Elsevier

Gynecologic Oncology

Volume 101, Issue 3, June 2006, Pages 464-469
Gynecologic Oncology

Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: Single center experience with 10 cases and review of the literature

https://doi.org/10.1016/j.ygyno.2005.11.010Get rights and content

Abstract

Endometrial stromal sarcoma (ESS) is a rare disease with probably less than 700 new cases in the US or EU per year. ESS usually expresses steroidal receptors and is regarded to be hormone-sensitive. A higher risk in women receiving estrogen replacement therapy (ERT) or tamoxifen has been suspected, and remissions following treatment with progestins have been reported in case studies. Aromatase inhibitors represent an interesting new treatment option. Due to the rarity of the tumor, only few case series and no prospective studies are published. We therefore conducted a retrospective study to evaluate the influence of hormonal treatment to ESS.

Methods.

Our institutional sarcoma data bank was screened for cases of ESS since 1999. All corresponding files and radiographs were reviewed retrospectively.

Results.

Ten patients with low-grade ESS were identified. Diagnosis was established before or by hysterectomy in 6 patients, by local recurrence after previous hysterectomy for nonmalignant disease in 3 patients or by pulmonary metastases with no primary tumor found so far in 1 patient. 5/10 patients were on ERT and 3/10 on tamoxifen at the time of diagnosis of metastatic disease. Treatment strategies consisted of stopping ERT and tamoxifen, respectively, or initiation of the progestin MPA or letrozole. Three patients achieved stable disease after stopping ERT. 2/3 patients responded to MPA as first-line treatment (1 CR; 50+ months, 1 PR; 9 months). 4/5 patients responded to letrozole as first-line therapy (3 PR;3+, 9+ and 10+ months) or second-line treatment after MPA (1 PR; 37+ months). 9/10 patients are alive 33 to 255 months after hysterectomy. Survival since diagnosis of metastatic disease is 4 to 164 months.

Conclusions.

Patients with a previous history of low-grade ESS should not be treated with estrogens or tamoxifen. If nevertheless present, withdrawal of ERT or tamoxifen is strongly advised, resulting in disease stabilization in some cases. MPA and letrozole, in particular, are highly effective and lead to sustained disease control in most cases.

Introduction

Endometrial stromal sarcomas (ESS) are very rare malignant tumors that make up approximately 10% of all uterine sarcomas but only around 0.2% of all uterine malignancies. The annual incidence of ESS is 1–2 per million women [1], [2], accounting for 400 to 700 new cases each year in Europe.

Frequently, ESS are detected by chance at hysterectomy for uterine myomas. Sometimes, the disease is not diagnosed until metastases are detected in patients with a history of hysterectomy but no evidence of malignancy. In such cases, an occult uterine primary tumor must be presumed.

The prognostic factors after initial diagnosis and resection of ESS have been examined in a series of retrospective analyses. It emerged that mitotic count is the only independent negative prognostic variable [3], [4], [5], [6], [7]. It also can be used to distinguish between the two subentities of low-grade ESS [LGESS] (<10 mitoses per 10 high-power fields (HPF) and high-grade ESS [HGESS] (>10 mitoses per 10 HPF) [4]. Not only is the prognosis of HGESS considerably worse than that of LGESS, but the two tumors also differ in several biological and histological features. Accordingly, several authors have concluded that two separate disease entities exist and, respectively, that HGESS should be regarded as an undifferentiated sarcoma or as a unique type of high-grade uterine sarcoma (e.g. carcinosarcoma without any detectable carcinoma portion) [8], [9], [10], [11]. Given these criteria, only LGESS would be classified as an ESS in the narrower sense. LGESS are characterized by a very low mitotic count and a very high degree of differentiation that is also present in the recurrence and show a strong expression for estrogen receptors (ER+) and/or progesterone receptors (PgR+). The prognosis for LGESS is very good and much better than for other uterine sarcomas, including HGESS.

Hysterectomy is the treatment of choice for non-metastatic ESS. Although the merits of concurrent bilateral salpingo-oophorectomy remain to be verified, most authors nevertheless recommend the procedure [3], [5], [12], [13], [14]. To date, no prospective studies have investigated the merits of adjuvant radiation and/or chemotherapy or hormonal treatment following resection of ESS. However, numerous retrospective analyses addressing this issue have been published. As the data on adjuvant chemotherapy are largely inconclusive, adjuvant chemotherapy following resection of ESS is not indicated outside of clinical trials [3], [13], [15]. Data pertaining to the benefits of adjuvant radiation therapy are controversial. A review of all publications has not revealed any clear effect on overall survival but a potential effect on local recurrence-free survival [3], [7], [13], [16], [17], [18], [19], [20], [21]. Specifically, in HGESS, post-resection adjuvant irradiation might indeed improve survival [22], [20].

When recurrence develops secondary to resection of ESS, it usually includes multiple lung metastases, peritoneal metastases, and/or local recurrences [3], [5], [13]. Particularly in patients with LGESS, recurrences are occasionally seen even after very long disease-free periods [5], [23] or metastases lead to the diagnosis without evidence of a primary tumor many years after hysterectomy at which no malignancy was detected [8], [24], [25], [26]. In the overwhelming majority of cases, both the primary tumor and the recurrent manifestations were strongly estrogen-receptor- (ER+) and/or progesterone-receptor-positive (PgR+) [8], [14], [24], [26], [27], [28].

Section snippets

Material and methods

Our institutional sarcoma database containing approximately 800 patients was screened for all cases of metastatic ESS diagnosed since 1999. All corresponding files and radiographs were reviewed retrospectively. Clinical courses were specifically evaluated for:

  • Concomitant diseases, including other malignancies

  • Hormone replacement therapy and tamoxifen treatment associated with disease progression and/or treatment response

  • Other hormone treatments such as administration of progestins or aromatase

Patient characteristics

A total of 11 patients with metastatic endometrial stromal sarcoma treated in our institution from 1999 to 2005 were identified. Ten patients had low-grade ESS according to the classification of Norris et al. [4]. One patient had high-grade ESS and was therefore excluded from further analysis (Table 1).

A hysterectomy had been performed in 9/10 patients at a median age of 47 years (range 39–67). In only six patients diagnosis of ESS was established. In three patients, first diagnosis of ESS was

Discussion

It is well documented that the incidence of endometrial carcinomas and uterine sarcomas, including carcinosarcomas (i.e. malignant mixed Mullerian tumors), is higher in patients on hormone replacement regimens containing estrogens (ERT) and in patients receiving tamoxifen treatment [30], [31], [32], [33], [34], [35], [36], [37], [38]. Evidence has emerged that this risk can be lowered when progestins are added continuously to estrogen, but not when progestins are only added cyclically [37]. Due

Conclusions

Based on previously published data and supported by our series, it can be concluded that patients with a previous history of ESS must not be treated with estrogens or tamoxifen. If nevertheless present, withdrawal of ERT or tamoxifen is strongly advised, resulting in disease stabilization in some cases. MPA and letrozole, in particular, are highly effective and lead to sustained disease control in most cases. Anthracycline-based chemotherapy is an option for patients failing hormonal treatment,

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