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) [11].
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. Morcellation is an iatrogenic, negative prognostic factor for recurrence with a threefold increase in PFS [12, 13]. An impact on OS could not consistently be shown by reviews [13–16]. 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. This data is 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, 11, 17–20].
To get a useful sample size in rare tumors at one center, long observation periods are needed [21]. Change of classifications as well as modification in histopathological work-up 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 DFS but did not correlate with OS [22]. In a Norwegian study, higher PR score was related to longer OS in a series of 147 stage I LMS tumors [23]. 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 [7]. Following German guidelines, radiation should not be performed in stage I and II tumors after complete surgical resection [9, 24]. 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 [25, 26]. 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 [27]. 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. 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 evaluation. It has been shown that sarcoma patients benefit from multidisciplinary tumor boards at specialized treatment centers including secondary pathologic review prior to treatment [28]. Blay et al. showed that patients showed longer recurrence free survival rates and a trend to longer OS when presented and discussed in a board [28]. 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) [8, 29]. Testing the use of targeted therapies, for example growth-factor-antibodies, in US is still ongoing [30–32]. 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.