Endometrial stromal sarcomas: a retrospective analysis of 28 patients, single center experience for 20 years

A retrospective analysis was performed involving 28 patients with histolo gic-proven ESSs treated at our institution between 1987 and 2006.

The median follow-up was 54.7±63.1 months and the 5-year survival rate was 82.0%. Twent y-two (81.5%) and 5 patients (18.5%) had low- and hi gh-grade disease, respectively . Univariate analysis revealed that the histologic grades, based on mitotic count, were asso- ciated with longer survival (p=0.004). However , amon g those patients with low-grade tumors, 5/20 patients (25%) had a recurrence and 2/21 patients (9.5%) had distant metastasis during the follow-up period. With the exception of 2 patients, 26 patients with ESSs underwent h ysterectomy as primar y treatment. Ad juvant treatment after surgery was administered to 14/26 patients (53.8%). Hormone therapy with progesterone, chemotherap y, and/or radiotherapy did not influence overall survival. However, the postoperative adjuvant therapy group, re- gardless of the treatment modality , was associated with relatively increased overall survival when compared to the surgery only group (p=0.054).

The preoperative differential diagnosis of ESSs from other benign gynecologic diseases is often difficult. We recommend adjuvant therapy be ad- ministered after hysterectomy in patients with ESS to pre - vent recurrence or distant metastasis. (Cancer Res Treat. 2008;40:6-10) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏 Key Words: Endometrial, Stromal, Sarcoma, Radiothe- rapy, Chemotherapy, Treatment outcome Correspondence: Jae Wook Kim, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Kwandong University College of Medicine, 697-24, Hwajeong-dong, Deokyang-gu, Goyang 412-270, Korea. (Tel) 82-31-810-5003, (Fax) 82-31-964-6649, (E-mail) [email protected] Received November 16, 2007, Accepted January 28, 2008

Endometrial stromal sarcomas (ESSs) are very rare, malig- nant uterine tumors, comprising ＜1% of all uterine cancers (1). Frequently, ESSs are detected by chance at the time of diagnostic dilatation and cu rettage (D&C), myomectomy, or hysterectomy for presumed benign uterine disease. Because of the non-specific characteristics o f ESSs, little is known regar - ding the pathogenesis, risk factors, optimal therapy, or out- comes. The following characteristi cs have been shown to have prognostic significance for ESSs: tumor size, FIGO stage, grade, age, and menopaus al status (2). The most reliable known prognostic factors are the grade of tumor and the extent of disease (3). ESSs can be divided into low- and high-grade ESSs based on a mitotic count of less or more than 10 mitoses/10 high power fields and characteri zed by a proliferation cells wi th endometrial stromal differentiation (4). Low-grade ESS has an indolent clinical course, whereas high-grade ESS behaves in a more aggressive manner with a poorer overall prognosis. Accordingly, it has been suggested that high-grade ESS should be regarded as a different disease entity altogether (5). However, some authors are of the opinion that mitotic count is not indicative of tumor recurrence or tumor-related deaths (6). The fundamental treatment for ESSs consists of total hysterectomy with bilateral salpingo-oophorectomy. However, Li et al(7) recently demonstrat ed that ovarian preservation could be a safe option for surgical treatment in stage I, low-grade ESS. The importance of surgical staging, including lymphadenectomy, is still unknown (3). Due to the high recurrence risk, even with localized tumors, many clinicians advocate the use of adjuvan t therapy (2); however, no prospective studies have been c onducted regarding the merits of adjuvant radiation and/or chemotherapy or hormonal treatment. Of note, the overall survival does not appear to improve with adjuvant therapy (8,9). T h e a i m o f t h i s s t u d y w a s t o e v a l u a t e t h e b e h a v i o r o f E S S s in relation to its clinical and pathogenic features and to determine the optimal treatment strategy. Eun Ji Nam, et al ：Diagnosis and Management of Endometrial Stromal Sarcomas 7 Fig. 1. Low-grade ESS. The tumor resembles normal stroma of proliferat ive endometrium, characterized by generally uniform cells with minimal nuclear pleomorphism and cytologic atypia, hyalinized c onnective tissue, and a rich, vascularized background (left, he matoxylin and eosin; right, corresponding pa rt of the left slide stained positive for CD10). Fig. 2. High-grade ESS. The tumor is composed of anaplastic spindle ce lls that have a high mitotic index and frequently encountered abnormal mitotic figures. (left, hematoxylin and eosin; right, corresponding part of the left slide stained negative for CD10) .

This study included 28 patients with histologic-proven ESS treated between 1987 and 2006 in the Department of Obstetrics and Gynecology of Yonsei University College of Medicine. Data were retrospectively reviewed and included age at the time of diagnosis, patient demographics , clinical presentation, exte nt of surgery performed, adjuvant therapy, patient outcome, recurrence patterns, and follow-up status. Twenty-two cases of low-grade ESS and 5 cases of high- grade ESS were identified. One c ase was not classified as eithe r low- or high-grade ESS due to diagnostic ambiguity. Surgical staging was based retrospectively on the 1988 FIGO guidelines for cancer of the uter ine corpus (10). Total hysterectomy and removal of as much tumor as possible was performed as a surgical procedures. With respect to the patients who made up the current study, the decision to perform adjuvant therapy was left to the individual physician, thus the adjuvant and non-adjuvant groups were not necessarily s imilar. The adjuvant group was administered chemotherapy, radiotherapy, or hormonal therapy. Some patients had a combination of the therapies. Megestrol acetate (120 ∼320 mg/day for 6 ∼12 months) was used as hormonal therapy. Chemotherapeutic regimens were variable; however, mainly consisted of a combination of ifosfamide, adriamycin, and platinum based-agents. Survival analysis was used to compare patients with or without specific clinicopathologi c parameters in terms of pro- gression-free and overall surviva l. The Kaplan-Meier method was used to estimate survival curves, and the log-rank statisti c was used to test the equality of the survival functions between the patients with or without sp ecific clinicopathologic para- meters. 8 Cancer Res Treat. 2008;40(1) Fig. 3. Overall survival as a function of ESS grade. Fig. 4. Overall survival based on adjuvant therapy after surgical treatment. Table 1. Patient characteristics Characteristics Patients (n=28) A g e M e d i a n 4 7 Range 20 ∼76 Stage I 16 (57.1%) III 4 (14.3%) IV 3 (10.7%) Unknown 5 (17.9%) Grade Low 22 (78.6%) High 5 (17.9%) Unknown 1 (3.6%) Distant metastasis No 22 (78.6%) Yes 5 (17.9%) Unknown 1 (3.6%) Hysterectomy Yes 26 (92.9%) No 2 (7.1%) Table 2. Adjuvant therapy after surgical treatment (n=26) Low-grade ESS High-grade ESS (n=21) (n=5) Observation 9 (42.9%) 3 (60.0%) RTx* 2 (9.5%) 0 CTx † 3 (14.3%) 0 HTx‡ 5 (23.8%) 0 RTx+CTx 1 (4.8%) 1 (20.0%) RTx+HTx 1 (4.8%) 0 RTx+CTx+HTx 0 1 (20.0%) *radiotherapy, †chemotherapy, ‡hormonal treatment. Table 3. Clinical outcomes of patients Low-grade ESS High-grade ESSOutcomes (n=22) (n=5) No evidence of disease 15 (68.1%) 1 (20.0%) Alive with disease 4 (18.2%) 0 Dead of disease 1 (4.5%) 2 (40.0%) Missing 2 (9.1%) 2 (40.0%)

The median age at the time of diagnosis was 47.0 years (range, 20 ∼76 years). Sixteen patient s (57.1%) were referred to our institution from private clinics for definitive treatmen t of ESSs. They had previously undergone either hysterectomy, myomectomy, D&C, or hysteroscopy for presumed benign gynecologic conditions. Experien ced pathologists analyzed all s p e c i m e n s ( F i g . 1 , 2 ) . P a t i e n t c h a r a c t e r i s t i c s a r e l i s t e d i n T able 1. Twenty-six of 28 patients had undergone total hysterectomy with or without bilateral salpingo-oophorectomy as part of thei r initial surgical treatment. Two patients had rad iotherapy for their initial treatment. More than one-half of the patients (16 /26 [61.5%]) were stage I. Distant metastasis outside the pelvis at the time of diagnosis had occurred in 5 patients (17.9%); para-aortic lymph node metastasis occurred in 1 patient each from the low- and high-grade ESS. Also, one patient with a high-grade ESS had metastasis to the omentum, and 2 patients with low-grade ESSs had metastasis to the bladder and lung (i.e., stage IV), respectively. Adjuvant therapy after surgery was performed in 14/26 cases (53.8%; Table 2). The most common choice for adjuvant therapy in low-grade ESSs was hormonal treatment with mege- strol acetate. In 5 patients with high-grade ESSs, 2 patients were treated with radiation therapy in combination with chemotherapy as adjuvant treatme nt. One of the patients also had hormonal treatment with me gestrol acetate (480 mg/day). One patient with a high-grade ESS voluntarily discontinued adjuvant treatment because of he r advanced age, and the other 2 patients voluntarily discontinued treatment due to poor performance status with extensive disease. The median overall survival was 56.5 months [95% CI: 47.0 ∼97.6] and the 5-year survival rate was 82.0%. Five patients Eun Ji Nam, et al ：Diagnosis and Management of Endometrial Stromal Sarcomas 9 (22.7%) with low-grade ESSs developed disease recurrence, one of whom died from the disease (Table 3). However, only 1 patient (20.0%) with a high- grade ESS showed no evidence of disease in a recent follow-up visit. Three patients with recurrent, low-grade ESS had intra-abdominal recurrent disease a few years after the initial diagnosis of their disease, while 1 patient had lung metastasis 13 years after diagnosis; the oth er patient had metastasis to the a bdominal wall 12 years after the initial diagnosis. Univariate analysis revealed that the histologic grade according to the mitotic count was associated with longer s u r v i v a l ( p = 0 . 0 0 4 ; F i g . 3 ) . O t h e r potential prognostic factors, such as stage, existence of lymph node metastasis, and age did not influence either disease-free survival or overall survival. Postoperative adjuvant therapy, hormone therapy, chemotherapy, and/or radiotherapy did not individually influence overall survival. However, the postoperative adjuvant therapy group, regardless of the treatment modality, was associated with relatively increased overall survival when compared to the no adjuvant therapy group (p=0.054; Fig. 4).

E S S i s a t u m o r a r i s i n g f r o m t h e c e l l s o f t h e e n d o m e t r i a l stroma. It can originate from the endometrium, adenomyosis, and occasionally, endometriosis. Because of the rarity of ESS, only small numbers of retrospective studies exist regarding the early diagnosis, prognostic factors, tumor behavior, and treatment guidelines. Due to the great similarity of ESS with normal endometrium, it may be impossible to diagnose low-grade ESS with certainty on curettage fragments, and the definitive diagnosis can be made only on a hysterectomy specimen (11). Only 5 patients were diagnosed with malignancy in our series by D&C. Imaging studies, such as magn etic resonance imaging or sonography, have only a limited role in the diagnosis of ESS from endometrial cancer, uter ine myoma, or adenomyosis (12,13). In the current study, 16/28 (57.1%) patients were referred from local clinics after hysterectomy, myomectomy, D&C, or hysteroscopy for presumed benign gynecologic con- ditions (57.1%). A recent study r eported that optimal cytore- ductive surgery could improve the median survival of patients with ESSs (14). Appropriate diagnostic modalities would therefore lead to a reduction in the rate of re-operations. Optimized therapeutic guidelines have not been agreed upon. Surgery has always been descr ibed as the most effective t r e a t m e n t f o r u t e r i n e s a r c o m a s ( 2 , 1 5 ) . H o w e v e r , t h e e x t e n t o f surgery, especially the role of lymphadenectomy, is contro- versial. When patients are referred to our institute after hyst ere- ctomy, they usually undergo radiation therapy as a primary treatment, whereas when referred after D&C or myomectomy, patients typically undergo surgical staging, including lymph- adenectomy. One study patient who underwent lymphadectomy for low-grade ESS had lymph node metastasis in the para-aortic area. In agreement with our study, recent data suggests that th e rate of lymph node involvement in low-grade ESSs may be higher than expected ( 16). However, the ther apeutic benefit of radical lymphadenectomy is still uncertain. Consistent with previous reports, the grade of tumor was the most significant prognostic factor in our study. Patients with low-grade ESSs had better surviv al compared to those patients with high-grade ESSs (3,14,17). However, patients with low-grade ESSs are frequently diagnosed in an early tumor stage, but still experience late recurrence or metastasis. Five p a t i e n t s ( 2 2 . 7 % ) w i t h l o w - grade ESSs developed disease recurrence, one of whom died of disease in our series. There- fore, this could be the rational e for adjuvant therapy to preve nt late recurrence or metastasis. Adjuvant therapy for patients w ith ESSs is still controversia l (17). One study reported no di fference in the recurrence rate in patients who had surgery with adjuvant therapy versus surgery alone (8). However, with respect to the presumed need to treat those patients perceived to be at higher risk with adjuvant therapy, the current study showed that the postoperative adjuvant therapy group regardless of the treatmen t modality was associated with relatively increased overall survival when compared to no adjuvant therapy group (p= 0.054). Therefore, strong consideration should be given to performing adjuvant therapy, even in patients with low-grade ESSs. Unfortunately, the optimal choice of adjuvant therapy for ESSs is unknown, with options including radiation therapy, chemotherapy, and hormonal therapy either alone or in varying combinations. Chemotherapeutic regimens utilized to treat ESS have included both single and combination agent therapy, including ifosfamide, cyclophosphamide, doxorubicin, adriamycin, cisplatin, etoposide, parclitaxel , and carboplatin (15,18 ∼21). Non- randomized studies have descri bed a favorable response with doxorubicin-based chemotherapy (8). Randomized controlled trials have suggested that the most effective single agent appears to be ifosfamide, with a 33% response rate (a 14% complete response and a 19% partial response) in a phase II trial by the Gynecologic Oncology Group for recurrent or metastatic disease (18). Similar to chemotherapy, no d efinite recommendations exist for adjuvant hormone therapy in patients, especially with low-grade ESS. Sever al reports have been published on the efficacy of progestin (4,22) and aromatase inhibitors in the treatment of metastatic ESS (23) . One advantage of adjuvant hormone therapy is that it allows long-term maintenance therapy. In addition, it appears that women with advanced stage disease benefit from adjuv ant hormone therapy (24). A combination of surgery and adjuvant radiotherapy may improve the treatment outcome c ompared to surgery alone (25). However, Gadducci et al. show ed no big difference in the outcome of patients with low-grade ESSs treated by surgery alone and surgery with adjuvant radiotherapy (3). For more convincing results, prospective studies with larger case series are necessary to help define the optimal choice of treatment. Taken together, we have show n that clinical outcomes can be readily depicted based on th e g r a d e o f t h e E S S . A l s o , w e recommend adjuvant therapy to be performed after hysterec- tomy to prevent recurrence or dis tant metastasis, even in low- grade ESSs. 10 Cancer Res Treat. 2008;40(1)

The differential diagnosis of ESSs from other benign gynecologic diseases before surg ery is often difficult. Though it is known that grade is the most important prognostic factor for patients with ESSs, recurrenc e or distant metastasis are no t rare in low-grade tumors. Accordingly, it is advised that adju- vant therapy be performed after hysterectomy to prevent recurrence or distant metastasis.

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