Therapeutic effect of dienogest on adenosarcoma arising from endometriosis: a case report
© Tasaka et al.; licensee Springer. 2013
Received: 29 August 2013
Accepted: 6 November 2013
Published: 20 November 2013
Dienogest is a novel synthesized progestin used for treatment of endometriosis. This is the first case report describing a therapeutic effect of dienogest on a gynecologic malignancy. The patient was a 44-year-old woman with advanced adenosarcoma arising from the endometriosis in the rectovaginal space and infiltrating the left pelvic wall, left ureter, rectum and vagina. The residual tumor after tumor debulking surgery was resistant to both chemotherapy and radiotherapy. Dienogest was used as a substitute for medroxyprogesterone acetate because of the presence of deep vein thrombosis. Based on the RECIST criteria, partial response was obtained with oral dienogest therapy at six months and the serum CA125 level also decreased from 70 U/ml to 16 U/ml. The tumor remained stable up to 21 months. Thromboembolism or other adverse effects did not occur during the dienogest therapy. Dienogest may be useful for the treatment of adenosarcoma arising from endometriosis.
Müllerian adenosarcoma is a rare tumor characterized by a benign epithelial component and a sarcomatous stromal component (Clement et al. 1974; Clement et al. 1990). These tumors most commonly appear as lesions in the uterus, derived from the endometrium. To date, however, several cases of extrauterine adenosarcoma arising from a background of endometriosis have been reported (Hines et al. 2002; Liu et al. 2003; Raffaelli et al. 2004; Huang et al. 2009). Müllerian adenosarcoma is relatively insensitive to chemotherapy and radiation; thus, an optimal therapy for advanced or recurrent tumors remains to be defined. Histological finding of sarcomatous overgrowth is associated with a highly aggressive clinical behavior of the tumor.
Medroxyprogesterone acetate (MPA), a synthesized progestin, has a therapeutic effect on gynecological malignancies such as adenosarcoma (Hines et al. 2002; Lee et al. 2010), low-grade endometrial stromal sarcoma (Amant et al. 2009), and grade 1 endometrial carcinoma (Ushijima et al. 2007). However, MPA is not used for women that are at risk of thromboembolism because it is the most significant side-effect of MPA therapy (Kuhl et al. 2006).
We experienced a case of advanced adenosarcoma that was insensitive to either chemotherapy or radiotherapy. Since she had asymptomatic deep vein thrombosis, dienogest was used as a substitute for MPA for progesterone therapy.
Endometriosis has been reported to give rise to malignant transformation more frequently in ovarian (5.6%) than at extraovarian sites of endometriosis (1.6%) (Stern et al. 2001). In malignant tumors associated with extraovarian endometriosis, adenosarcoma is the second most common tumor after clear cell adenocarcinoma (Stern et al. 2001). In this case, adenocarcinoma appeared to arise from endometriosis in the rectovaginal space. The microscopic foci in the endometrium were found to be contiguous with the malignant stromal tissue and no other possible primary tumor site was found.
Progestins are usually used in the treatment of endometriosis, as well as for contraception and hormone replacement therapy. These compounds interact with progesterone receptors (PRs) to activate or repress gene expression in target cells. Synthetic progestines are structurally classified into two major chemical classes (Benagiano et al. 2004). Medroxyprogesterone acetate (MPA) is a 17β-hydroxyprogesterone derivative (C-21 progestogen) that is structurally related to progesterone, while norethisterone (NET) and levonorgestrel (LNG) are derivatives of 19-northesteron (C-19 nortestosterone) that are structurally related to testosterone. Of these compounds, it has been reported that MPA has a therapeutic effect on gynecological malignancies such as atypical endometrial hyperplasia (Ushijima et al. 2007), grade 1 endometrial carcinoma (Ushijima et al. 2007), low-grade endometrial stromal sarcoma (Amant et al. 2009), and adenosarcoma (Hines et al. 2002; Lee et al. 2010). However, thromboembolism is one of the most serious side-effects of MPA (Kuhl et al. 2006). Vein thromboembolism is found in 9.9% of women with endometrial cancer (Satoh et al. 2008) and 4.9% of those women with uterine sarcoma (Rodriguez et al. 2011). Thus, the use of MPA in the treatment of these malignancies may be limited.
Dienogest (DNG: 17α-cyanomethyl-17β-hydroxyestra-4,9-dien-3 one) is a novel ‘hybrid progestogen’ that has pharmacodynamic properties typical of the two main classes of progestogens (Ruan et al. 2012). DNG has antiovulatory activity that reduces serum estrogen level in vivo (Harada et al. 2009), and direct antiprolirative and anti-inflammatory effects on endometrial stromal cells in vitro (Okada et al. 2001). Therefore, DNG has a therapeutic effect on endometriosis (Harada et al. 2009). Although DNG has recently been launched for the treatment of endometriosis, DNG also has antiproliferative effects on estrogen receptosr (ERs)- and/or PR-positive endometrial and breast cancer cells in vitro, suggesting potential usefulness in the treatment of ER/PR-positive malignant tumors (Katsuki et al. 1997; Banno et al. 2012). DNG has considerable antiandrogenic activity; however, it has little effect on the metabolic and cardiovascular systems (Ruan et al. 2012). More importantly, DNG lacks glucocorticoid activity that can be associated with an increased risk of venous or arterial thromboembolism (Ruan et al. 2012; Herkert et al. 2001). To date, DNG-related thromboembolism has not been reported, even in long-term use (Momoeda et al. 2009) or high dose therapy (Schindler et al. 2010). Given its lack of hemostatic action, DNG appears to be more suitable for the treatment of endometrial cancer and uterine sarcoma than MPA because women with these tumors are at an increased risk of venous thrombosis (Satoh et al. 2008; Rodriguez et al. 2011).
In the presented case, the adenosarcoma underwent very rapid growth. In addition, this aggressive tumor was insensitive to either chemotherapy or radiotherapy. Several case reports have suggested that MPA may be effective in the treatment of adenosarcoma; however, MPA was contraindicated in the present case because she had deep vein thrombosis. Therefore, DNG was used as a substitute for MPA for progesterone therapy. A successful partial response was obtained at six months after initiating oral DNG treatment and the tumor was stable up to 21 months.
The rapid regrowth of the tumor following a long-term stable status may have been due to the reduction of ER and PR expression via histological evolution to sarcomatous overgrowth. In previous reports of adenosarcoma, successful treatment with MPA was demonstrated only for ER- and PR-positive tumors (Hines et al. 2002; Lee et al. 2010). Therefore, substantial levels of ER and PR expression may be necessary to induce the therapeutic effect of DNG, as well as MPA.
In conclusion, we experienced a case of advanced adenosarcoma that was treated with DNG. To the best of our knowledge, this is the first case report describing a therapeutic effect of DNG on a gynecologic malignancy. In this case, no adverse effects, including thromboembolism, were observed. DNG may be useful in the treatment of gynecologic malignancies, such as adenosarcoma, low-grade endometrial stromal sarcoma and grade 1 endometrial carcinoma, even for women who are at risk of thromboembolism.
Oral informed consent was obtained from the patient for the publication of this report and any accompanying images before her death. Written informed consent was obtained from the family of the patient for the publication of this report and any accompanying images.
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