sevier.com/locate/ygyno

Gynecologic Oncology 10

Harm or benefit of hormonal treatment in metastatic low-grade

endometrial stromal sarcoma: Single center experience with

10 cases and review of the literature

Daniel Pink a, Tanja Lindner a, Alicia Mrozek a, Albrecht Kretzschmar a,

Peter C. Thuss-Patience b, Bernd Dorken a,b, Peter Reichardt a,b,*

a Medizinische Klinik mit Schwerpunkt Hamatologie, Onkologie und Tumorimmunologie, HELIOS-Klinikum Berlin-Buch, Robert-Rossle-Klink,

Charite Campus Buch, Lindenberger Weg 80, D-13125 Berlin, Germanyb Medizinische Klinik mit Schwerpunkt Hamatologie und Onkologie, Charite Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany

Received 26 August 2005

Available online 20 December 2005

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.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Low-grade endometrial stromal sarcoma; Tamoxifen; MPA; Letrozole

Introduction

Endometrial stromal sarcomas (ESS) are very rare malignant

tumors that make up approximately 10% of all uterine

0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ygyno.2005.11.010

* Corresponding author. Medizinische Klinik mit Schwerpunkt Hamatologie,

Onkologie und Tumorimmunologie, HELIOS-Klinikum Berlin-Buch, Robert-

Rossle-Klink, Charite Campus Buch, Lindenberger Weg 80, D-13125 Berlin,

Germany. Fax: +49 30 9417 1053.

E-mail address: peter.reichardt@charite.de (P. Reichardt).

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 hysterec-

tomy 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

1 (2006) 464 – 469

www.el

D. Pink et al. / Gynecologic Oncology 101 (2006) 464–469 465

analyses. It emerged that mitotic count is the only independent

negative prognostic variable [3–7]. 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 undiffer-

entiated sarcoma or as a unique type of high-grade uterine

sarcoma (e.g. carcinosarcoma without any detectable carcino-

ma portion) [8–11]. 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 [3,5,12–14]. 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–

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 metasta-

ses, 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

[8,24–26]. 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+) [8,14,24,26–28].

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

inhibitors and their outcomes

& Chemotherapies and their outcomes

& Pathological subtype of the disease entity (LGESS vs. HGESS) and

presence of ER and/or PgR positivity in the tumor manifestations measured

by immunohistochemistry

Treatment results were classified as complete remission (CR), partial

remission (PR), stable disease (SD), or progressive disease (PD) according to

RECIST criteria [29].

A systematic search of ‘‘PubMed’’ was additionally undertaken using the

key words ‘‘uterus’’ or ‘‘uterine’’ and ‘‘stromal’’ or ‘‘stroma’’ and ‘‘sarcoma’’ or

‘‘tumor’’ as well as ‘‘hormone’’ and ‘‘tamoxifen’’. Furthermore, a review was

performed on all articles cited as sources in the aforementioned publications

that addressed the key questions pertinent to our analysis but which had not

been identified by our initial search.

Results

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 based on local recurrence or peritoneal

spread after previous hysterectomy for nonmalignant disease.

In 1 patient, pulmonary metastases were diagnosed, and the

primary tumor was later identified in the uterus. The median

age at first diagnosis of malignant disease was 52 years

(range 39–68).

7/10 patients suffered either from local recurrence or

peritoneal spread; 7/10 patients developed pulmonary metas-

tases. The median time from first diagnosis or hysterectomy

(presumed, but undiagnosed primary tumor) to metastasis was

67 months (range 0–252). At the time metastatic disease was

diagnosed, 3/10 patients were receiving tamoxifen, and 5/10

patients were on estrogen replacement therapy for 3 to 11

years. ERT consisted of continuous estrogen monotherapy in 2

patients and cyclic estrogen/progestin combination therapy in 3

cases.

Treatment strategies

Treatment strategies consisted of stopping ERT or tamox-

ifen, respectively, in patients where slowly progressing meta-

static disease had developed during such therapy or all

metastases were removed. If disease progression was more

pronounced or diagnosed when the patients were off ERT or

tamoxifen, a regimen with medroxyprogesterone acetate

(MPA) or letrozole was started. In one patient, a second-line

therapy with letrozole was given if progression was observed

on MPA. Chemotherapy was given after progression secondary

to hormone treatment.

Table 2

Clinical outcome by patients

Case 1st line Response

(duration in

months)

2nd line Response

(duration in

months)

3rd line Response

(duration in

months)

Status Alive since primary

diagnosis (months)

Alive since

diagnosis of

metastases or

recurrence

(months)

1. MPA

1000 mg/day

PD Letrozole

2.5 mg/day

PR (37+) AWD 42+ 42+

2. Letrozole

2.5 mg/day

PR (9+) AWD 184+ 12+

3. Letrozole

2.5 mg/day

PR (10+) AWD 71+ 30+

4. MPA

500 mg/day

CR (50+) NED 252+ 66+

5. MPA

1000 mg/day

PR (9) CTX

(ifosfamide

and caelyx)

PR (18) DOD 276 after hysterectomy,

37 after diagnosis

(peritoneal spread)

37

6. Stopping

ERT after

removal of

all lung mets

NED (60+) NED 102+ 60+

7. Stopping ERT SD (8+) AWD 96+ after hysterectomy,

8+ after diagnosis

(metastatic disease)

8+

8. Stopping T PD Letrozole

2.5 mg/day

PD CTX

(doxorubicin

and dacarbacin)

PR (5+) AWD 36+ 16+

9. Stopping ERT SD (6+) AWD 252+ after hysterectomy,

4+ after diagnosis

(peritoneal spread)

4+

10. Letrozole

2.5 mg/day

PR (3+) AWD 164+ after hysterectomy

and peritoneal spread

164+

ERT: estrogen replacement therapy; T: tamoxifen; CTX: systemic chemotherapy; NED: no evidence of disease; CR: complete response; PR: partial response; SD:

stable disease; PD: progressive disease; AWD: alive with disease; NED: no evidence of disease, DOD: died of disease; mets: metastases.

Table 1

Patient characteristics

Case Previous

hysterectomy?

Age at

hysterectomy

Diagnosis of

malignant disease

(ESS) at

hysterectomy?

Age at

diagnosis

Sites of lesions at diagnosis Interval from

diagnosis to

metastases or

recurrence

(months)

Histology Therapy with ERT

or tamoxifen prior

to recurrence

1. No – 63 Lung metastases, later

diagnosis of uterine primary

0 Low-grade; ER+++/PR+++ No

2. Yes, 55 Yes 55 Uterine primary tumor only 172 Low-grade; ER+++/PR+++ Yes (ERT)

3. Yes, 39 Yes 39 Uterine primary tumor only 41 Low-grade; ER+++/PR+++ No

4. Yes, 42 Yes 42 Uterine primary tumor only 186 Low-grade; ER++/PR+++ Yes (tamoxifen)

5. Yes, 47 No 58 Peritoneal spread 11 y after

hysterectomy

239 or 0 Low-grade; ER+++/PR+++ Yes (ERT)

6. Yes, 48 Yes 48 Uterine primary tumor only 42 Low-grade; ER+++/PR+++ Yes (ERT)

7. Yes, 42 No 49 Pelvic tumor, peritoneal and

lung mets 7 y after hysterectomy

92 or 0 Low-grade; ER+++/PR+++ Yes (ERT)

8. Yes, 67 Yes 67 Uterine primary tumor only 20 Low-grade; ER++/PR++ Yes (tamoxifen)

9. Yes, 47 No 68 Peritoneal spread 21 y after

hysterectomy

252 or 0 Low-grade; ER+++/PR not done Yes (ERT)

10. Yes, 47 Yes 47 Uterine primary tumor and

peritoneal metastases

0 Low-grade; ER+/PR+++ Yes (tamoxifen)

ER: estrogen receptor; PR: progesterone receptor; ERT: estrogen replacement therapy; H: hysterectomy; AWD: alive with disease; NED: no evidence of disease,

DOD: died of disease; mets: metastases.

D. Pink et al. / Gynecologic Oncology 101 (2006) 464–469466

D. Pink et al. / Gynecologic Oncology 101 (2006) 464–469 467

Treatment results

Clinical outcomes are listed in Table 2.

In three patients [cases 6, 7, 9], ERTwas stopped as an initial

measure in one of them after resection of all lung metastases

[case 6]. Five years on, the status of this patient has remained

unchanged with no evidence of disease (NED); the 2nd and the

3rd patient’s [case 7 and 9] disease has been stable for 8+ and 3+

months respectively.

Three patients presented with progressive disease while

receiving tamoxifen. Two patients were on adjuvant therapy

with tamoxifen [cases 4, 8], one of them [case 8] since

resection of her ESS. The initial measure in this patient was

to stop tamoxifen only, however, this strategy led to further

disease progression. The other patient [case 4] was being

treated with tamoxifen for concurrent breast cancer and had

initially undergone several metastasis resections. Histology of

the resections had revealed ESS in each instance, and

tamoxifen therapy was continued. After referral to our

hospital, tamoxifen was stopped, and treatment with MPA

started. The third patient [case 10] had a progression-free

survival of 10 years after complete resection of primary tumor

and peritoneal metastases. Tamoxifen was started after

resection of a peritoneal recurrence. Five months later, she

developed multiple rapidly growing peritoneal metastases.

Tamoxifen was stopped, and letrozole 2.5 mg/day was

initiated.

In total, three patients had received progestins (MPA 500–

1000 mg/day) as initial therapy [cases 1, 4, 5]. One of them

achieved a sustained complete response (CR) after MPA was

started simultaneous to the withdrawal of tamoxifen [case 4],

and one patient achieved a partial response for 9 months [case

5]. The third patient [case 1] did not respond to therapy and was

switched to letrozole. Four patients had received first-line

treatment with letrozole, with three patients achieving a

sustained partial remission [cases 2, 3, 10]. One patient did

Table 3

Response by treatment modality

Patients

(n)

NED

(Months)

CR

(Months)

PR

(Months)

SD

(Months)

PD

Withdrawal

of ERT

3 1 (60+) 2 (3+, 8+)

Withdrawal

of T

1 1

MPA 1st

line

3 1 (50+) 1 (9) 1

Letrozole

1st line

4 3

(3+, 9+, 10+)

1

Letrozole

after MPA

1 1 (37+)

Letrozole

1st +

2nd line

5 4 1

Chemotherapy

(2nd +

3rd line)

2 2 (18, 5+)

NED: no evidence of disease; CR: complete response; PR: partial response;

SD: stable disease; PD: progressive disease.

not respond to primary therapy with letrozole after withdrawal

of tamoxifen [case 8]. After failing MPA, a further patient

received letrozole as second-line treatment and achieved a

sustained PR [case 1].

After hormone treatment failed, two patients [cases 5, 7]

were treated with anthracycline-based combination chemother-

apy (Doxorubicin + DTIC, or caelyx + ifosfamide) and

achieved a PR lasting for several months.

A summary of treatment results is shown in Table 3.

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 [30–38].

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 to the rarity of

ESS, relatively few publications have addressed this issue, with

most data published so far being case reports. Nevertheless,

ESS development and/or ESS recurrences also seem to be

negatively impacted by ERT and tamoxifen [14,31,39–43].

In our series, eight of the ten patients with metastatic ESS

developed disease progression and/or metastases associated

with either the long-term use of estrogens or estrogen/progestin

combinations (5/10) or treatment with tamoxifen (3/10), thus

supporting the previous findings.

Several case reports have been published on the efficacy of

progestins [4,14,23,27,44–46] and the aromatase inhibitors

aminoglutethimide, letrozole or anastrozole (the latter in

combination with progestin) in the treatment of metastatic

ESS [26,28,47,48]. However, no systematic reviews or

prospective studies on hormone treatment for ESS have been

published yet.

In our retrospective analysis, two of the four patients treated

with MPA derived no benefit from therapy at any point in time.

By contrast, therapy with letrozole was initially effective in

four of five patients and in one patient who failed therapy with

MPA.

Another patient who suffered a secondary progression after

receiving 12 months’ therapy which led to a partial remission

initially had an LGESS with strong ER and PgR expression.

She later developed new metastases which similarly exhibited

features of LGESS but did not express ER and PgR.

While systematic studies on the merits of chemotherapy in

metastatic ESS do not exist, several retrospective analyses have

demonstrated a certain level of efficacy with doxorubicin and

ifosfamide-containing chemotherapy regimens [3,15,49–51].

Both patients who were treated with an anthracycline-contain-

ing chemotherapy in our series achieved a partial remission.

Conclusions

Based on previously published data and supported by our

series, it can be concluded that patients with a previous history

D. Pink et al. / Gynecologic Oncology 101 (2006) 464–469468

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, especially in HGESS. A prospective trial with

letrozole in patients with metastatic ESS is strongly warranted.

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