Undifferentiated uterine sarcoma : experience of a single center

Abstract

Objectives

To investigate the clinicopathological characteristics and prognosis of patients with undifferentiated uterine sarcomas (UUS).

Methods

29 patients with UUS who were treated at our institution between 2001 and 2020 were analyzed.

Results

The median age at diagnosis was 52 years (range: 26–70 years). The FIGO 2009 distribution by stage was as follows: stage I, 17 patients (58.6%); stage II, 5 patients (17.2%); stage III, 4 patients (13.8%); and stage IV, 3 patients (10.3%). For 28 patients who underwent surgical treatment, 27 patients (96.4%) underwent total/sub-radical/radical hysterectomy combined bilateral salpingo-oophorectomy, 17 (58.6%) pelvic lymphadenectomy, 7 (24.1%) para-aortic lymphadenectomy and 8 (28.6%) patients underwent omentectomy, as part of the initial surgical treatment. The median follow-up was 23.4 months (range: 4.5–200.2 months). 18 patients (62.1%) died during follow up, and 13 patients (72.2%, 13/18) died within 2 years after diagnosis. Median progression-free survival (mPFS) and overall survival (mOS) for the entire cohort were 15.5 and 27.4 months, respectively. 2-year and 5-year PFS were 40.3% and 26.9%. 2-year and 5-year OS were 54.0% and 36.5%. Stage-specific median PFS and OS were as follows: stage I-II—17.7 and 35.5 months, stage III-IV—6.0 and 6.7 months. Patients with recurrent UUS who underwent cytoreduction surgery associated with an improved overall survival (mOS: 52.9 vs. 17.9 months), but the difference was not statistically significant (P = 0.081).

Conclusions

UUS are a rare group of tumors with an aggressive behavior and poor outcomes. A majority rapidly develops distant metastases despite surgical resection.

Introduction

Uterine sarcomas account for approximately 3-7% of all uterine cancers [1]. Endometrial stromal tumors are rare uterine malignancies that account for approximately 7–15% of all uterine sarcomas [2]. The 2014 World Health Organization recognizes 4 categories of endometrial stromal tumor: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS) [3]. Because of their low incidence and the lack of prospective studies, it is very difficult to reach conclusions as to the best disease management recommendations for UUS [4, 5]. There is no evident prognostic factor in UUS. The aim of the present study was to evaluate the characteristics and clinical outcomes of a series of 29 patients with UUS treated at our institution over a 20-year period and provide information to the literature about the treatment of UUS.

Patients and methods

Patients

This study was approved by the Cancer Hospital, Chinese Academy of Medical Sciences Institutional Review Board (IRB). Following Institutional Review Board approval, we performed a retrospective analysis of all patients diagnosed with UUS from January 1, 2001 to January 1, 2020 who received treatment in the Department of Gynecological Oncology of Cancer Hospital, Chinese Academy of Medical Sciences, National Cancer Center. Only patients with a diagnosis of undifferentiated uterine sarcoma confirmed by an experienced gynecologic pathologist in our hospital were included. The patients’ full medical records were included in this study. Clinical and pathologic variables, treatment modalities, and outcomes were assessed. Stage was retrospectively assigned using the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system for uterine sarcomas. This study was approved by the Research and Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences, National Cancer Center. Investigation was conducted in accordance with ethical standards, the Declaration of Helsinki and Chinese and international guidelines.

Statistical analyses

For the survival analyses, progression-free survival (PFS) was defined as the time from initial surgical staging or cytoreductive surgery to first recurrence (local or distant), or death (whatever the cause). Overall survival (OS) was defined as the time from initial surgical staging or cytoreductive surgery to death (whatever the cause). Data were analyzed and reported based on all patient data up to the data cut-off date of 1 January 2022. Survival was estimated using the Kaplan–Meier product-limit method, and differences were tested for statistical significance using the log-rank test. Cox proportional hazards regression models were used to identify the prognostic factor [HR and 95% confidence intervals (CI)]. Two-sided P values less than 0.05 were considered to be statistically significant. All analyses were performed using the SPSS Statistics 20.0 software.

Results

Patient characteristics

The median age at diagnosis was 52 years (range: 26–70 years). 65.5% (19/29) of them was diagnosed after 50 years (Table 1). The median body mass index (BMI) was 23.4 kg/m² (range: 19.9–36.6 kg/m²). 48.3% (14/29) patients had a BMI ≥ 24 kg/ m². 65.5% (19/29) patients presented with vaginal bleeding which was the most common primary symptom (Table 1). The proportion of patients with smaller tumor (< 5 cm) was only 6.9%, compared to 44.8% for 5 to 10 cm, 48.3% for ≥ 10 cm (Table 1). The FIGO 2008 distribution by stage was: stage I, 17 patients (58.6%); stage II, 5 patients (17.2%); stage III, 4 patients (13.8%); and stage IV, 3 patients (10.3%) (Table 1).

Table 1 Clinical and pathological characteristics of patients with UUS

Treatment

Overall, 4 patients (13.8%) received neoadjuvant chemotherapy. 28 patients (96.6%) received surgical treatment and only one patient underwent neoadjuvant chemotherapy with paclitaxel/platinum and had not received surgical treatment because of the locally advanced disease (FIGO IIIA) progressed.

Neoadjuvant chemotherapy

4 patients (13.8%, 4/29) received neoadjuvant chemotherapy, 3 for paclitaxel and carboplatin regimen, 1 for doxorubicin/ifosfamide/cisplatin regimen. Clinical response to neoadjuvant chemotherapy was noted; partial clinical response was achieved in 3 (75.0%), and progression disease in 1 (25.0%) patient.

Surgical treatment

For 28 patients received surgical treatment, 22 patients (78.6%) underwent total hysterectomy, 3 patients (10.7%) underwent sub-radical hysterectomy, 2 patients (7.1%) underwent radical hysterectomy, all these patients underwent bilateral salpingo-oophorectomy concurrently as part of the initial surgical treatment. 1 patient only received unilateral salpingo-oophorectomy because of the advanced disease. All patients who underwent surgery, 17 (58.6%) pelvic lymphadenectomy, 7 (24.1%) para-aortic lymphadenectomy and 8 (28.6%) patients underwent omentectomy. 11.8% (2/17) patients had lymph node metastasis. Of patients who received hysterectomy (n = 27), 16 patients (59.3%) had deep myometrial invasion (> 1/2), and 4 (14.8%) cervical involvement.

Adjuvant therapy

Twenty-three (82.1%) of 28 patients received adjuvant chemotherapy. The treatment regimens included: doxorubicin/ifosfamide/cisplatin (18), gemcitabine/docetaxel (1), dacarbazine/etoposide/cisplatin (1), and paclitaxel/platinum (3). Only 1 patient (3.6%) received adjuvant intravaginal brachytherapy after surgery.

Survival analysis

The median follow-up was 23.4 months (range: 4.5–200.2 months). 18 patients (62.1%) died during follow up, and 13 patients (72.2%, 13/18) died within 2 years after diagnosis. Median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 15.5 and 27.4 months, respectively (Fig. 1). 2-year PFS and 5-year PFS were 40.3% and 26.9%. 2-year OS and 5-year OS were 54.0% and 36.5%. Stage-specific median PFS and OS were as follows: stage I-II—17.7 and 35.5 months, stage III-IV—6.0 and 6.7 months.

Fig. 1

Progression-free survival (PFS) and overall survival (OS) analyses by the Kaplan–Meier method in the entire cohort. (A) PFS; (B) OS

FIGO stage I-II had a significantly better survival (5-year PFS: 32.3% vs. 14.3%, P = 0.003; 5-year OS: 40.2% vs. 28.6%, P = 0.087) (Fig. 2). Performance of omentectomy also associated with a better survival (5-year PFS: 72.9% vs. 14.3%, P = 0.016; 5-year OS: 87.5% vs. 23.8%, P = 0.078). Patients with larger tumors (≥ 10 cm), no lymphadenectomy, cervical involvement, deep myometrial invasion (> 1/2), had a tendency towards worse survival, although the observed differences were not statistically significant (Table 2).

Fig. 2

Progression-free survival (PFS) and overall survival (OS) analyses by the Kaplan–Meier method according to the FIGO stage in the entire cohort. (A) PFS; (B) OS

Table 2 Univariate survival analysis for patients with UUS

Recurrent disease

During follow-up, 20 patients (69.0%) had recurrence following primary treatment. Median time to first recurrence was 13.6 (range 1–26) months. The most common site of recurrence was the pelvic/abdominal cavity, diagnosed in 13 (65.0%) patients, followed by lung metastases in 4 (20.0%) patients, lymph node involvement in 1 (5.0%) patient, liver metastases in 1 (5.0%) patient, and abdominal wall metastases in 1 (5.0%) patient.

Five patients (25.0%, 5/20) with pelvic/abdominal cavity or abdominal wall metastases underwent cytoreduction surgery and completed resection of localized tumor. 1 patient underwent a repeated cytoreductive surgery for the second pelvic recurrence. Patients with recurrent UUS who underwent cytoreduction surgery associated with an improved overall survival (median OS: 52.9 months vs. 17.9 months), but the difference was not statistically significant (P = 0.081).

Discussion

Undifferentiated uterine sarcomas (UUS) are a rare group of tumors with an aggressive behavior and poor outcomes. In the present study, twenty-nine patients with UUS treated at our institution from 2001 to 2020 were analyzed. Our series is one of the largest to report on surgical and treatment outcomes for patients with UUS in a single center.

As reported in other studies, we found the most common primary symptom was vaginal bleeding for UUS. Most UUS patients were diagnosed by dilation and curettage, which was different from other uterine sarcomas that were often found incidentally. Most UUS patients had advanced-stage disease at the time of diagnosis, with nearly 50% having stage III-IV disease [6]. The high incidence of metastasis suggests the need for more accurate initial assessment by radiologic imaging. UUS represents a distinct histologic subtype of uterine sarcoma with poor outcomes regardless of the stage and the treatment received by the patients [7, 8]. Poor prognosis is described by other authors with the 25% for the 5 years overall survival and the median OS usually ranges from 7 to 23 months [6, 8,9,10]. Our results demonstrated a median OS for 27.4 months which compared favorably to other studies. One of the underlying reasons was that the percentage of stage I-II UUS patients was high in our study.

Because of the rarity of the disease, it is difficult to identify a reliable prognostic factor. While no significant predictor of prognosis was found for UUS [8]. As reported in other studies, lympho-vascular invasion, deep myometrial invasion and tumor size may be related to a worse outcome. We found FIGO stage I-II and performance of omentectomy associated with an improved survival. Patients with larger tumors (≥ 10 cm), no lymphadenectomy, cervical involvement, deep myometrial invasion, had a tendency towards a worse survival, although the observed difference was not statistically significant.

Because of their low incidence and the lack of prospective studies, it is very difficult to reach conclusions as to the best disease management recommendations for UUS. Total hysterectomy and bilateral salpingo-oophorectomy is the standard recommended surgical treatment for localized UUS [10]. Some authors have advocated surgical debulking for extra-uterine UUS, in order to palliate symptoms, and possibly improve survival. Survival in patients with UUS appears to be related to amount of residual disease at the completion of initial surgery and would suggest the need for aggressive cytoreduction [9, 11]. Patients who attained complete resection displayed a tendency towards enhanced OS than patients with incomplete resection [9, 11]. In the present study, only two patients had not received hysterectomy owing to locally advanced disease.

The benefit of lymph node resection has already been discussed for other uterine sarcomas. Lymph node metastasis is more common in UUS than in others [8, 11]. Leath et al. report the incidence of lymph node metastasis at primary surgery (18% for pelvic nodes and 15% for para-aortic nodes) for UUS [11]. But for UUS patients, the poor prognosis was mainly related to the presence of extrapelvic sites of recurrence in the majority of cases. So some authors recommended systematic lymphadenectomy should not be carried out for such patients unless there was a suspicion of nodal involvement from clinical or imaging data [9]. We found patients who received lymphadenectomy had an non-significantly improved overall survival. Strong consideration should be given to performing lymph node sampling or lymphadenectomy for these patients.

The effect of postoperative treatment among patients who have undergone surgical resection is a subject for debate [5, 9, 12]. It is reasonable to offer most patients with measurable disease first-line treatment with cytotoxic agents that have known activity in soft tissue sarcomas and leiomyosarcoma; however, patients should be informed that response duration is likely to be short [13]. In the present study, although not statistically different, median PFS was better among patients who received postoperative chemotherapy than among those who did not (10.2 versus 5.9 months, respectively), which consistent with previous reports. Radiotherapy seems to have benefited patients [14]. Adjuvant radiotherapy correlated with improved survival in UUS patients [7, 15]. Because of the scarcity and heterogeneity of available evidence, it is not possible to draw a definitive conclusion on the survival impact of adjuvant radiotherapy in patients with HGESS or UUS [8].

Patients with UUS have a high risk for recurrence. No recommendation can be provided for advanced and metastatic UUS owing to the rarity. Systematic chemotherapy may be an important treatment for recurrent disease. Surgery for synchronous metastasis in uterine sarcomas can be proposed as an option only after a complete debulking surgery and if they are all resectable [6]. Secondary cytoreduction prolongs overall survival in women with recurrent uterine leiomyosarcoma [15]. There are no specific data on UUS and surgery in metastatic or recurrent disease. In our present study, cytoreduction surgery for recurrent UUS associated with an improved survival.

Soft tissue sarcomas (STS) including UUS are a heterogeneous and challenging group of rare cancers to treat. Molecular profiling of sarcoma are gradually being discovered. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors [16]. Furthermore, Kolin et al. proposed Inactivation of SMARCA4 (encoding the BRG1 protein) occurred in a rare subset of undifferentiated uterine sarcomas with distinctive rhabdoid morphology and aggressive behavior [17]. This tumor type may be a rational candidate for targeted therapy (such as EZH2 inhibitors and anti-PD-1 therapy) [17].

There are three limitations to our study. Because of the rarity of UUS, the sample size of our study was small. The current study was retrospective, and the primary treatment was not assigned at randomized. In addition, the treatments were heterogeneous since the enrolled patients had a long time span. Therefore, caution is required when interpreting our results. International multicenter retrospective or prospective large studies are warranted to validate these findings. Organizations such as EORTC Soft Tissue and Bone Sarcoma Group can initiate the rare tumor registries and establish an open database. More international clinical trials like STRASS and TOLERANCE should be carried out to explore new treatment options for UUS.

Conclusions

UUS are a rare group of tumors with an aggressive behavior and poor outcomes. A majority rapidly develops distant metastases despite surgical resection.