonsteroidal triazole derivative, derives from its potent inhibition of aromatase; it does not interfere with the steroid pathways. At a daily dose of 2.5 mg letrozole, estradiol and estrone levels fall by 68% and 81%, respectively, and letrozole inhibits aromatization by about 99% [7]. Because of its mechanism of action, letrozole has been evaluated in breast cancer. Two separate phase III trials of patients with locally advanced or metastatic breast cancer showed superior results of letrozole over megestrol acetate in terms of response rates, overall survival, and toxicity [8]. Another source of estrogen in postmenopausal women is HRT. Regarding the role of these exogenous hormones in sarcoma development, no definitive conclusions can be drawn. Only case reports have suggested that exogenous estrogens might have such a carcinogenic action in the uterus. Nevertheless, a potential relationship, particularly for ER- and PR-positive endometrial stromal sarcoma, must be taken into consideration. For instance, long-term HRT may influence disease evolution. A recent report on the effect of exogenous estrogen therapy or HRT on the occurrence of leiomyosarcoma and hormone dependent sarcomas did not conclude to a clear relationship [9]. In our case, peripheral aromatization might have been the major cause of tumor recurrence. However, it cannot be excluded that the 1-year HRT also caused an acceleration of the tumor growth. Based on the superior response rates and outcomes observed in breast cancer patients, and the lower incidence of drug-related side effects, we selected letrozole as a reasonable treatment option in our patient. This is the first
771
report on the use of letrozole as sole and first-line long-term therapeutic agent for a recurrent low-grade endometrial stromal sarcoma. Because of the good tolerance and the potential superiority over progestins, further studies are warranted to evaluate the efficacy of aromatase inhibitors as first-line hormonal therapy in these tumors.
References [1] Koss LG, Spiro RH, Brunschwig A. Endometrial stromal sarcoma. Surg Gynecol Obstet 1965;121:531 – 7. [2] Sabini G, Chumas JC, Mann WJ. Steroid hormones receptors in endometrial stromal sarcomas: a biochemical and immunohistochemical study. Am J Clin Pathol 1992;97:381 – 6. [3] Gloor E, Schnyder P, Cikes M, Hofstetter J, Cordey R, Burnier K, et al. Endolymphatic stromal myosis: surgical and hormonal treatment of extensive abdominal recurrence 20 years after hysterectomy. Cancer 1982;50:1888 – 93. [4] Maluf FC, Sabbatini P, Schwartz L, Xia J, Aghajanian C. Endometrial stromal sarcoma: objective response to letrozole. Gynecol Oncol 2001;82:384 – 8. [5] Piver MS, Rutledge MJ, Copeland L, Webster K, Blumenson L, Suh O. Uterine endolymphatic myosis: a collaborative study. Obstet Gynecol 1984;64:173 – 8. [6] Mansi J, Ramachandra S, Wiltshaw E, Fisher C. Endometrial stromal sarcoma. Gynecol Oncol 1990;36:113 – 8. [7] Dowsett M, Jones A, Johnston SRD. In vivo measurement of aromatase inhibition by letrozole (CGS20267) in postmenopausal women with breast cancer. Clin Cancer Res 1995;1:1511 – 5. [8] Dombernowsky P, Smith I, Falkson G. Letrozole (Femara), a new oral aromatase inhibitor for advanced breast cancer: double-blind randomised trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998;16:453 – 61. [9] Spano JP, Soria J-C, Kambouchner M, Piperno-Neuman S, Morin F, Morere J-F, Martin A, Breau J-L. Long term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol 2003;20:87 – 93.