Prognostic factors and survival of patients with uterine sarcoma: a German unicenter analysis

Uterine sarcoma (US) is a very rare mesenchymal tumor entity with an incidence of 3% of all uterine malignancies [1‐3]. It appears more frequently in women over 50 years of age.

The World Health Organization (WHO) classification system of 2014 divides US in four subtypes: leiomyosarcoma (LMS), low- and high-grade endometrial stromal sarcoma (LG-ESS and HG-ESS), undifferentiated uterine sarcoma (UUS) and adenosarcoma (AS) [4]. LMS is the most common with 60–70%, low and high-grade ESS as well as UUS are each diagnosed in 10%, AS and heterologous sarcomas in 5% [5]. Prognosis of US is poor with 70% tumor recurrence and 5-year overall survival (OS) rates around 40% [5, 6]. Diagnosis of this tumor entity is generally late due to unspecific early symptoms, resembling uterine myoma or adenomyosis. In more than half of all cases, the finding of US is incidental [7]. Neither curettage nor preoperative imaging are able to securely exclude US [5, 8]. Primarily treatment is surgical, including hysterectomy without morcellation together with bilateral adnexectomy and in advanced stages complete cytoreduction. Systematic lymphadenectomy is not mandatory. So far, no adjuvant therapy could show convincing benefit on patients’ survival. For LG-ESS with positive hormonal receptor status adjuvant endocrine therapy is offered. Close postoperative follow-up care, consisting of gynecologic examination and sonography, is mandatory. The histological workup and diagnosis are essential, but very often challenging. Frequently, immunohistochemically or additional molecular pathological methods as well as a reference pathological opinion are needed [9].

The aim of this study was to provide survival data and identify prognostic factors of patients with US from a German tertiary academic hospital.

57 patients with US treated between June 1999 and August 2017 with last follow-up in March 2020 were included into this study. The observation period was 250 months and the median time of follow-up was 35 months (range 4–240 months).

This is a retrospective unicenter study on 57 uterine sarcoma patients with an inclusion period of 18 years and a median follow-up of 35 months.

Age over 52 years was a negative prognostic factor for PFS and OS in the univariate analysis of the total cohort, as well as for PFS in the multivariate analysis. For LMS patients, it was statistically significant in the univariate analyses for OS. This accords to prior findings in LMS patients in the SEER database (patients under or 52 years: disease-specific survival 73.5% vs over 52 years 56.1%, p < 0.001) [10].

Preoperative diagnosis is often challenging and sometimes leads to inadequate surgical treatment. In this report, the initial malignant diagnose LMS was missed in three cases and was only diagnosed at tumor recurrence. The risk of the occurrence of unexpected LMS during hysterectomy or myomectomy for presumed benign fibroids according to the American Food and Drug Administration is 1 in 1100 women undergoing surgery [11]. According to a Dutch study, women between 40 and 50 years presenting with abnormal uterine bleeding are most at risk for unexpected LMS [12]. This aligns with the fact that patients with morcellation treatment in this study had a mean age at first diagnosis of 43.7 years. Morcellation is an iatrogenic, negative prognostic factor for recurrence with a threefold increase in PFS [13, 14]. An impact on OS could not consistently be shown by reviews [14‐17]. Three cases with initial morcellation of the sarcoma were included in our study. Subsequent staging laparotomy and hysterectomy revealed no residual tumor followed by a long OS with 99 months and all three patients still alive. These data are in contrast to other published data and might point out isolated cases in a small cohort but suggests to further investigate the value of second look laparotomy and hysterectomy.

Known prognostic factors on PFS and OS in LMS patients are tumor stage as well as tumor size, age, the amount of mitotic figures, a complete surgical resection and blood vessel invasion [5, 10, 18‐21]. To get a useful sample size in rare tumors at one center, long observation periods are needed [22]. Change of classifications as well as modification in histopathological workup over time impede retrospective analyses. In our analysis neither for the total cohort, nor for LMS patients, FIGO stage could show a significant impact on PFS or OS. PR negativity was a negative prognostic marker in our univariate and multivariate analyses for uterine sarcomas. For LMS in univariate analyses, it was a significant negative variable for both PFS and OS. This was confirmed for PFS but not for OS in multivariate analysis, though there was a trend to shorter OS. In a small 25 case study, PR as well as androgen receptor expression was associated with longer disease free survival (DFS) but did not correlate with OS [23]. In a Norwegian study, higher PR score was related to longer OS in a series of 147 stage I LMS tumors [24]. Multicenter databases with larger sample size are warranted for further investigation.

Survival benefit of adjuvant treatment of LMS was not yet shown in randomized controlled trials [5]. Following German guidelines, radiation should not be performed in stage I and II tumors after complete surgical resection [8, 25]. In these stages, adjuvant chemotherapy can be discussed with positive effects on PFS and OS incorporating toxicities based on a study with 23% carcinosarcoma patients [26, 27]. In a study by Ricci et al., neither chemotherapy nor radiation was able to lower the recurrence rate of LMS, but chemotherapy did have an impact on overall survival in stage I and II LMS patients [28]. In this study, the use of chemotherapy at any point in time during course of disease had a significant negative impact both on PFS and on OS. This could be seen for the total US cohort, as well as for LMS patients. The negative effect could not be confirmed in the multivariate analysis, therefore, chemotherapy could be a confounding factor. Given the known and strong side-effects and toxicities limiting patients’ quality of life, chemotherapy should only be administered after comprehensive patients counseling and joint decision, taking life quality and quantity into account. Further and bigger studies are needed for thorough elaboration. It has been shown that sarcoma patients benefit from multidisciplinary tumor boards at specialized treatment centers including secondary pathologic review prior to treatment [29]. Blay et al. showed that patients had longer recurrence-free survival rates and a trend to longer OS when presented and discussed in a board [29]. This highlights the need of centralized diagnostic and treatment with expert pathological departments.

Since uterine sarcomas and their recurrences are rare cases with probably unfavorable prognosis, treatment tends to individualized strategies. Consequent multicenter registration of every individual case and trial participation would be helpful to build a bigger data pool and provide treatment recommendations for the future. Such is the German registry for gynecologic sarcomas (REGSA) [7, 30]. Testing the use of targeted therapies, for example growth-factor-antibodies, in US is still ongoing [31‐33]. International cooperations as the ENGOT rare cancer group are necessary to establish international data collection and launch multinational trials on targeted therapies in rare cancers.

In this study, tumor histology, age at time of diagnosis and progesterone receptor status are significant prognostic markers in univariate analysis. Consequent and standardized immunohistopathological workup as a basis for molecular tumor boards in centralized oncological centers is worthwhile. More randomized controlled trials on adjuvant therapy are necessary to give physicians convincing treatment options especially in the recurrent situation.