![Open Access](/resources/images/iconopenaccess.png)
Letrozole as second-line hormonal treatment for recurrent low-grade endometrial stromal sarcoma: A case report and review of the literature
- Authors:
- Published online on: September 26, 2016 https://doi.org/10.3892/ol.2016.5186
- Pages: 3856-3860
-
Copyright: © Nakamura et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Endometrial stromal sarcoma (ESS) is an uncommon malignancy, accounting for <1% of all uterine carcinomas and 7–15% of all uterine sarcomas (1). ESS is classified as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS) and undifferentiated uterine sarcoma (2). LGESS shows minimal to no cytological atypia and low mitotic activity (usually <5 mitoses per 10 high-power fields (HPFs). HGESS shows high mitotic activity (typically >10 per 10 HPFs) and is typically very striking. LGESS is generally a slow-growing malignancy with an indolent clinical course, but with a tendency for late recurrence, while HGESS is more aggressive, frequently metastasizes and has an extremely poor outcome.
Although no universal staging system exists for ESS, the International Federation of Gynecology and Obstetrics surgical staging system for endometrial cancer is typically used (2). Total abdominal hysterectomy and bilateral salpingo-oophorectomy is recommended as the primary treatment, with debulking recommended when extrauterine disease is apparent. The role of chemotherapy, radiation or hormonal treatment as adjuvant therapy has not yet been established. A number of studies have demonstrated estrogen and progesterone receptor expression in LGESS (3,4). Furthermore, LGESS has previously been shown to be responsive to hormonal therapy, including aromatase inhibitors and megestrol acetate (3,5,6). Studies have shown that synthesized progestins, including medroxyprogesterone acetate (MPA), are an effective conservative treatment for endometrial cancer (7,8).
In our previous study, we reported the cases of 2 patients with metastatic LGESS lesions who experienced prolonged survival following treatment with MPA (9). However, to the best of our knowledge, only 5 case reports detailing recurrent LGESS treated with aromatase inhibitors are reported in the literature. The present study reports a case of recurrent LGESS that was treated with surgery, followed by MPA for 2 years as first-line therapy and the aromatase inhibitor letrozole for 6 years as second-line hormonal therapy. The patient has survived for 13 years since the initial surgery.
Case report
A 58-year-old (gravida 2, para 2) woman was referred to Shimane University School of Medicine (Izumo, Japan) in May 2002 due to persistent abnormal vaginal bleeding. The patient reported a history of rheumatoid arthritis, but no other significant past medical or surgical history. Endometrial curettage revealed LGESS, based on the characteristics of the cells observed, which resembled the stromal cells of proliferative endometrium. In consequence, a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed in May 2002. The resected specimens were sectioned (section thickness, 3 µm), and stained with hematoxylin and eosin. Subsequently, the specimens were immunohistochemically stained with the following antibodies: Anti-cluster of differentiation (CD) 10 (1:1; pre-diluted rabbit monoclonal; clone SP67; Roche Diagnostics, Basel, Switzerland); anti-estrogen receptor (1:1; pre-diluted rabbit monoclonal; clone SP1; Roche Diagnostics); anti-progesteron receptor (1:1; pre-diluted rabbit monoclonal; clone 1E2; Roche Diagnostics); anti-h-caldesmon (1:50; mouse monoclonal; clone h-CD; Dako, Glostrup, Denmark); anti-cytokeratin AE1/AE3/PCK26 (1:1; pre-diluted; clone AE1/AE3/PCK26; Roche Diagnostics); anti-cytokeratin Cam5.2 (1:2; mouse monoclonal; clone Cam5.2; Roche Diagnostics); anti-desmin (1:100; mouse monocolonal; clone D33; Dako); anti-α-smooth muscle actin (1:100; mouse monoclonal; clone 1A4; Dako); anti-Melan A (1:1; pre-diluted mouse monoclonal; clone A103; Dako); and anti-human melanoma black-45 (1:50; mouse monoclonal; clone HMB-45; Dako). The histopathological result was of stage IC, low-grade ESS of the corpus uteri (Fig. 1). In addition, immunostaining revealed that the tumor tissue was positive for estrogen receptor (Fig. 2), progesterone receptor (Fig. 3) and CD10, and negative for h-caldesmon, AE1/AE3, Cam5.2, desmin, α-smooth muscle actin, Melan A and human melanoma black 45.
Post-operatively, the patient was started on 600 mg daily MPA as adjuvant therapy. The patient experienced no recurrence for 19 months, but was forced to discontinue MPA at that time, as it worsened the rheumatoid arthritis symptoms. Another 2 months later, computed tomography (CT) revealed enlargement of the common iliac lymph nodes. The patient underwent chemotherapy with 6 cycles of doxorubicin (25 mg/m2 on days 1–2) and ifosfamide (1 mg/m2 on days 1–5) every 3 weeks, along with lymph-node radiation. Three months after completing chemotherapy, MPA was restarted as the rheumatoid arthritis symptoms had improved. The lymph nodes gradually decreased in size and this partial response was maintained for 3 years.
In January 2008, CT revealed a mass in the left lung measuring 19×13 mm (Fig. 4) and a para-aortic lymph node enlarged to 20×12 mm, compressing the right common iliac vein. MPA treatment was discontinued at this point and the patient underwent a secondary complete resection of the lung tumor. Similarly to the endometrial curettage result, the histopathological result confirmed disease metastasis. Post-operatively, informed consent was obtained for treatment with 2.5 mg daily letrozole. The patient has continued letrozole treatment to this date, and has remained asymptomatic and progression-free for 7 years.
Discussion
ESS is classified as low grade, high grade and undifferentiated based on morphology and mitotic rate. Although LGESS exhibits a relatively indolent behavior, the possibility of late recurrences and distant metastases exists (10). The risk of recurrence is believed to be as much as 50%, although such tumors usually grow slowly and the recurrence occurs late (10). In a previous large case series, the time between diagnosis or hysterectomy and recurrence was reported as between 3 months and 23 years, with a median time of 3 years (10). In the largest clinical study to date on LGESS, the median time between hysterectomy and relapse was recorded as 5.4 years for stage I disease and 9 months for disease at stages III–IV (11). In our previous series, the median disease-free time was 50 months (12).
Lymphadenectomy has not been determined to confer long-term survival in patients with LGESS (13,14). The patient in the present study was diagnosed with LGESS following surgery, which did not include either pelvic or para-aortic lymphadenectomy. Although there has been no systematic study on the advantages of adjuvant chemotherapy in LGESS, a number of retrospective analyses have shown that doxorubicin and ifosfamide combination chemotherapy exhibit a certain degree of efficacy (15–18). The present patient experienced a partial response to doxorubicin and ifosfamide-containing chemotherapy and MPA following the first recurrence.
There are few reports on the effectiveness of aromatase inhibitors in patients with recurrent LGESS due to the rarity of the disease. To the best of our knowledge, there are only 5 case reports describing aromatase inhibitors as either first- or second-line treatment for recurrent LGESS (5,19–22). Table I shows the demographic features of the patients in these cases, including the patient featured in the present study.
![]() | Table I.Previous cases of recurrent low-grade endometrial stromal sarcoma treated with aromatase inhibitors. |
Several studies have described estrogen and progesterone receptor expression in ESS tumors, and have evaluated the efficacy of progestins as a treatment modality (2,23–26). In all previous patients treated with aromatase inhibitors, immunostaining was positive for estrogen and progesterone receptors; this also applied to the present patient. All studies in the present literature review have suggested the effectiveness of aromatase inhibitors, including letrozole and anastrozole, in the treatment of recurrent LGESS (5,19–22). No definitive conclusions about treatment with aromatase inhibitors can be drawn, but this option should be taken into consideration for patients with recurrent LGESS and positive immunostaining for estrogen and progesterone receptors. We recommend that immunostaining be performed when the tumor is first determined to be ESS.
Aromatase inhibitors were used as second-line treatment in 3 previous studies and as first-line treatment in only 1 study by Leunen et al (5). Therefore, no conclusions can be drawn as to the priority of MPA or aromatase inhibitors as first-line treatment. Due to their efficacy, further studies are warranted to evaluate aromatase inhibitors as first-line hormonal therapy in these neoplasms.
In summary, the present case reported a recurrent LGESS that responded to treatment with the aromatase inhibitor letrozole, and our experience suggests that aromatase inhibitor treatment may be effective for patients with recurrent LGESS. A number of additional case studies will be necessary to confirm these findings and support the suggested treatment.
References
Echt G, Jepson J, Steel J, Langholz B, Luxton G, Hernandez W, Astrahan M and Petrovich Z: Treatment of uterine sarcomas. Cancer. 66:35–39. 1990. View Article : Google Scholar : PubMed/NCBI | |
Kurman RJ, Carcangiu ML, Herrington S and Young RH: World Health Organization Classification of Tumours of Female Reproductive Organs. 4th. IARC Press; Lyon, France: | |
Tsukamoto N, Kamura T, Matsukuma K, Imachi M, Uchino H, Saito T and Ono M: Endolymphatic stromal myosis: A case with positive estrogen and progesterone receptors and good response to progestins. Gynecol Oncol. 20:120–128. 1985. View Article : Google Scholar : PubMed/NCBI | |
Sabini G, Chumas JC and Mann WJ: Steroid hormone receptors in endometrial stromal sarcomas. A biochemical and immunohistochemical study. Am J Clin Pathol. 97:381–386. 1992. View Article : Google Scholar : PubMed/NCBI | |
Leunen M, Breugelmans M, De Sutter P, Bourgain C and Amy JJ: Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole. Gynecol Oncol. 95:769–771. 2004. View Article : Google Scholar : PubMed/NCBI | |
Pink D, Lindner T, Mrozek A, Kretzschmar A, Thuss-Patience PC, Dörken B and Reichardt P: Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: Single center experience with 10 cases and review of the literature. Gynecol Oncol. 101:464–469. 2006. View Article : Google Scholar : PubMed/NCBI | |
Kaku T, Yoshikawa H, Tsuda H, Sakamoto A, Fukunaga M, Kuwabara Y, Hataeg M, Kodama S, Kuzuya K, Sato S, et al: Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: Central pathologic review and treatment outcome. Cancer Lett. 167:39–48. 2001. View Article : Google Scholar : PubMed/NCBI | |
Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, Nakanishi T, Sasaki H, Saji F, Iwasaka T, et al: Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol. 25:2798–2803. 2007. View Article : Google Scholar : PubMed/NCBI | |
Ishibashi M, Nakayama K, Shamima Y, Katagiri A, Iida K, Nakayama N and Miyazaki K: Two cases of endometrial stromal sarcoma (ESS) in which survival was prolonged by administration of MPA. Gan To Kagaku Ryoho. 35:857–861. 2008.(In Japanese). PubMed/NCBI | |
Stadsvold JL, Molpus KL, Baker JJ, Michael K and Remmenga SW: Conservative management of a myxoid endometrial stromal sarcoma in a 16-year-old nulliparous woman. Gynecol Oncol. 99:243–245. 2005. View Article : Google Scholar : PubMed/NCBI | |
Amant F, Moerman P, Cadron I, Neven P, Berteloot P and Vergote I: The diagnostic problem of endometrial stromal sarcoma: Report on six cases. Gynecol Oncol. 90:37–43. 2003. View Article : Google Scholar : PubMed/NCBI | |
Nakayama K, Ishikawa M, Nagai Y, Yaegashi N, Aoki Y and Miyazaki K: Prolonged long-term survival of low-grade endometrial stromal sarcoma patients with lung metastasis following treatment with medroxyprogesterone acetate. Int J Clin Oncol. 15:179–183. 2010. View Article : Google Scholar : PubMed/NCBI | |
Shah JP, Bryant CS, Kumar S, Ali-Fehmi R, Malone JM Jr and Morris RT: Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma. Obstet Gynecol. 112:1102–1108. 2008. View Article : Google Scholar : PubMed/NCBI | |
Thomas MB, Keeney GL, Podratz KC and Dowdy SC: Endometrial stromal sarcoma: Treatment and patterns of recurrence. Int J Gynecol Cancer. 19:253–256. 2009. View Article : Google Scholar : PubMed/NCBI | |
Haberal A, Kayikçioğlu F, Boran N, Calişkan E, Ozgül N and Köse MF: Endometrial stromal sarcoma of the uterus: Analysis of 25 patients. Eur J Obstet Gynecol Reprod Biol. 109:209–213. 2003. View Article : Google Scholar : PubMed/NCBI | |
Omura GA, Blessing JA, Major F, Lifshitz S, Ehrlich CE, Mangan C, Beecham J, Park R and Silverberg S: A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: A gynecologic oncology group study. J Clin Oncol. 3:1240–1245. 1985.PubMed/NCBI | |
Pautier P, Genestie C, Fizazi K, Morice P, Mottet C, Haie-Meder C, Le Cesne A and Lhommé C: Cisplatin-based chemotherapy regimen (DECAV) for uterine sarcomas. Int J Gynecol Cancer. 12:749–754. 2002. View Article : Google Scholar : PubMed/NCBI | |
Kim WY, Lee JW, Choi CH, Kang H, Kim TJ, Kim BG, Lee JH and Bae DS: Low-grade endometrial stromal sarcoma: A single center's experience with 22 cases. Int J Gynecol Cancer. 18:1084–1089. 2008. View Article : Google Scholar : PubMed/NCBI | |
Spano JP, Soria JC, Kambouchner M, Piperno-Neuman S, Morin F, Morere JF, Martin A and Breau JL: Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol. 20:87–93. 2003. View Article : Google Scholar : PubMed/NCBI | |
Leiser AL, Hamid AM and Blanchard R: Recurrence of prolactin-producing endometrial stromal sarcoma with sex-cord stromal component treated with progestin and aromatase inhibitor. Gynecol Oncol. 94:567–571. 2004. View Article : Google Scholar : PubMed/NCBI | |
Maluf FC, Sabbatini P, Schwartz L, Xia J and Aghajanian C: Endometrial stromal sarcoma: Objective response to letrozole. Gynecol Oncol. 82:384–388. 2001. View Article : Google Scholar : PubMed/NCBI | |
Shoji K, Oda K, Nakagawa S, Kawana K, Yasugi T, Ikeda Y, Takazawa Y, Kozuma S and Taketani Y: Aromatase inhibitor anastrozole as a second-line hormonal treatment to a recurrent low-grade endometrial stromal sarcoma: A case report. Med Oncol. 28:771–774. 2011. View Article : Google Scholar : PubMed/NCBI | |
Chu MC, Mor G, Lim C, Zheng W, Parkash V and Schwartz PE: Low-grade endometrial stromal sarcoma: Hormonal aspects. Gynecol Oncol. 90:170–176. 2003. View Article : Google Scholar : PubMed/NCBI | |
Piver MS, Rutledge FN, Copeland L, Webster K, Blumenson L and Suh O: Uterine endolymphatic stromal myosis: A collaborative study. Obstet Gynecol. 64:173–178. 1984.PubMed/NCBI | |
Katz L, Merino MJ, Sakamoto H and Schwartz PE: Endometrial stromal sarcoma: A clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors. Gynecol Oncol. 26:87–97. 1987. View Article : Google Scholar : PubMed/NCBI | |
Scribner DR Jr and Walker JL: Low-grade endometrial stromal sarcoma preoperative treatment with Depo-Lupron and Megace. Gynecol Oncol. 71:458–460. 1998. View Article : Google Scholar : PubMed/NCBI |