Uterine sarcomas are rare tumors, accounting for less than 3% of all female genital tract malignancies and 3% to 7% of malignant tumors of the uterine corpus.1 Most reports have analyzed the 3 histological subtypes of leiomyosarcoma, mixed malignant müllerian tumor, and endometrial stromal sarcoma (ESS) as 1 entity. Endometrial stromal sarcoma is a less common type of uterine sarcomas; in 1 study, ESSs represent 19% (19/100) of all uterine sarcoma cases.2 Traditionally, ESS is classified to 2 subtypes on the basis of mitotic rate: low-grade ESS (LGESS) and high-grade ESS (HGESS),3 the latter is currently named undifferentiated endometrial sarcoma (UES) or undifferentiated uterine sarcoma according to the 2003 World Health Organization Classification of Tumours.4 To avoid the confusion of the terminology, we keep the term of LGESS in this study, whereas HGESS is used instead of UES. The rarity and histological differences in ESS underlie the difficulty in diagnosis and treatment strategy. This retrospective study is aimed at evaluating the clinical characteristics, diagnosis, management, and prognosis of ESS patients in Peking Union Medical College Hospital (PUMCH) over a 22-year period.
MATERIALS AND METHODS
One hundred fifty-eight consecutive patients with histologically verified uterine sarcoma were treated at PUMCH during the period from 1983 to 2005. Of the 158 patients, 47 have LGESS, 23 with UES, 68 with leiomyosarcoma, 17 with mixed müllerian tumor, and 3 have other rare types, accounting for 29.7%, 14.6%, 43.0%, 10.8%, and 1.9% respectively.
Among 70 LGESS and UES patients, 52 cases (74.3%) were treated primarily at PUMCH, and 18 patients were referred to PUMCH after the primary operation. Demographic, clinicopathologic, treatment, and survival information of these women was retrospectively reviewed. The time of diagnosis was considered to be the date of primary surgical procedure. Staging was based on the 1988 International Federation of Gynecology and Obstetrics staging system.5 Adjuvant therapy data were recorded. Time to recurrence and latest contact were calculated. The pathological diagnosis was made by experienced pathologists at PUMCH. Low-grade ESSs are tumors with plexiform vasculature, rare mitotic figures, mild cytological atypia with up to 10 mitosis figures (MFs) per 10 high-power fields (HPFs). Undifferentiated endometrial sarcoma is poorly differentiated and shows a lack of plexiform vasculature, frequent atypical mitotic figures with more than 10 MFs/10 HPFs, and marked cytological atypia. Among these 70 patients, 51 patients completed the treatment and follow-up in our hospital, and the other 19 patients withdrew before the completion of adjuvant therapy because of socioeconomic reasons or lack of medical insurance.
The statistical analysis was performed using SPSS 11.5 (SPSS Inc, Chicago, Ill). The main outcome variables were disease-free survival (DFS) and overall survival (OS). The effect of tumor's classification, stage of the disease, initial surgery of ovarian preservation, and postoperative adjuvant therapy were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were carried out using the Cox proportional hazards regression model. P < 0.05 was considered statistically significant.
From 1983 to 2005, 70 consecutive ESS patients were treated in PUMCH. Forty-seven of them were diagnosed as having LGESS and 23 as having UES. The patient demographics, presentation, and diagnosis information based on the tumor's classification are depicted in Table 1. The most common presenting symptom and sign were abnormal vaginal bleeding and uterine enlargement. Diagnostic dilatation and curettage (D&C) was performed in 29 patients because of abnormal vaginal bleeding or uterine cavity lesion. Low-grade ESS or UES was diagnosed in 26 patients (26/29, 89.6%). That is, 37.2% (26/70) of the patients were diagnosed preoperatively. Diagnostic dilatation and curettage was performed more often in the UES patents (65.2%) because abnormal vaginal bleeding was complained more frequently in this arm (82.6%).
As mentioned above, only 51 patients completed the treatment and follow-up in our hospital, so that the treatment and prognostic variables were restricted to these patients. Among these 51 patients, 37 patients were diagnosed as having LGESS and 14 as having UES. The surgical pathological staging, initial surgery, and the adjuvant therapy information was present in Table 2.
Among the 51 patients, 36 patients (70.6%) had total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy as part of initial surgical treatment. Among them, 19 (19/36, 52.8%) patients had a debulking surgery including cytoreduction or comprehensive surgical staging. Another 15 patients (15/51, 29.4%) received an initial operation of myomectomy or TAH (ie, preserved 1 or both ovaries).
Thirty-three patients, including 23 of 37 LGESS and 10 of 14 UES, received adjuvant therapy. The most common choice of adjuvant therapy for LGESS was hormonal therapy with medroxyprogesterone combined with radiation or chemotherapy, and that for UES was chemotherapy.
The median OS time was 334 months, resulting in a 5-year survival rate of 87.8%. Five patients with UES died of the disease with a median OS of 38 months and 5-year survival rate of 34.6%. Only 1 patient with LGESS died of the disease at 325 months (P < 0.0001) (Fig. 1). The effect of age, tumor's classification, and the other selected variables on OS was analyzed using the Kaplan-Meier method (Table 3). Because of small sample size of dead cases, multivariate analysis was not carried out.
To further evaluate the risk factors of disease recurrence, we analyzed the DFS data. Twenty-six of 51 patients, including 14 with LGESS and 12 with UES, developed disease recurrence. The median DFS time was 130 months (95% confidence interval [CI], 18-242 months) for patients with LGESS and 11 months (95% CI, 8-14 months) for patients with UES (P < 0.0001) (Fig. 2). The univariate and multivariate analyses of age, tumor's classification, and the other selected variables on DFS were analyzed using Cox proportional hazards regression model (Tables 3 and 4).
Five patients with UES died of disease after recurrence, and the median survival time was 18 months. For the patients with LGESS, only 1 patient died at 315 months after disease recurrence, 6 patients had a complete remission, and the remaining 7 patients were alive with stable disease.
Endometrial stromal sarcomas are very rare uterine malignancies. According to an analysis of the Surveillance, Epidemiology, and End Results Program data, the annual incidence of ESS was only 0.19 in 100,000.6 Another epidemiology data from Norway estimated the ESS annual incidence being 1.7 per 100,000 females.7 In our study, the frequency of LGESS and UES in uterine sarcoma was 44.3% altogether, which was higher than that in other series from western countries (7%-18%) and Japan (18.9%, 20 of 106),8-10 whereas the incidence was similar to a series from Taiwan (46.4%).11 These data indicated that ESS and UES are more common in Chinese. However, it remains unclear whether this is influenced by the small number of patients or represents a true racial bias.
Inconsistent findings in differences based on age, in terms of histology breakdown into LGESS and UES, have been reported.8,12-14 A multi-institutional review including 105 patients found a lower mean age for patients with LGESS than in those with UES (50 vs 64 years, respectively).15 Our results showed that the mean age of the patients was lower than the data above, and there was no significant difference between the patient with LGESS and UES (42.4 vs 45.9 years, respectively), which is coincident with previous studies from Turkey, Japan, and Taiwan.9-11 It seemed that LGESS and UES were prominent in the older postmenopausal women in western countries, whereas they were common in childbearing-aged Asian women. We think it was due to the racial difference.
The rarity of this tumor makes the preoperative diagnosis quite difficult. In most studies,3,11 only 20% to 23.9% of the patients were diagnosed preoperatively. In this study, the percentage of patients diagnosed preoperatively was higher (37.1%), and the positive rate of D&C was extremely high (89.6%). Furthermore, our data revealed that abnormal bleeding was the most prominent presenting symptom. It is reasonable that D&C should be considered to these patients, and it may be the most important procedure for the diagnosis of LGESS and UES preoperatively.
Traditionally, ESS has been divided into LGESS and HGESS based on microscopic and pathological findings. This division has been used in clinical practice for many years and seems to accurately predict clinical behavior and outcomes.3 There is universal agreement that LGESSs are indolent tumors associated with long-term survival despite recurrences and metastases. Higher survival probability for patients with LGESS is often reported.16,17 According to our data, the 5-year OS was 87.8%, which was higher than those in the studies of Bodner et al8 (62%), Haberal et al9 (79%), Vongatama et al16 (61%), and Nordal and Thoresen18 (69%). However, HGESS, exhibiting 10 or more MFs per 10 HPFs and/or grade 2 or 3 nuclear atypia, grows rapidly, metastasizes early, and has a fatal prognosis in most patients, which has been variously better classified as UES in 2003.4 But the classification and terminology of UES are also controversial. A recent study19 has pointed out that UES showing nuclear uniformity may represent an intermediate subcategory of endometrial stromal tumors (formerly HGESS) that shares some molecular genetic and immunohistochemical features with LGESS and is associated with better outcome than undifferentiated sarcomas exhibiting nuclear pleomorphism. That is, UES showing nuclear uniformity has some degree of differentiation toward endometrial stromal cells and the traditional nomenclature HGESS may be more suitable for it.20 In some series, other factors such as free resection margins at primary surgery, malignancy grade, tumor diameter, menopausal status, and DNA index were important prognostic factors.21,22 In the present study, LGESS was significantly associated with longer DFS and OS, which is in accordance with the other retrospective studies.8,9,17 The other factors, including ovarian removal in the initial surgery and adjuvant therapy, may also show beneficial effects on DFS and OS.
Standard surgery management for both LGESS and UES consists of total hysterectomy and bilateral salpingo-oophorectomy. Removal of the ovaries is especially recommended for these low-grade tumors because they are characterized by high levels of estrogen and progesterone receptors and often respond to hormonal therapy. Berchuck et al13 reported on 19 unstaged patients with uterine-confined endolymphatic stromal myosis and found that patients who underwent ovarian preservation had a higher rate of recurrence than those who had their ovaries removed, 100% (6/6) compared with 43% (6/13), respectively. Conversely, Li et al22 performed a case-control study of 36 patients with LGESS and found that ovarian preservation had no effect on recurrences or OS. The above studies are limited by a small sample size that prevents any multivariable analysis for confounding factors. In a recent study, Shah et al23 reported that the effect of ovarian preservation did not affect OS in the LGESS patients, although they did not discuss the effect on DFS. Our data revealed that ovarian removal was effective to delay the disease recurrences but had no significant effect on OS.
Both types of ESS express steroid receptors-like estrogen and progesterone hormone receptor. Thus, treatment attempts with hormonal therapy have been made. Low-grade ESS has a higher median estrogen receptor expression than UES.24 Because of the rarity of ESS, only few case series about hormone therapy are published. There are neither randomized nor phases 1 and 2 trials available. In recurrent disease, hormone therapy is recommended for patients with LGESS, whereas chemotherapy seems to be more appropriate for patients with high-grade tumors. Low-grade ESS tends to grow slowly, and long-term survival has been reported after disease recurrence. Therefore, long-term maintenance therapy seemed to be beneficial.25 In our series, patients with LGESS had a long-time survival and good therapy response after disease recurrence (only 1 patient died at 315 months, 6 patients had a complete remission, and 7 patients maintained stable disease). Therefore, for the patients with LGESS, hormonal therapy is strongly recommended for adjuvant therapy after initial surgery and recurrence.
In conclusion, ESS is a rare kind of uterine malignancy. It is difficult to diagnose before operation. The possibilities of preoperative diagnosis may be improved by diagnostic curettage. Low-grade ESS and UES represent 2 distinct clinical entities and should be treated as such. The tumor's terminology and classification may be independent prognostic factors.
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Keywords:Copyright © 2010 by IGCS and ESGO
Endometrial stromal sarcoma; Undifferentiated endometrial sarcoma; Diagnosis; Treatment