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Hormonal treatment with aromatase inhibitors for patients with endometrial stromal sarcoma
Letters to the Editor
173
G. Lialios Department of Obstetrics and Gynecology, University Hospital of Thessalia, Proussis 20, 43331 Larissa, Greece E-mail address: [email protected]. Corresponding author. G. Plataniotis Department of Radiation Oncology, University of Thessalia, Greece
Photo 4. The vaginal lesion 2 months after radiotherapy.
On the other hand, renal cell carcinomas (RCC) can present with hematuria, flank pain, palpable mass, or with a wide variety of paraneoplastic manifestations such as hypercalcemia, hypertension, hyperglycemia, erythrocytosis, etc. [3]. Symptoms from metastatic disease from RCC may be the presenting complaint in up to 30% of patients [4]. Nevertheless, metastatic RCC presenting with vaginal bleeding is rare. An interesting case of metastatic renal cell carcinoma presenting as a vaginal metastasis with thrombocytopenia as a paraneoplastic manifestation has been reported by Allard et al. [2]. Most reported cases of vaginal secondaries from RCC involve metastases from left-sided tumours. Metastatic deposits to the vagina from renal tumours arise through retrograde spread from the renal vein along the ovarian vein [4,5]. Although less than 80 cases of vaginal metastasis from renal cell carcinoma have been reported [2,6], a vaginal clear cell adenocarcinoma should always prompt a clinical and radiological search for an occult RCC, while gynecological examination in female patients should always be included in the staging procedure in case of a RCC [6].
References [1] Ovesen H, Gerstenberg T. Vaginal metastasis as the first sign of renal cell carcinoma: a case report and review of the literature. Scand J Urol Nephrol 1990;24:237 – 8. [2] Allard JE, McBroom JW, Zahn CM, McLeod D, Maxwell GL. Vaginal metastasis and thrombocytopenia from renal cell carcinoma. Gynecol Oncol 2004;92(3):970 – 3. [3] Papac RJ, Poo-Hwu W-J. Renal cell carcinoma: a paradigm of lanthanic disease. Am J Clin Oncol 1999;22:223 – 31. [4] Abraham R, Thomas DR, Foster MC. Vaginal bleeding as a presentation of metastatic renal cell carcinoma. BJU Int 1999;84(3):384. [5] Griffin SJ, Grainger R, Loftus BG, McDermott TED. Renal cell carcinoma presenting with vaginal metastasis. Ir Med Jour 2003;96(4): 115 – 6. [6] Tarraza HM, Meltzer SE, DeCain M, Jones MA. Vaginal metastases from renal cell carcinoma: report of four cases and review of the literature. Eur J Gynaecol Oncol 1998;19:14 – 8.
A. Kallitsaris Department of Obstetrics and Gynecology, University Hospital of Thessalia, Proussis 20, 43331 Larissa, Greece M.A. Theofanopoulou Department of Radiation Oncology, University of Thessalia, Greece G. Skoufi Department of Radiation Oncology, University of Thessalia, Greece I.E. Messinis Department of Obstetrics and Gynaecology, University Hospital of Thessalia, Proussis 20, 43331 Larissa, Greece 8 March 2005
doi:10.1016/j.ygyno.2005.03.024
Hormonal treatment with aromatase inhibitors for patients with endometrial stromal sarcoma To the Editor, We read with interest the paper by M. Leunen et al. [1] reporting a first-line hormonal treatment in a 76-yearold patient with endometrial stromal sarcoma (ESS) with the aromatase inhibitor letrozole. ESS are hormonesensitive tumors and estrogens can act as a growth stimulus [2]. Most women with ESS undergo bilateral salpingo-oophorectomy as part of primary treatment but estrogen also can be produced by extraovarian sources. This extra-ovarian estrogen production depends on conversion of circulating androgens to estrogens via the aromatase enzyme complex. The aromatase enzyme complex consists of the CYP19 gene product aromatase cytochrome P450 and a flavoprotein NADPH-cytochrome P450 reductase and is located in the endoplasmic reticulum of estrogen-producing cells. The treatment results of letrozole in the reported patient is explained
174
Letters to the Editor
via blockage of peripheral aromatization. However, in ESS, aromatase inhibitors reduce estrogen levels by inhibiting estrogen synthesis not only in peripheral sites, but also in the tumor cells themselves [3,4]. Using cytosol-based biochemical examinations, Tseng et al. [3] were the first to demonstrate aromatase in 8 uterine sarcomas at levels within the range of activity found in normal proliferative endometrium or above normal levels. We described aromatase expression in 23 ESS in an immunohistochemical study [4]. Aromatase-positive tumor cells were demonstrated in 83% of ESS with a monoclonal antibody and in 87% of tumors with a polyclonal antibody. Aromatase inhibitor have become a valuable treatment choice for patients with ESS. Spano et al. [5] reported 2 patients with metastatic ESS, who had a complete response after treatment with an aromatase inhibitor. Among 64 patients with ESS, who we are following, 12 women (19%) are presently receiving aromatase inhibitors as part of their postoperative hormonal treatment. For 7 patients, aromatase inhibitors are administered to prevent recurrences. Five of these patients are receiving aromatase inhibitors for treatment of metastatic disease. References [1] Leunen M, Breugelmans M, De Sutter Ph, Bourgain C, Amy JJ. Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole: case report. Gynecol Oncol 2004;95(3):769–71. [2] Reich O, Regauer S, Urdl W, Lahousen M, Winter R. Expression of estrogen and progesterone receptors in low-grade endometrial stromal sarcomas. Br J Cancer 2000;82:1030 – 4. [3] Tseng L, Tseng JK, Mann WJ, Chumas JC, Stone ML, Mazella J, et al. Endocrine aspects of human uterine sarcoma: a preliminary study. Am J Obstet Gynecol 1986;155:95 – 101. [4] Reich O, Regauer S. Aromatase expression in low-grade endometrial stromal sarcomas: a immunohistochemical study. Mod Pathol 2004; 17:104 – 8. [5] Spano JP, Soria JC, Kambouchner M, Piperno-Neuman S, Morin F, Morere JF, et al. Long term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol 2003; 20:87 – 93.
Olaf Reich Department of Obstetrics and Gynecology Medical University of Graz Auenbruggerplatz 14, A-8036 Graz, Austria E-mail address: [email protected]. Corresponding author. Fax: +43 316 3852072. Sigrid Regauer Institute of Pathology, Medical University of Graz, Austria 8 November 2004
doi:10.1016/j.ygyno.2004.12.003
Reply to letter to the editor by Reich and Regauer: Hormonal treatment with aromatase inhibitors for patients with endometrial stromal sarcoma We would like to thank Dr. Reich and Prof. Regauer for their interest in our paper [1]. They pointed out that the effect of aromatase inhibitors (e.g., letrozole) may not only be explained by the inhibition of estrogen synthesis in the peripheral sites but also by such inhibition in the tumor cells themselves [2]. Aromatase is the key enzyme in estrogen synthesis, and estrogen seems to be the promoting factor in low-grade endometrial stromal sarcomas. As Dr. Reich and Prof. Regauer demonstrated an aromatase expression in tumor cells of endometrial stromal sarcomas, it can be hypothesized that aromatase inhibitors will act directly on tumor cells as well. In our case, the diagnosis was made on a small transvaginal trough-cut biopsy. An immunohistochemical staining for aromatase, kindly performed on this biopsy specimen by Prof. Regauer, showed no aromatase expression. This leaves us with two possibilities: either the tumor is negative for aromatase expression, or only focally positive. Although we were unable to prove aromatase expression by immunohistochemical staining in our case, and thus could not explain the reduction in size of the tumor, we believe that aromatase expression indeed plays a role in explaining the effect of the aromatase inhibitor. A literature research with Pubmed NCBI only revealed the article by Dr. Reich et al. [2] using the keyword dstromal sarcomasT (in the plural!). Any other keyword search (daromatase and stromal sarcomaT, daromatase expression and stromal sarcomaT, daromatase inhibition and stromal sarcomaT) failed to retrieve the abovementioned paper. We are most grateful to Dr. Reich and Prof. Regauer for their extremely valuable help in unraveling our specific case.
References [1] Leunen M, Breugelmans M, De Sutter Ph, Bourgain C, Amy JJ. Lowgrade endometrial stromal sarcoma treated by letrozole (FemaraR): case report. Gynecol Oncol 2004;95(3):769 – 71. [2] Reich O, Regauer S. Aromatase expression in low-grade endometrial sarcomas: a immunohistochemical study. Mod Path 2004;17: 104 – 8
M. LeunenT M. Breugelmans Ph. De Sutter J.J. Amy Department of Gynecology, Andrology and Obstetrics, Academisch Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium E-mail address: [email protected]. TCorresponding author. Fax: +32 2 477 65 46.
173
G. Lialios Department of Obstetrics and Gynecology, University Hospital of Thessalia, Proussis 20, 43331 Larissa, Greece E-mail address: [email protected]. Corresponding author. G. Plataniotis Department of Radiation Oncology, University of Thessalia, Greece
Photo 4. The vaginal lesion 2 months after radiotherapy.
On the other hand, renal cell carcinomas (RCC) can present with hematuria, flank pain, palpable mass, or with a wide variety of paraneoplastic manifestations such as hypercalcemia, hypertension, hyperglycemia, erythrocytosis, etc. [3]. Symptoms from metastatic disease from RCC may be the presenting complaint in up to 30% of patients [4]. Nevertheless, metastatic RCC presenting with vaginal bleeding is rare. An interesting case of metastatic renal cell carcinoma presenting as a vaginal metastasis with thrombocytopenia as a paraneoplastic manifestation has been reported by Allard et al. [2]. Most reported cases of vaginal secondaries from RCC involve metastases from left-sided tumours. Metastatic deposits to the vagina from renal tumours arise through retrograde spread from the renal vein along the ovarian vein [4,5]. Although less than 80 cases of vaginal metastasis from renal cell carcinoma have been reported [2,6], a vaginal clear cell adenocarcinoma should always prompt a clinical and radiological search for an occult RCC, while gynecological examination in female patients should always be included in the staging procedure in case of a RCC [6].
References [1] Ovesen H, Gerstenberg T. Vaginal metastasis as the first sign of renal cell carcinoma: a case report and review of the literature. Scand J Urol Nephrol 1990;24:237 – 8. [2] Allard JE, McBroom JW, Zahn CM, McLeod D, Maxwell GL. Vaginal metastasis and thrombocytopenia from renal cell carcinoma. Gynecol Oncol 2004;92(3):970 – 3. [3] Papac RJ, Poo-Hwu W-J. Renal cell carcinoma: a paradigm of lanthanic disease. Am J Clin Oncol 1999;22:223 – 31. [4] Abraham R, Thomas DR, Foster MC. Vaginal bleeding as a presentation of metastatic renal cell carcinoma. BJU Int 1999;84(3):384. [5] Griffin SJ, Grainger R, Loftus BG, McDermott TED. Renal cell carcinoma presenting with vaginal metastasis. Ir Med Jour 2003;96(4): 115 – 6. [6] Tarraza HM, Meltzer SE, DeCain M, Jones MA. Vaginal metastases from renal cell carcinoma: report of four cases and review of the literature. Eur J Gynaecol Oncol 1998;19:14 – 8.
A. Kallitsaris Department of Obstetrics and Gynecology, University Hospital of Thessalia, Proussis 20, 43331 Larissa, Greece M.A. Theofanopoulou Department of Radiation Oncology, University of Thessalia, Greece G. Skoufi Department of Radiation Oncology, University of Thessalia, Greece I.E. Messinis Department of Obstetrics and Gynaecology, University Hospital of Thessalia, Proussis 20, 43331 Larissa, Greece 8 March 2005
doi:10.1016/j.ygyno.2005.03.024
Hormonal treatment with aromatase inhibitors for patients with endometrial stromal sarcoma To the Editor, We read with interest the paper by M. Leunen et al. [1] reporting a first-line hormonal treatment in a 76-yearold patient with endometrial stromal sarcoma (ESS) with the aromatase inhibitor letrozole. ESS are hormonesensitive tumors and estrogens can act as a growth stimulus [2]. Most women with ESS undergo bilateral salpingo-oophorectomy as part of primary treatment but estrogen also can be produced by extraovarian sources. This extra-ovarian estrogen production depends on conversion of circulating androgens to estrogens via the aromatase enzyme complex. The aromatase enzyme complex consists of the CYP19 gene product aromatase cytochrome P450 and a flavoprotein NADPH-cytochrome P450 reductase and is located in the endoplasmic reticulum of estrogen-producing cells. The treatment results of letrozole in the reported patient is explained
174
Letters to the Editor
via blockage of peripheral aromatization. However, in ESS, aromatase inhibitors reduce estrogen levels by inhibiting estrogen synthesis not only in peripheral sites, but also in the tumor cells themselves [3,4]. Using cytosol-based biochemical examinations, Tseng et al. [3] were the first to demonstrate aromatase in 8 uterine sarcomas at levels within the range of activity found in normal proliferative endometrium or above normal levels. We described aromatase expression in 23 ESS in an immunohistochemical study [4]. Aromatase-positive tumor cells were demonstrated in 83% of ESS with a monoclonal antibody and in 87% of tumors with a polyclonal antibody. Aromatase inhibitor have become a valuable treatment choice for patients with ESS. Spano et al. [5] reported 2 patients with metastatic ESS, who had a complete response after treatment with an aromatase inhibitor. Among 64 patients with ESS, who we are following, 12 women (19%) are presently receiving aromatase inhibitors as part of their postoperative hormonal treatment. For 7 patients, aromatase inhibitors are administered to prevent recurrences. Five of these patients are receiving aromatase inhibitors for treatment of metastatic disease. References [1] Leunen M, Breugelmans M, De Sutter Ph, Bourgain C, Amy JJ. Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole: case report. Gynecol Oncol 2004;95(3):769–71. [2] Reich O, Regauer S, Urdl W, Lahousen M, Winter R. Expression of estrogen and progesterone receptors in low-grade endometrial stromal sarcomas. Br J Cancer 2000;82:1030 – 4. [3] Tseng L, Tseng JK, Mann WJ, Chumas JC, Stone ML, Mazella J, et al. Endocrine aspects of human uterine sarcoma: a preliminary study. Am J Obstet Gynecol 1986;155:95 – 101. [4] Reich O, Regauer S. Aromatase expression in low-grade endometrial stromal sarcomas: a immunohistochemical study. Mod Pathol 2004; 17:104 – 8. [5] Spano JP, Soria JC, Kambouchner M, Piperno-Neuman S, Morin F, Morere JF, et al. Long term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol 2003; 20:87 – 93.
Olaf Reich Department of Obstetrics and Gynecology Medical University of Graz Auenbruggerplatz 14, A-8036 Graz, Austria E-mail address: [email protected]. Corresponding author. Fax: +43 316 3852072. Sigrid Regauer Institute of Pathology, Medical University of Graz, Austria 8 November 2004
doi:10.1016/j.ygyno.2004.12.003
Reply to letter to the editor by Reich and Regauer: Hormonal treatment with aromatase inhibitors for patients with endometrial stromal sarcoma We would like to thank Dr. Reich and Prof. Regauer for their interest in our paper [1]. They pointed out that the effect of aromatase inhibitors (e.g., letrozole) may not only be explained by the inhibition of estrogen synthesis in the peripheral sites but also by such inhibition in the tumor cells themselves [2]. Aromatase is the key enzyme in estrogen synthesis, and estrogen seems to be the promoting factor in low-grade endometrial stromal sarcomas. As Dr. Reich and Prof. Regauer demonstrated an aromatase expression in tumor cells of endometrial stromal sarcomas, it can be hypothesized that aromatase inhibitors will act directly on tumor cells as well. In our case, the diagnosis was made on a small transvaginal trough-cut biopsy. An immunohistochemical staining for aromatase, kindly performed on this biopsy specimen by Prof. Regauer, showed no aromatase expression. This leaves us with two possibilities: either the tumor is negative for aromatase expression, or only focally positive. Although we were unable to prove aromatase expression by immunohistochemical staining in our case, and thus could not explain the reduction in size of the tumor, we believe that aromatase expression indeed plays a role in explaining the effect of the aromatase inhibitor. A literature research with Pubmed NCBI only revealed the article by Dr. Reich et al. [2] using the keyword dstromal sarcomasT (in the plural!). Any other keyword search (daromatase and stromal sarcomaT, daromatase expression and stromal sarcomaT, daromatase inhibition and stromal sarcomaT) failed to retrieve the abovementioned paper. We are most grateful to Dr. Reich and Prof. Regauer for their extremely valuable help in unraveling our specific case.
References [1] Leunen M, Breugelmans M, De Sutter Ph, Bourgain C, Amy JJ. Lowgrade endometrial stromal sarcoma treated by letrozole (FemaraR): case report. Gynecol Oncol 2004;95(3):769 – 71. [2] Reich O, Regauer S. Aromatase expression in low-grade endometrial sarcomas: a immunohistochemical study. Mod Path 2004;17: 104 – 8
M. LeunenT M. Breugelmans Ph. De Sutter J.J. Amy Department of Gynecology, Andrology and Obstetrics, Academisch Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium E-mail address: [email protected]. TCorresponding author. Fax: +32 2 477 65 46.