Endometrial stromal sarcomas are rare uterine neoplasms that are typically classified into 3 clinicopathologic entities: endometrial stromal nodules, endolymphatic stromal myosis or low-grade endometrial stromal sarcomas, and high-grade endometrial stromal sarcomas.1 Low-grade endometrial stromal sarcoma is the most common uterine stromal sarcoma, accounting for approximately 80% of all stromal neoplasms. The clinical course of this disease is typically indolent, with a protracted interval to recurrence. Several prognostic factors have been described for low-grade endometrial stromal sarcoma but remain controversial; these have included mitotic count, tumor size, stage, grade, age, and menopause status.2–6
The diagnosis of low-grade endometrial stromal sarcoma is frequently made incidentally after hysterectomy or myomectomy in premenopausal women undergoing surgery for benign indications. Historically, standard therapy has included total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO), with radical cytoreductive surgery for extrauterine involvement.7 Recommendation for BSO has been supported by small case series identifying an increased risk of recurrence in those women who have retained ovarian function.8,9 The rationale for ovarian extirpation is also supported by immunohistochemical studies indicating a rich expression of estrogen and progesterone receptors in the primary uterine tumor, suggesting that low-grade endometrial stromal sarcoma is a hormonally responsive disease.10–13
Recent data in other hormonally responsive gynecologic malignancies have suggested that ovarian preservation does not adversely influence disease course. Preservation of the contralateral ovary does not appear to adversely impact survival in early stage epithelial ovarian cancers, nor does retention of ovarian function affect recurrence in uterine leiomyosarcomas.14–16 Given the premenopausal status of many women incidentally diagnosed with low-grade endometrial stromal sarcoma, we hypothesized that ovarian preservation may be considered in women with stage I disease diagnosed incidentally. Our objectives in this case-control study were twofold: to characterize treatment and recurrence patterns in stage I low-grade endometrial stromal sarcoma and to examine the role of bilateral oophorectomy in the context of time to recurrence and overall survival.
MATERIALS AND METHODS
This retrospective multicenter study included patients with low-grade endometrial stromal sarcomas treated at the Cedars-Sinai Medical Center, the David Geffen School of Medicine at UCLA, the University of Texas Southwestern Medical Center, the Thomas Jefferson University Hospital, and the Johns Hopkins Medical Institute. Patients were identified for inclusion through a pathology database search from 1976 to 2002. Those diagnosed with stage I disease were included for review. Patients diagnosed with recurrent disease in this interval were included if their initial disease was limited to the uterine corpus. Clinical and pathologic data were abstracted from medical records under an institutional review board–approved protocol at all 5 institutions.
All patients underwent primary surgical management that included total hysterectomy. Abdominal versus vaginal approach, BSO, peritoneal cytology, omentectomy, pelvic and para-aortic lymph node dissection, and/or peritoneal biopsies were performed at the discretion of the primary surgeon. Disease was retrospectively staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer; only patients with stage I disease (tumor confined to the corpus) were included for review. In cases of incomplete surgical staging, stage was assigned on the basis of available pathologic findings with unevaluated areas considered negative for metastatic disease. Adjuvant therapy was recommended without standard protocols by the primary gynecologic oncologist and typically included pelvic radiotherapy or progestins. No patient received adjuvant cytotoxic chemotherapy.
Pathologists specializing in gynecologic malignancies at each institution reviewed all histologic materials. Low-grade endometrial stromal sarcoma was diagnosed with identification of endometrial stromal cell proliferation with less than 10 mitoses per 10 high power fields. Patients with endometrial stromal nodules, high-grade endometrial stromal sarcomas, leiomyosarcomas, and carcinosarcomas were excluded from review.
Immunohistochemical staining for estrogen and progesterone receptor expression was performed on available paraffin-embedded tumor samples. Slides were prepared and stained according to standard protocols.17 Staining was performed according to manufacturer’s recommendations on the Ventana Benchmark XT using the Ventana iVIEW detection system. Estrogen and progesterone receptor antibodies were prediluted from Ventana Medical Systems (Tucson, AZ). All slides were stained with diaminobenzidine (DAB) chromogen and counterstained with Mayer’s hematoxylin. Presence or absence of estrogen and progesterone receptors in previously stained sections of breast and ovarian carcinomas were used as positive and negative controls. Two observers independently scored the intensity and distribution of nuclear staining for estrogen and progesterone receptors. A scale of 0 (no staining) to 3+ (intense staining), with a distribution of less than 10% to more than 75% was used. Samples were considered positive if greater than 10% of nuclei stained with an intensity of more than 1+.
Case-control evaluations were performed after matching patients with retained ovarian function to those who had undergone BSO. Because all patients had stage I disease and were, by definition, low grade, cases and controls were matched first for age and then by use of adjuvant therapy. Because tumor size and mitotic count have not been consistently shown to influence clinical outcome, these variables were not included in the matching process.2–6 The Wilcoxon rank-sum test was used to compare ages between groups. The matching process should result in 2 comparable groups, which differ only with respect to the variable of interest.18 Data were further examined with the Student t, χ2, Cox regression, and Kaplan-Meier survival analyses. A P value of less than .05 was considered statistically significant.
Thirty-six women were identified with stage I low-grade endometrial stromal sarcomas; the case group comprised 12 patients who were all premenopausal and underwent hysterectomy only, without BSO or adjuvant pelvic radiotherapy. Of the 12 case patients, 8 underwent total abdominal hysterectomy, and 4 underwent total vaginal hysterectomy. Each case was matched by age and use of adjuvant therapy to 2 controls who had undergone BSO. If an exact match could not be obtained, controls were selected that matched the case patients as closely as possible in age, followed by use of adjuvant therapy. Seventeen control patients were premenopausal (71%); none of the control patients received estrogen replacement therapy. All controls underwent total abdominal hysterectomy with BSO; 12 underwent additional staging procedures, including omentectomy and/or pelvic and para-aortic lymph node dissection.
Median age at diagnosis was 46 years for cases (range 26–50) and 45 years for controls (range 25–59), a difference not clinically or statistically significant. Adjuvant therapy was prescribed without standard protocols, but no differences between the 2 groups were identified regarding use of adjuvant progestin therapy (25% in cases versus 21% in controls) or adjuvant pelvic radiation (0% in cases versus 17% in controls; Tables 1 and 2). Because radiotherapy has been demonstrated to have either no effect or a decreased risk of local recurrence,3,19,20 the inclusion of 4 patients receiving this adjuvant treatment in the control group may introduce potential bias favoring the BSO group.
To estimate whether BSO affects time to recurrence or overall survival, Kaplan-Meier curves for cases and controls were compared by using the log-rank test for differences in outcomes. No differences in progression-free survival were identified between patients with and those without ovarian function (91.3 months versus 68.6 months, P = .44). Furthermore, cases and controls demonstrated no differences in overall survival (median survival not yet reached versus 406 months, P = .82; Fig. 1A and 1B). With 12 cases and 24 controls, using a 2-sided log-rank test and a .05 significance level, we had 13% power to detect the observed difference in median disease-free survival.
To examine potential patterns of metastasis in stage I low-grade endometrial stromal sarcomas, sites of disease were identified in patients with recurrence. Overall, 14/36 (39%) in this cohort had documented recurrent disease. Disease recurred in 4 of 12 (33%) case patients, compared with 10 of 24 (42%) control patients (P = .63). Recurrences were identified in the pelvis (in 2 cases and in 5 controls), abdomen (in 1 case and in 2 controls), lung (in no cases and in 1 control), or lymphatics (in 1 case and in 2 controls); in case patients, no disease recurred in the ovaries. No differences in pattern of recurrence were identified between patients undergoing oophorectomy and those with retention of ovarian function.
To identify potential factors predictive of recurrence, Cox regression analysis was performed to control for potential prognostic factors, including age, use of adjuvant hormone therapy, adjuvant pelvic radiation, and BSO. All patients had disease confined to the uterus and were low grade by definition. Thus, stage and grade were not included. Multivariable analysis identified only older age as an independent poor prognostic factor for progression-free survival (P = .008; Table 2). Oophorectomy did not impact time to recurrence in this cohort.
To assess hormone responsiveness of these tumors, we performed immunohistochemistry in 22 available primary tumors. Nine tumors were available in cases (75%), and 15 tumors were available in controls (63%). All tumors demonstrated positive estrogen and progesterone receptor expression. Of the 14 recurrences, immunohistochemistry confirmed positive estrogen and progesterone receptor expression as well.
Low-grade endometrial stromal sarcoma is a rare gynecologic malignancy, which limits detailed study of clinical factors that may potentially influence survival. A review of the literature through the PubMed database in English from 1950 to June 2005, using the search term “low grade endometrial stromal sarcoma,” confirms that this multi-institutional report represents the largest cohort of women with stage I disease and is the only case-control analysis to examine the role of BSO in primary management. Despite expression of steroid hormone receptors, we identified no differences in time to recurrence or overall survival in women with disease confined to the uterus who retained ovarian function. Furthermore, BSO did not appear to impact patterns of recurrence, and older age was the only independent poor prognostic factor for progression-free survival.
Despite traditional recommendations to include BSO in the primary surgical management of this disease, data supporting oophorectomy are limited. Berchuck et al8 retrospectively studied 22 women with all stages of low-grade endometrial stromal sarcoma and found that disease recurred in all women with residual ovarian tissue, compared with a recurrence rate of 43% in those who had undergone BSO. In a more recent retrospective analysis, Chu et al10 identified recurrence in 4 of 8 (50%) women with retained ovarian function, of whom 6 were stage I. This compared favorably with 6 of 14 (43%) patients with BSO whose disease recurred. Our findings are consistent with these data and support the conclusions proposed by Chu et al that suggest ovarian function may be preserved in stage I disease. The wide variation of recurrence rates identified in women with retained ovarian function (0–100%) in other small series (consisting of 3–7 cases of retained ovaries) may potentially reflect differences in age and/or advanced stage that were not well controlled.9,21,22
Intuitively, the expression of estrogen and progesterone receptors in low-grade endometrial stromal sarcoma suggests the potential hormonal responsiveness of this disease. Our immunohistochemical findings are consistent with several other studies that identify expression of steroid hormone receptors in low-grade endometrial stromal sarcomas.10,11 Sex steroid hormones may promote cellular proliferation and/or recurrence, yet no in vitro studies have confirmed such a relationship in low-grade endometrial stromal sarcomas. Although several case reports have identified response of primary advanced-stage and recurrent low-grade endometrial stromal sarcomas to gonadotropin-releasing hormone agonists, aromatase inhibitors, and progestins, the impact of these in the adjuvant setting is not well defined for early-stage disease.23–26 Furthermore, recent data in other hormonally responsive gynecologic neoplasms suggest that preservation of ovarian function may be considered in early stage disease. Both epithelial ovarian carcinomas and uterine leiomyosarcomas strongly express estrogen and progesterone receptors in Western blot and immunohistochemical studies.27,28 In stage I disease, retention of ovarian function (in the absence of metastasis) does not appear to impact risk of recurrence or overall survival in either of these disease sites.14–16
Our study challenges the inclusion of BSO as standard surgical therapy in patients with disease limited to the uterus. Young women may be candidates for ovarian preservation after an incidental finding of low-grade endometrial stromal sarcoma at hysterectomy for benign indications. For patients approaching menopause, retention of ovarian function may be of less concern, but these women may not need additional procedures if BSO was not performed at the time of initial hysterectomy. We recognize these data are constrained by the limited power, but this study remains the largest and only case-control analysis of women with stage I low-grade endometrial stromal sarcoma. Given the rare incidence and indolent course of this disease, it is unlikely that randomized control trials would accrue the greater than 200 patients necessary to determine equivalency between ovarian preservation and BSO in a statistically meaningful manner. Our findings suggest that despite the rich expression of estrogen and progesterone receptors in low-grade endometrial stromal sarcoma, retention of ovarian function does not adversely impact the survival of completely excised stage I disease.
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