Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole

doi:10.1016/j.ygyno.2004.07.063

Gynecologic Oncology

Volume 95, Issue 3, December 2004, Pages 769-771

https://doi.org/10.1016/j.ygyno.2004.07.063 Get rights and content

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 α-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.

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 salpingo-oophorectomy 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.

Section snippets

Case report

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-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

Discussion

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

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Endometrial stromal sarcoma (ESS) is a rare malignancy of uterine in middle aged women. There are numerous subtypes for ESS which share the same clinical picture of uterine bleeding and pelvic pain. Consequently, diagnosis and treatment modalities of LG-ESS with metastasis are challenging. However, both molecular and immunological study of samples can be useful.
In this case study, we report a 52-year-old woman presenting with the chief complaint of unusual uterine bleeding. There was no specific finding in her past medical history. The CT study revealed enlarged bilateral ovary with a significantly large left ovarian mass and suspicious mass in uterus. By the diagnosis of ovarian mass, patient went under total abdominal hysterectomy with bilateral salpingo-oophorectomy (BSO), greater omentectomy, and appendectomy followed by post-op hormone therapy. Her follow-up was uneventful. The IHC and pathological study of samples revealed incidental LG-ESS uterus mass with metastasis to ovaries despite her primary diagnosis.
LG-ESS has low metastasis rate. Surgical modalities and neoadjuvant therapies are recommended base on the stage of ESS. In the following study, we represent a case of incidental LG-ESS with bilateral ovarian invasion who was initially diagnosed as an ovarian mass.
Our patient was successfully managed by surgical intervention. Despite scarcity of LG-ESS, it is advised to consider LG-ESS as a differential diagnosis in management of patients with a uterus mass with bilateral ovarian involvement.
Extra-uterine endometrial stromal sarcoma of the left adnexa and distal ureter: A case report
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There appears to be very limited benefit to adjuvant chemotherapy or radiation in treatment of EESS. The majority of the literature focuses on hormonal adjuvant therapies given the known PR and ER positivity of these tumors (Sylvestre and Dunton, 2010; Dahhan et al., 2009; Buchholz et al., 2017; Leunen et al., 2004; Yamaguchi et al., 2015). The benefit of hormonal therapy in ESS and EESS appears to be limited to advanced or metastatic disease (Dahhan et al., 2009; Leunen et al., 2004; Yamaguchi et al., 2015).
Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903)
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Historically, patients were treated with progestins and case reports and small retrospective case series reported response rates of around 50% [16–19]. Aromatase inhibitors (AIs) were first reported to be active as second line treatment in a patient following progression on medroxyprogesterone in 2001 [20], and following this there was an increasing number of additional case reports of first-line treatment with an AI [21–26]. The activity of AIs in LGESS is thought to be due to the high expression of aromatase in this tumor type, which can be inhibited by AIs as these agents block peripheral aromatization and the conversion of androstenedione to estrone [16,27].
Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers.
An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity.
15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48–89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2–29.8%), partial response in three (20%, 95% CI 7.1–45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2–NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5–63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects.
The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.
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We present a case of low-grade endometrial stromal sarcoma (ESS) that metastasized to the breast 25 years after the original diagnosis, with clinical, radiographic and pathologic follow-up data. The diagnosis of metastatic ESS was supported by the morphologic features of the breast tumor and its immunohistochemical profile, which included positive staining for CD10, WT1, estrogen receptor (ER) and progesterone receptor (PR). The diagnosis of metastatic ESS was confirmed by fluorescence in situ hybridization (FISH) testing, which revealed a characteristic JAZF1 gene rearrangement. The unusual clinical presentation raised a differential diagnosis that included mammary myofibroblastoma of the breast. We compared the morphologic characteristics and immunohistochemical profile of 15 low-grade ESS cases (8 primary and 7 metastatic) to eight cases of mammary myofibroblastoma. Immunostains that differentiated between these entities included CD34, retinoblastoma protein (Rb) and FOXL2. The pathologist can play a key role in the recognition of uncommon metastases to breast, and although rare, metastatic low-grade ESS should be included in the differential diagnosis of spindle cell tumors of the breast.
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The spectrum of uterine lesions of mesenchymal and mixed mesenchymal-epithelial type has expanded in recent years, largely due to the cumulative experience reported in larger case series, as well as the identification of recurrent gene fusions and other molecular alterations. In routine practice, the approach to most mesenchymal neoplasms encountered of the uterus starts with a judicious morphologic approach, which in many cases suffices for the diagnosis. Smooth muscle tumors predominate, most of them being benign. Distinction of conventional and variant leiomyoma types from leiomyosarcoma is important but on occasion challenging, and some lesions remain in the category of unknown malignant potential. Endometrial stromal neoplasms follow in frequency; their distinction from other mesenchymal lesions may be difficult, and molecular testing is gaining momentum as a key ancillary tool in their diagnosis. These two major categories are covered in depth here, along with other mesenchymal lesions with significant occurrence in the uterus. An emphasis is given on the differential diagnosis of each entity. The chapter also covers neoplasms with mixed mesenchymal and epithelial components (except endometrial polyp, which is presented in Chapter 9); of these, the most important clinically is adenosarcoma. The chapter concludes with miscellaneous lesions of histopathologic diagnostic importance.
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Case ReportLow-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole

Abstract

Background

Case

Conclusion

Introduction

Section snippets

Case report

Discussion

Gynecol. Oncol.

Gynecol. Oncol.

Endometrial stromal sarcoma

Surg. Gynecol. Obstet.

Steroid hormones receptors in endometrial stromal sarcomas: a biochemical and immunohistochemical study

Am. J. Clin. Pathol.

Case Report
Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole