Arch Gynecol Obstet DOI 10.1007/s00404-014-3320-7
GYNECOLOGIC ONCOLOGY
Clinical characteristics, pathological reevaluation, surgical management and adjuvant therapy of patients with endometrial stromal tumors R. Rothmund • A. Hartkopf • C. Joachim • C. B. Walter • M. Wallwiener • B. Kraemer S. Y. Brucker • A. Staebler • F. A. Taran
•
Received: 6 March 2014 / Accepted: 13 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To review a single-center experience over a 27-year period in the management of endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) for insight into clinical characteristics, pathological diagnosis, surgical practice, adjuvant therapy and clinical outcome. Materials and methods This was a retrospective study of women with histologically proven ESS and UES who were treated at the Department of Obstetrics and Gynecology, University of Tuebingen, Germany, between 1983 and 2010. Available tumor tissue, as well as inpatient and ambulatory records were reviewed; follow-up and survival data were ascertained. Results The study sample comprised ten patients with ESS and seven patients with UES. Primary surgical treatment consisted of total hysterectomy in nine patients (90.0 %) with ESS and six patients (85.7 %) with UES; one patient (10.0 %) with ESS and one patient (14.3 %) with UES underwent debulking surgery. All patients (100 %) from the ESS group and six patients (85.7 %)
from the UES group underwent bilateral salpingo-oophorectomy. Seven women (70.0 %) with ESS and six women (85.7 %) with UES underwent lymphadenectomy. Median DFS was 83.8 months (95 % CI 80.6–87.0) and median OS was 232.6 (95 % CI 49.3–415.9) for patients with ESS; median DFS was 12.9 months (95 % CI 0–284.1) and median OS was 17.6 (95 % CI 0–37.0) for patients with UES. There was no significant difference in DFS between patients with ESS as compared with patients with UES. However, patients with ESS had a significantly better OS when compared to patients with UES (p = 0.011). Conclusion ESS and UES are very rare uterine neoplasms. Surgery consisting of total hysterectomy with or without bilateral salpingo-oophorectomy is the most important treatment-element in patients with ESS or UES. Keywords Endometrial stromal tumors Endometrial stromal sarcoma Undifferentiated endometrial sarcoma Lymphadenectomy Adjuvant therapy
Introduction A. Staebler and F. A. Taran have contributed equally to this work. R. Rothmund A. Hartkopf C. Joachim C. B. Walter B. Kraemer S. Y. Brucker F. A. Taran (&) Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany e-mail: [email protected] M. Wallwiener Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany A. Staebler Institute of Pathology, University of Tuebingen, Tuebingen, Germany
Endometrial stromal tumors are rare tumors of mesenchymal origin, affecting both women of reproductive and postmenopausal age and represent the second most common pure mesenchymal tumors of the uterus, even though they account for less than 10 % of all such tumors [1, 2]. In the latest 2003 World Health Organization (WHO) classification the term endometrial stromal tumor is applied to uterine neoplasms typically composed of cells that resemble endometrial stromal cells of the proliferative endometrium [3]. Endometrial stromal tumors are divided into three categories: endometrial stromal nodules, endometrial stromal
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sarcoma (ESS) (historically referred to as ‘‘low-grade endometrial sarcoma’’) and undifferentiated endometrial sarcoma (UES) (historically referred to as ‘‘high-grade endometrial sarcoma’’). ESS accounts for only 0.2 % of female genital tract malignancies and is a hormone-sensitive tumor [3]. UES is less common and arises by different pathogenetic mechanisms as compared with ESS. Some cases show severe nuclear pleomorphism, high mitotic activity, and/or tumor cell necrosis and represent a pleomorphic subtype. Other cases show a deceptively monomorphic histology with increased proliferation [3, 4]. Undifferentiated stromal sarcomas frequently show a reduction or complete loss of typical stromal differentiation markers like CD10 and therefore pose a unique diagnostic challenge. Symptoms of ESS are commonly reported as abnormal uterine bleeding, abdominal pain, and dysmenorrhea but as many as 25 % of the patients are asymptomatic [5]. Additionally, the absence of pathognomonic features on imaging techniques like ultrasonography and MRI makes a reliable preoperative diagnosis of uterine ESS difficult [4]. Thus, hysterectomy is advocated when imaging modalities cannot exclude a malignancy [4]. While ESS is an indolent tumor with good prognosis, UES has a very poor prognosis and most patients die within 2 years of initial diagnosis [5–8]. Surgery is the most important element in the therapy of endometrial stromal tumors; total hysterectomy with or without bilateral salpingo-oophorectomy (BSO) represents the initial standard management for both ESS and UES [1, 2, 4, 9–11]. Furthermore, for patients with advanced-stage disease, complete cytoreduction and secondary cytoreductive surgery can help to achieve favorable prognoses in patients with both ESS and UES [4, 10]. The role of adjuvant therapy (adjuvant hormone therapy, adjuvant chemotherapy, adjuvant radiation therapy) after surgery for endometrial stromal tumors continues to be undefined. Due to the rareness of ESS and UES and consequently lack of data from large-scale, prospective randomized trials, guidelines of therapeutic management for endometrial stromal tumors are not available. Hence, there is a continued need for review of past and current practice. The present study reviews the experience over a 27-year period of the Department of Obstetrics and Gynecology, University of Tuebingen, Germany, in the management of ESS and UES for insight into clinical characteristics, pathological diagnosis, surgical practice, adjuvant therapy and outcome.
Materials and methods This was a retrospective study conducted at the Department of Obstetrics and Gynecology, University of Tuebingen.
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Using institutional databases from the clinical cancer registry of the Comprehensive Cancer Centre (CCC) Tuebingen, we identified all women who were included in the registry with ‘‘uterine sarcoma’’ as final diagnosis between January 1st, 1983 and January 31st, 2010. Among the women included in the registry, a total of 28 patients with an initial diagnosis of endometrial stromal tumor were identified. The specific diagnoses of the identified cases were then manually compared with the pathology reports. The correct classification and pathologic diagnosis of endometrial stromal tumors is of great clinical relevance because prognosis and treatment vary depending on tumor type [2, 12]. Thus, only pathologically confirmed cases of endometrial stromal tumors with available tumor tissue for reevaluation that underwent primary surgical therapy at our institution were analyzed in the present study. Accordingly, five patients were excluded because they underwent primary surgical therapy elsewhere and were sent to our institution as a consultation for adjuvant therapy and four patients were excluded because tumor tissue was not available for pathologic review. Thus, a total of 19 patients with a histologic diagnosis of endometrial stromal tumor and available tumor tissue were reevaluated by a pathologist (AS) specializing in gynecologic diseases, using the latest 2003 WHO classification for endometrial stromal tumors. Out of the 19 cases, one case (initially classified as high-grade endometrial sarcoma) was reclassified as primitive neuroectodermal tumor of the uterus and one case (initially classified as low-grade endometrial sarcoma) was reclassified as stromal proliferation in an endometrial polyp. Thus, our study sample comprised 17 women with a diagnosis of endometrial stromal tumor; 10 women had a diagnosis of ESS and 7 women had a diagnosis of UES. A retrospective medical record review of both inpatient and ambulatory records was performed to ascertain sociodemographic and anthropometric variables, as well as to confirm intraoperative and pathologic findings. Tumor location, size and weight were obtained from the pathology report and/or the operative notes; immunohistochemical studies had already been performed in the majority of the cases and were obtained from the pathology report. Furthermore, adjuvant therapy data were recorded. The clinical cancer registry of the CCC, Tuebingen, provided follow-up and survival data. Time-to-disease recurrence and death or last contact was calculated. Premenopausal status was defined as occurrence of at least one menstrual period within 12 months before surgery. Adjuvant treatment was performed in selected patients at the discretion of the tumor board. We assessed the disease stage retrospectively for every patient using the new 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system, used specifically for uterine sarcomas [13].
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Data was coded and entered into an Excel spreadsheet version 2007 (Microsoft, Redmond, Washington DC, USA). Statistical analysis was carried out using JMP for Windows version 8.0 (SAS Institute Cary, NC, USA) and Prism 5 (GraphPad Software, La Jolla, CA, USA). Means, standard deviations (SD) and medians are reported for continuous variables and frequency counts and percentages for categorical variables. The survival curve was generated using the Kaplan–Meier method and compared using the long-rank test. p values \ 0.05 were considered statistically significant in all statistical analyses.
Results The study sample comprised a total of 17 patients, with a diagnosis of ESS (10 patients, 58.8 %) or UES (7 patients, 41.2 %) on pathologic review, that underwent treatment at our institution. Between January, 1st 1983 and December, 31st 1999 a total of four cases were indentified, between January, 1st 2000 and January, 31st 2010 we identified 13 women that underwent treatment for endometrial stromal tumors. The median follow-up for survivors was 64.2 months (95 % CI 0–131.3). Patient characteristics are summarized in Table 1. The mean age for patients with ESS was 46.1 years (SD ± 4.9 years) and the mean age for patients with UES was 59.7 years (SD ± 4.9 years) (p = 0.019). At the time of primary surgical treatment only 30.0 % of the patients with ESS were premenopausal compared to 85.7 % of the patients with UES (Table 1). Interestingly, in two women (20 %) with ESS the diagnosis of endometrial stromal tumor was an incidental finding during surgery for presumed benign disease: one patient underwent myomectomy and one patient underwent supracervical hysterectomy. Both patients had salvage therapy and underwent secondary surgery after diagnosis certainty; one of the patients had disease recurrence. There were three patients (30.0 %) in the ESS group and one patient (14.3 %) in the UES group with FIGO stage I disease, three patients (30.0 %) in the ESS group and two patients (28.6 %) in the UES group with stage II disease, three patients (30.0 %) in the ESS group and three patients (42.8 %) in the UES group with stage III disease and one patient in each group with stage IV disease (Table 1). Primary surgical treatment consisted of total abdominal hysterectomy and laparoscopic total hysterectomy in the majority of patients in each group. Two patients, one patient with ESS and one patient with UES underwent debulking surgery for advanced disease (Table 1). BSO was performed in 94.1 % of the patients (16/17) included in the study. All patients from the ESS group and six patients (85.7 %) from the UES group underwent BSO. Seven women (70.0 %) with ESS and six women (85.7 %)
Table 1 Characteristics of the patients with endometrial stromal sarcoma (ESS) and patients with undifferentiated endometrial sarcoma (UES) (n = 17) Characteristic
No. (%) ESS (n = 10)
UES (n = 7)
7 (70.0) 3 (30.0)
1 (14.3) 6 (85.7)
Menopausal status Premenopausal Postmenopausal
Mean
Mean
Age at diagnosis (±SD) (years)
46.1 (10.9)
59.7 (13.8)
Size uterine lesion (±SD) (cm)
3.3 (2.4)
4.1 (2.5)
Uterine/composite compound weight (±SD) (g)
261.6 (181.3)
165.9 (78.2)
No. (%)
No. (%)
Tumor FIGO Stage I
3 (30.0)
1 (14.3)
II
3 (30.0)
2 (28.6)
III
3 (30.0)
3 (42.8)
IV
1 (10.0)
1 (14.3)
Surgical therapy Total abdominal hysterectomy
6 (60.0)
4 (57.1)
Total laparoscopic hysterectomy
3 (30.0)
2 (28.6)
Debulking surgery
1 (10.0)
1 (14.3)
Bilateral salpingo-oophorectomy
10 (100)
6 (85.7)
Lymphadenectomy
7 (70.0)
5 (71.4)
Pelvic
5 (50.0)
3 (42.8)
Pelvic/paraaortic
2 (20.0)
2 (28.6)
Adjuvant therapy Adjuvant endocrine therapy
4 (40.0)
0
Adjuvant chemotherapy
0
1 (14.3)
Adjuvant radiation therapy
2 (20.0)
4 (57.1)
Combined adjuvant therapy
0
1 (14.3)
with UES underwent lymphadenectomy. Among those, five women with ESS underwent pelvic lymphadenectomy and two women with ESS underwent pelvic and paraaortic lymphadenectomy; three women with UES underwent pelvic lymphadenectomy and two women with UES underwent pelvic and paraaortic lymphadenectomy (Table 1). There was one patient with FIGO stage II disease and reported positive pelvic lymph nodes among patients with ESS. Two patients with UES had positive pelvic lymph nodes. There were no reported positive paraaortic lymph nodes in the two groups. A total of six patients (60.0 %) with ESS received adjuvant therapy. Four patients (40.0 %) received adjuvant endocrine therapy and two patients (20.0 %) received adjuvant radiation therapy. Adjuvant chemotherapy with doxorubicin and adjuvant radiation therapy was
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administered to one patient (14.3 %) with FIGO stage III UES. Furthermore, four patients with UES (57.1 %) received adjuvant radiation therapy (Table 1). Immunohistochemical studies had been performed as part of the initial workup in several cases, to support difficult differential diagnosis. The following antigens were identified in a subset of cases (positive/total shown in parenthesis): CD 10 (9/11), progesterone receptor (PR) (5/8), estrogen receptor (ER) (4/8), inhibin (0/3), S100 (0/3), smooth muscle actin (SMA) (2/6), CD 34 (0/6), CD 117(0/3), caldesmon (0/2). There were a total of nine disease recurrences in our study group, five recurrences in patients with ESS and four recurrences in patients with UES. Four patients with ESS had pelvic recurrences, and one patient had distant recurrence in the lung. Two patients with UES had both pelvic and distant (lung) recurrences, and two patients had distant lung recurrences. A total of four patients (two patients with ESS and two patients with UES) underwent therapy for disease recurrence. The two patients with ESS underwent debulking surgery, one patient with UES undwerwent debulking surgery, and one patient with UES received chemotherapy and radiation therapy for disease recurrence. Median DFS was 83.8 months (95 % CI 80.6–87.0) and median OS was 232.6 (95 % CI 49.3–415.9) for patients with ESS. Median DFS was 12.9 months (95 % CI 0–284.1) and median OS was 17.6 (95 % CI 0–37.0) for patients with UES. Although median DFS showed a large difference between the two groups, this was not statistically significant, probably due to the small number of cases. However, patients with ESS had a significantly better OS when compared to patients with UES (p = 0.011) (Fig. 1).
Discussion Endometrial stromal tumors (ESS and UES) are rare uterine malignancies. In consequence, high-level evidencebased guidelines of therapeutic management are absent. Hence, there is a need for individual centers to report even retrospective data of pathological diagnosis, surgical management, adjuvant treatment and clinical outcome in patients with this disease. The present study reviewed the experience over a 27-year period in our department in the management of ESS and UES. Five-year survival rates for patients with ESS have been reported to range between 84 and 98 % for patients with stage I disease and 62–66 % for patients with stage II, III and IV disease [5, 14–16]. In contrast, we noted a five-year survival rate of only 50 % in patients with ESS. Possible explanations for this discrepancy to previously published data might be the small sample size of our study and the inclusion of a high proportion of ESS patients with high-
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Fig. 1 Kaplan–Meier analysis of overall survival (OS) of patients with endometrial stromal sarcoma (ESS) versus patients with undifferentiated endometrial sarcoma (UES)
stage disease. Additionally, the failure to use standardized histopathologic criteria in some studies and inclusion of patients with various treatment approaches make a survival comparison between different study cohorts of patients with endometrial stromal tumors very difficult. The five-year survival rate of 20 % for patients with UES is in accordance with several other studies that reported five-year survival rates ranging from 25 to 55 % [17, 18]. It is clear that UES is characterized by an extremely aggressive biological behavior, since dismal survival results have been noted in nearly all series of patients [2, 4]. Surgery is the most important treatment-element in patients with ESS and UES. Many investigators recommend total hysterectomy with bilateral BSO as the standard treatment for patients with ESS. Although surgical castration is a logical intervention for hormone-sensitive disease, the clinical benefit remains unproven [4]. However, all premenopausal patients in our study underwent BSO at primary surgery. Thus, given the side effects associated with BSO in premenopausal patients, this issue deserves critical analysis. On one hand, a recent retrospective study in 114 patients with ESS revealed ovarian preservation as an independent predictor for poorer recurrence-free survival [19]. However, on the other hand, several small and large non-randomised studies that addressed the issue of preservation of ovaries in premenopausal women with ESS, suggested that ovarian preservation did not adversely affect outcome [20–23]. Moreover, estrogen replacement therapy was shown to have an adverse effect on outcome in five women with a history of ESS [20]. In consequence, we advocate
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individualized treatment regarding BSO in young patients with early stage ESS. Amant et al. suggested that in women younger than 35 years with small tumors (\2–3 cm) hysterectomy without BSO may be an appropriate treatment [4]. The role of lymphadenectomy in patients with ESS and UES is unclear. Nevertheless, a large proportion of the patients included in the present study underwent pelvic and/or paraaortic lymphadenectomy. The observed rate of positive lymph nodes in patients from both groups (10.0 % in the ESS group and 14.2 % in the UES group) is in accordance with other studies. The highest reported rate of lymph node metastases in patients with ESS is 45 %, however, the two largest studies, that included a total of 1,214 patients reported lymph node positivity in 7 and 9.9 % of the patients, respectively [15, 24–27]. In both studies positive lymph node status was shown to be an independent predictor of poorer survival [15, 24]. However, lymphadenectomy had no effect on survival in patients with ESS [15, 24]. Lymph node infiltration does appear to also be of prognostic significance in patients with UES [9]. Thus, lymph node status may offer both prognostic and information and guide adjuvant therapy decisions [2]. Involvement of lymph nodes in patients with ESS or UES is mostly associated with advanced stage disease or with macroscopically visible enlargement of the lymph nodes in early stage disease. Consequently, lymphadenectomy should definitely be considered as part of the cytoreductive procedure [4]. However, the exact role of lymphadenectomy in the primary surgical treatment of patients with endometrial stromal tumors warrants further evaluation. In our series of patients a large proportion of women from both groups developed disease recurrence. Consistent with other studies, the majority of recurrences involved the pelvis/abdomen in patients with ESS [5, 17]. Consequently, aggressive and repeated surgery is a valuable option in patients with endometrial stromal tumors [4]. Secondary and tertiary debulking procedures including resection of distant metastases should also be considered in patients with ESS [4]. It was suggested that some of the pelvic and abdominal recurrences may result from accidental tumor morcellation during primary surgery [2]. In two patients from our study group the tumor was morcellated accidentally and one of the patients had ESS recurrence. Park et al. [28] showed that, in patients with apparently early ESS of the uterus, inadvertent tumor morcellation during surgery is associated with a significantly higher rate of abdominopelvic recurrence and significantly lower DFS rates . However, because most patients who had abdominopelvic recurrence were successfully salvaged by secondary surgery followed by
systemic and/or radiation therapy, OS was not significantly compromised [28]. Nevertheless, surgeons should make every effort to avoid inadvertent tumor morcellation during surgery in patients with endometrial stromal tumors. In order to prevent and reduce local and distant relapses, the use of adjuvant therapy could be an attractive option in patients with ESS or UES. However, evidence on the role of adjuvant therapy in patients with ESS is limited and almost non-existent in patients with UES [1, 2, 4]. Adjuvant hormonal treatment seems to reduce recurrence in patients with ESS; however, prospective data on the role of adjuvant hormonal therapy in ESS are lacking [21]. Patients with metastatic or recurrent ESS may also be candidates for hormone therapy. Medroxyprogesterone, megestrol and aromatase inhibitors have been suggested to have a benefit in small studies in both the adjuvant and palliative setting [20, 21, 29]. However, the available data are unable to inform decisions on the duration of treatment and effects of the menopausal status are unknown [4]. In patients with ESS who have developed progression of disease after hormone therapy chemotherapy with ifosfamide or doxorubicin may be indicated [2, 4]. Furthermore, chemotherapy may also be indicated for patients with UES [1, 2]. Regarding the use of radiation therapy, to date, there have been no prospective, randomized studies showing a survival advantage for patients with endometrial stromal tumors [2]. Major limitations of this study are its retrospective design and the small number of patients with ESS and UES included. However, the pathologic review and the long follow-up augment the assessment of clinical characteristics of the patients included. Prospective, international, cooperative studies with larger cohorts including new prognostic factors would be important to be able to predict the prognosis of patients with ESS and UES and to gain insight in the pathogenesis of these rare diseases in a better way. Additionally, future prospective studies should address the role of adjuvant and palliative therapy, patient selection criteria, and optimal therapy regimes for patients with ESS and UES. Acknowledgments We acknowledge the assistance of Brigit Trilling in obtaining patient follow-up data. Conflict of interest
None.
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GYNECOLOGIC ONCOLOGY
Clinical characteristics, pathological reevaluation, surgical management and adjuvant therapy of patients with endometrial stromal tumors R. Rothmund • A. Hartkopf • C. Joachim • C. B. Walter • M. Wallwiener • B. Kraemer S. Y. Brucker • A. Staebler • F. A. Taran
•
Received: 6 March 2014 / Accepted: 13 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To review a single-center experience over a 27-year period in the management of endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) for insight into clinical characteristics, pathological diagnosis, surgical practice, adjuvant therapy and clinical outcome. Materials and methods This was a retrospective study of women with histologically proven ESS and UES who were treated at the Department of Obstetrics and Gynecology, University of Tuebingen, Germany, between 1983 and 2010. Available tumor tissue, as well as inpatient and ambulatory records were reviewed; follow-up and survival data were ascertained. Results The study sample comprised ten patients with ESS and seven patients with UES. Primary surgical treatment consisted of total hysterectomy in nine patients (90.0 %) with ESS and six patients (85.7 %) with UES; one patient (10.0 %) with ESS and one patient (14.3 %) with UES underwent debulking surgery. All patients (100 %) from the ESS group and six patients (85.7 %)
from the UES group underwent bilateral salpingo-oophorectomy. Seven women (70.0 %) with ESS and six women (85.7 %) with UES underwent lymphadenectomy. Median DFS was 83.8 months (95 % CI 80.6–87.0) and median OS was 232.6 (95 % CI 49.3–415.9) for patients with ESS; median DFS was 12.9 months (95 % CI 0–284.1) and median OS was 17.6 (95 % CI 0–37.0) for patients with UES. There was no significant difference in DFS between patients with ESS as compared with patients with UES. However, patients with ESS had a significantly better OS when compared to patients with UES (p = 0.011). Conclusion ESS and UES are very rare uterine neoplasms. Surgery consisting of total hysterectomy with or without bilateral salpingo-oophorectomy is the most important treatment-element in patients with ESS or UES. Keywords Endometrial stromal tumors Endometrial stromal sarcoma Undifferentiated endometrial sarcoma Lymphadenectomy Adjuvant therapy
Introduction A. Staebler and F. A. Taran have contributed equally to this work. R. Rothmund A. Hartkopf C. Joachim C. B. Walter B. Kraemer S. Y. Brucker F. A. Taran (&) Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany e-mail: [email protected] M. Wallwiener Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany A. Staebler Institute of Pathology, University of Tuebingen, Tuebingen, Germany
Endometrial stromal tumors are rare tumors of mesenchymal origin, affecting both women of reproductive and postmenopausal age and represent the second most common pure mesenchymal tumors of the uterus, even though they account for less than 10 % of all such tumors [1, 2]. In the latest 2003 World Health Organization (WHO) classification the term endometrial stromal tumor is applied to uterine neoplasms typically composed of cells that resemble endometrial stromal cells of the proliferative endometrium [3]. Endometrial stromal tumors are divided into three categories: endometrial stromal nodules, endometrial stromal
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sarcoma (ESS) (historically referred to as ‘‘low-grade endometrial sarcoma’’) and undifferentiated endometrial sarcoma (UES) (historically referred to as ‘‘high-grade endometrial sarcoma’’). ESS accounts for only 0.2 % of female genital tract malignancies and is a hormone-sensitive tumor [3]. UES is less common and arises by different pathogenetic mechanisms as compared with ESS. Some cases show severe nuclear pleomorphism, high mitotic activity, and/or tumor cell necrosis and represent a pleomorphic subtype. Other cases show a deceptively monomorphic histology with increased proliferation [3, 4]. Undifferentiated stromal sarcomas frequently show a reduction or complete loss of typical stromal differentiation markers like CD10 and therefore pose a unique diagnostic challenge. Symptoms of ESS are commonly reported as abnormal uterine bleeding, abdominal pain, and dysmenorrhea but as many as 25 % of the patients are asymptomatic [5]. Additionally, the absence of pathognomonic features on imaging techniques like ultrasonography and MRI makes a reliable preoperative diagnosis of uterine ESS difficult [4]. Thus, hysterectomy is advocated when imaging modalities cannot exclude a malignancy [4]. While ESS is an indolent tumor with good prognosis, UES has a very poor prognosis and most patients die within 2 years of initial diagnosis [5–8]. Surgery is the most important element in the therapy of endometrial stromal tumors; total hysterectomy with or without bilateral salpingo-oophorectomy (BSO) represents the initial standard management for both ESS and UES [1, 2, 4, 9–11]. Furthermore, for patients with advanced-stage disease, complete cytoreduction and secondary cytoreductive surgery can help to achieve favorable prognoses in patients with both ESS and UES [4, 10]. The role of adjuvant therapy (adjuvant hormone therapy, adjuvant chemotherapy, adjuvant radiation therapy) after surgery for endometrial stromal tumors continues to be undefined. Due to the rareness of ESS and UES and consequently lack of data from large-scale, prospective randomized trials, guidelines of therapeutic management for endometrial stromal tumors are not available. Hence, there is a continued need for review of past and current practice. The present study reviews the experience over a 27-year period of the Department of Obstetrics and Gynecology, University of Tuebingen, Germany, in the management of ESS and UES for insight into clinical characteristics, pathological diagnosis, surgical practice, adjuvant therapy and outcome.
Materials and methods This was a retrospective study conducted at the Department of Obstetrics and Gynecology, University of Tuebingen.
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Using institutional databases from the clinical cancer registry of the Comprehensive Cancer Centre (CCC) Tuebingen, we identified all women who were included in the registry with ‘‘uterine sarcoma’’ as final diagnosis between January 1st, 1983 and January 31st, 2010. Among the women included in the registry, a total of 28 patients with an initial diagnosis of endometrial stromal tumor were identified. The specific diagnoses of the identified cases were then manually compared with the pathology reports. The correct classification and pathologic diagnosis of endometrial stromal tumors is of great clinical relevance because prognosis and treatment vary depending on tumor type [2, 12]. Thus, only pathologically confirmed cases of endometrial stromal tumors with available tumor tissue for reevaluation that underwent primary surgical therapy at our institution were analyzed in the present study. Accordingly, five patients were excluded because they underwent primary surgical therapy elsewhere and were sent to our institution as a consultation for adjuvant therapy and four patients were excluded because tumor tissue was not available for pathologic review. Thus, a total of 19 patients with a histologic diagnosis of endometrial stromal tumor and available tumor tissue were reevaluated by a pathologist (AS) specializing in gynecologic diseases, using the latest 2003 WHO classification for endometrial stromal tumors. Out of the 19 cases, one case (initially classified as high-grade endometrial sarcoma) was reclassified as primitive neuroectodermal tumor of the uterus and one case (initially classified as low-grade endometrial sarcoma) was reclassified as stromal proliferation in an endometrial polyp. Thus, our study sample comprised 17 women with a diagnosis of endometrial stromal tumor; 10 women had a diagnosis of ESS and 7 women had a diagnosis of UES. A retrospective medical record review of both inpatient and ambulatory records was performed to ascertain sociodemographic and anthropometric variables, as well as to confirm intraoperative and pathologic findings. Tumor location, size and weight were obtained from the pathology report and/or the operative notes; immunohistochemical studies had already been performed in the majority of the cases and were obtained from the pathology report. Furthermore, adjuvant therapy data were recorded. The clinical cancer registry of the CCC, Tuebingen, provided follow-up and survival data. Time-to-disease recurrence and death or last contact was calculated. Premenopausal status was defined as occurrence of at least one menstrual period within 12 months before surgery. Adjuvant treatment was performed in selected patients at the discretion of the tumor board. We assessed the disease stage retrospectively for every patient using the new 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system, used specifically for uterine sarcomas [13].
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Data was coded and entered into an Excel spreadsheet version 2007 (Microsoft, Redmond, Washington DC, USA). Statistical analysis was carried out using JMP for Windows version 8.0 (SAS Institute Cary, NC, USA) and Prism 5 (GraphPad Software, La Jolla, CA, USA). Means, standard deviations (SD) and medians are reported for continuous variables and frequency counts and percentages for categorical variables. The survival curve was generated using the Kaplan–Meier method and compared using the long-rank test. p values \ 0.05 were considered statistically significant in all statistical analyses.
Results The study sample comprised a total of 17 patients, with a diagnosis of ESS (10 patients, 58.8 %) or UES (7 patients, 41.2 %) on pathologic review, that underwent treatment at our institution. Between January, 1st 1983 and December, 31st 1999 a total of four cases were indentified, between January, 1st 2000 and January, 31st 2010 we identified 13 women that underwent treatment for endometrial stromal tumors. The median follow-up for survivors was 64.2 months (95 % CI 0–131.3). Patient characteristics are summarized in Table 1. The mean age for patients with ESS was 46.1 years (SD ± 4.9 years) and the mean age for patients with UES was 59.7 years (SD ± 4.9 years) (p = 0.019). At the time of primary surgical treatment only 30.0 % of the patients with ESS were premenopausal compared to 85.7 % of the patients with UES (Table 1). Interestingly, in two women (20 %) with ESS the diagnosis of endometrial stromal tumor was an incidental finding during surgery for presumed benign disease: one patient underwent myomectomy and one patient underwent supracervical hysterectomy. Both patients had salvage therapy and underwent secondary surgery after diagnosis certainty; one of the patients had disease recurrence. There were three patients (30.0 %) in the ESS group and one patient (14.3 %) in the UES group with FIGO stage I disease, three patients (30.0 %) in the ESS group and two patients (28.6 %) in the UES group with stage II disease, three patients (30.0 %) in the ESS group and three patients (42.8 %) in the UES group with stage III disease and one patient in each group with stage IV disease (Table 1). Primary surgical treatment consisted of total abdominal hysterectomy and laparoscopic total hysterectomy in the majority of patients in each group. Two patients, one patient with ESS and one patient with UES underwent debulking surgery for advanced disease (Table 1). BSO was performed in 94.1 % of the patients (16/17) included in the study. All patients from the ESS group and six patients (85.7 %) from the UES group underwent BSO. Seven women (70.0 %) with ESS and six women (85.7 %)
Table 1 Characteristics of the patients with endometrial stromal sarcoma (ESS) and patients with undifferentiated endometrial sarcoma (UES) (n = 17) Characteristic
No. (%) ESS (n = 10)
UES (n = 7)
7 (70.0) 3 (30.0)
1 (14.3) 6 (85.7)
Menopausal status Premenopausal Postmenopausal
Mean
Mean
Age at diagnosis (±SD) (years)
46.1 (10.9)
59.7 (13.8)
Size uterine lesion (±SD) (cm)
3.3 (2.4)
4.1 (2.5)
Uterine/composite compound weight (±SD) (g)
261.6 (181.3)
165.9 (78.2)
No. (%)
No. (%)
Tumor FIGO Stage I
3 (30.0)
1 (14.3)
II
3 (30.0)
2 (28.6)
III
3 (30.0)
3 (42.8)
IV
1 (10.0)
1 (14.3)
Surgical therapy Total abdominal hysterectomy
6 (60.0)
4 (57.1)
Total laparoscopic hysterectomy
3 (30.0)
2 (28.6)
Debulking surgery
1 (10.0)
1 (14.3)
Bilateral salpingo-oophorectomy
10 (100)
6 (85.7)
Lymphadenectomy
7 (70.0)
5 (71.4)
Pelvic
5 (50.0)
3 (42.8)
Pelvic/paraaortic
2 (20.0)
2 (28.6)
Adjuvant therapy Adjuvant endocrine therapy
4 (40.0)
0
Adjuvant chemotherapy
0
1 (14.3)
Adjuvant radiation therapy
2 (20.0)
4 (57.1)
Combined adjuvant therapy
0
1 (14.3)
with UES underwent lymphadenectomy. Among those, five women with ESS underwent pelvic lymphadenectomy and two women with ESS underwent pelvic and paraaortic lymphadenectomy; three women with UES underwent pelvic lymphadenectomy and two women with UES underwent pelvic and paraaortic lymphadenectomy (Table 1). There was one patient with FIGO stage II disease and reported positive pelvic lymph nodes among patients with ESS. Two patients with UES had positive pelvic lymph nodes. There were no reported positive paraaortic lymph nodes in the two groups. A total of six patients (60.0 %) with ESS received adjuvant therapy. Four patients (40.0 %) received adjuvant endocrine therapy and two patients (20.0 %) received adjuvant radiation therapy. Adjuvant chemotherapy with doxorubicin and adjuvant radiation therapy was
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administered to one patient (14.3 %) with FIGO stage III UES. Furthermore, four patients with UES (57.1 %) received adjuvant radiation therapy (Table 1). Immunohistochemical studies had been performed as part of the initial workup in several cases, to support difficult differential diagnosis. The following antigens were identified in a subset of cases (positive/total shown in parenthesis): CD 10 (9/11), progesterone receptor (PR) (5/8), estrogen receptor (ER) (4/8), inhibin (0/3), S100 (0/3), smooth muscle actin (SMA) (2/6), CD 34 (0/6), CD 117(0/3), caldesmon (0/2). There were a total of nine disease recurrences in our study group, five recurrences in patients with ESS and four recurrences in patients with UES. Four patients with ESS had pelvic recurrences, and one patient had distant recurrence in the lung. Two patients with UES had both pelvic and distant (lung) recurrences, and two patients had distant lung recurrences. A total of four patients (two patients with ESS and two patients with UES) underwent therapy for disease recurrence. The two patients with ESS underwent debulking surgery, one patient with UES undwerwent debulking surgery, and one patient with UES received chemotherapy and radiation therapy for disease recurrence. Median DFS was 83.8 months (95 % CI 80.6–87.0) and median OS was 232.6 (95 % CI 49.3–415.9) for patients with ESS. Median DFS was 12.9 months (95 % CI 0–284.1) and median OS was 17.6 (95 % CI 0–37.0) for patients with UES. Although median DFS showed a large difference between the two groups, this was not statistically significant, probably due to the small number of cases. However, patients with ESS had a significantly better OS when compared to patients with UES (p = 0.011) (Fig. 1).
Discussion Endometrial stromal tumors (ESS and UES) are rare uterine malignancies. In consequence, high-level evidencebased guidelines of therapeutic management are absent. Hence, there is a need for individual centers to report even retrospective data of pathological diagnosis, surgical management, adjuvant treatment and clinical outcome in patients with this disease. The present study reviewed the experience over a 27-year period in our department in the management of ESS and UES. Five-year survival rates for patients with ESS have been reported to range between 84 and 98 % for patients with stage I disease and 62–66 % for patients with stage II, III and IV disease [5, 14–16]. In contrast, we noted a five-year survival rate of only 50 % in patients with ESS. Possible explanations for this discrepancy to previously published data might be the small sample size of our study and the inclusion of a high proportion of ESS patients with high-
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Fig. 1 Kaplan–Meier analysis of overall survival (OS) of patients with endometrial stromal sarcoma (ESS) versus patients with undifferentiated endometrial sarcoma (UES)
stage disease. Additionally, the failure to use standardized histopathologic criteria in some studies and inclusion of patients with various treatment approaches make a survival comparison between different study cohorts of patients with endometrial stromal tumors very difficult. The five-year survival rate of 20 % for patients with UES is in accordance with several other studies that reported five-year survival rates ranging from 25 to 55 % [17, 18]. It is clear that UES is characterized by an extremely aggressive biological behavior, since dismal survival results have been noted in nearly all series of patients [2, 4]. Surgery is the most important treatment-element in patients with ESS and UES. Many investigators recommend total hysterectomy with bilateral BSO as the standard treatment for patients with ESS. Although surgical castration is a logical intervention for hormone-sensitive disease, the clinical benefit remains unproven [4]. However, all premenopausal patients in our study underwent BSO at primary surgery. Thus, given the side effects associated with BSO in premenopausal patients, this issue deserves critical analysis. On one hand, a recent retrospective study in 114 patients with ESS revealed ovarian preservation as an independent predictor for poorer recurrence-free survival [19]. However, on the other hand, several small and large non-randomised studies that addressed the issue of preservation of ovaries in premenopausal women with ESS, suggested that ovarian preservation did not adversely affect outcome [20–23]. Moreover, estrogen replacement therapy was shown to have an adverse effect on outcome in five women with a history of ESS [20]. In consequence, we advocate
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individualized treatment regarding BSO in young patients with early stage ESS. Amant et al. suggested that in women younger than 35 years with small tumors (\2–3 cm) hysterectomy without BSO may be an appropriate treatment [4]. The role of lymphadenectomy in patients with ESS and UES is unclear. Nevertheless, a large proportion of the patients included in the present study underwent pelvic and/or paraaortic lymphadenectomy. The observed rate of positive lymph nodes in patients from both groups (10.0 % in the ESS group and 14.2 % in the UES group) is in accordance with other studies. The highest reported rate of lymph node metastases in patients with ESS is 45 %, however, the two largest studies, that included a total of 1,214 patients reported lymph node positivity in 7 and 9.9 % of the patients, respectively [15, 24–27]. In both studies positive lymph node status was shown to be an independent predictor of poorer survival [15, 24]. However, lymphadenectomy had no effect on survival in patients with ESS [15, 24]. Lymph node infiltration does appear to also be of prognostic significance in patients with UES [9]. Thus, lymph node status may offer both prognostic and information and guide adjuvant therapy decisions [2]. Involvement of lymph nodes in patients with ESS or UES is mostly associated with advanced stage disease or with macroscopically visible enlargement of the lymph nodes in early stage disease. Consequently, lymphadenectomy should definitely be considered as part of the cytoreductive procedure [4]. However, the exact role of lymphadenectomy in the primary surgical treatment of patients with endometrial stromal tumors warrants further evaluation. In our series of patients a large proportion of women from both groups developed disease recurrence. Consistent with other studies, the majority of recurrences involved the pelvis/abdomen in patients with ESS [5, 17]. Consequently, aggressive and repeated surgery is a valuable option in patients with endometrial stromal tumors [4]. Secondary and tertiary debulking procedures including resection of distant metastases should also be considered in patients with ESS [4]. It was suggested that some of the pelvic and abdominal recurrences may result from accidental tumor morcellation during primary surgery [2]. In two patients from our study group the tumor was morcellated accidentally and one of the patients had ESS recurrence. Park et al. [28] showed that, in patients with apparently early ESS of the uterus, inadvertent tumor morcellation during surgery is associated with a significantly higher rate of abdominopelvic recurrence and significantly lower DFS rates . However, because most patients who had abdominopelvic recurrence were successfully salvaged by secondary surgery followed by
systemic and/or radiation therapy, OS was not significantly compromised [28]. Nevertheless, surgeons should make every effort to avoid inadvertent tumor morcellation during surgery in patients with endometrial stromal tumors. In order to prevent and reduce local and distant relapses, the use of adjuvant therapy could be an attractive option in patients with ESS or UES. However, evidence on the role of adjuvant therapy in patients with ESS is limited and almost non-existent in patients with UES [1, 2, 4]. Adjuvant hormonal treatment seems to reduce recurrence in patients with ESS; however, prospective data on the role of adjuvant hormonal therapy in ESS are lacking [21]. Patients with metastatic or recurrent ESS may also be candidates for hormone therapy. Medroxyprogesterone, megestrol and aromatase inhibitors have been suggested to have a benefit in small studies in both the adjuvant and palliative setting [20, 21, 29]. However, the available data are unable to inform decisions on the duration of treatment and effects of the menopausal status are unknown [4]. In patients with ESS who have developed progression of disease after hormone therapy chemotherapy with ifosfamide or doxorubicin may be indicated [2, 4]. Furthermore, chemotherapy may also be indicated for patients with UES [1, 2]. Regarding the use of radiation therapy, to date, there have been no prospective, randomized studies showing a survival advantage for patients with endometrial stromal tumors [2]. Major limitations of this study are its retrospective design and the small number of patients with ESS and UES included. However, the pathologic review and the long follow-up augment the assessment of clinical characteristics of the patients included. Prospective, international, cooperative studies with larger cohorts including new prognostic factors would be important to be able to predict the prognosis of patients with ESS and UES and to gain insight in the pathogenesis of these rare diseases in a better way. Additionally, future prospective studies should address the role of adjuvant and palliative therapy, patient selection criteria, and optimal therapy regimes for patients with ESS and UES. Acknowledgments We acknowledge the assistance of Brigit Trilling in obtaining patient follow-up data. Conflict of interest
None.
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