Clinical and strategic outcomes of metastatic synovial sarcoma on limb

Introduction

Synovial sarcoma (SS) is an aggressive mesenchymal neoplasm with distinct uniform cytopathological features.^[1] It can occur almost anywhere and affects people of all ages, with a propensity to occur in adolescents and young adults.^[2-4] SS accounts for 5–10% of soft-tissue sarcomas in adolescents and young adults.^{[2, 5, 6]} Most cases occur at extra-articular sites in the extremities.^[7] The treatment for local SS includes wide resection and adjuvant or neoadjuvant radiotherapy, which provides a satisfactory prognosis.^[8] Although SS is moderately sensitive to chemotherapy,^[9,10] the use of chemotherapy remains controversial.^[11,12] SS is regarded as a high-grade sarcoma, characterized by local invasiveness and metastatic propensity.^[13] The lung is the most common site of SS metastasis.^[6] Patients usually have a poor prognosis if they developed metastatic disease.^[7] Metastatic limb SS (LSS) is very rare, with no standard therapy. However, the demographic, prognostic, and outcomes data of metastatic LSS are poorly documented.

Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified all patients diagnosed with LSS with metastasis at presentation from 1975 to 2016. This study first examined the clinical features of LSS patients with metastasis at presentation and confirmed the prognostic factors for this patient population, which should improve clinicians’ understanding of this disease.

Patients and Methods

Results

Multivariate analysis

We integrated variables with P < 0.1 from univariate analysis into the multivariate analysis. Results of multivariate Cox regression analysis are shown in Table 4. Tumor size <10 cm, surgery, radiotherapy, and chemotherapy showed significant survival benefits.

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Figure 1:

Kaplan–Meier plot for estimating overall survival (a) and cancer-specific survival (b) among limb synovial sarcoma patients with metastasis at presentation stratified by surgery

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Table 1:

Characteristics of 217 patients with limb synovial sarcoma and metastasis at presentation

Category	Value
Age (years)
<40	106 (48.8%)
≥40	111 (51.2%)
Gender
Female	82 (37.8%)
Male	135 (62.2%)
Tumor grade
Low	11 (5.1%)
High	104 (47.9%)
Unknown	102 (47.0%)
Tumor type
Synovial sarcoma, NOS	108 (49.8%)
Synovial sarcoma, spindle cell	71 (32.7%)
Synovial sarcoma, biphasic	37 (17.1%)
Synovial sarcoma, epithelioid cell	1 (0.5%)
Tumor size
<10 cm	61 (28.1%)
≥10 cm	102 (47.0%)
Unknown	54 (24.9%)
Surgery
Yes	141 (65.0%)
No	76 (35.0%)
Radiation treatment
Yes	88 (40.6%)
No	129 (59.4%)
Chemotherapy
Yes	161 (74.2%)
No	56 (25.8%)
Dead
Yes	179 (82.5%)
No	38 (17.5%)
3-year OS rate	27.20%
3-year CSS rate	28.30%
5-year OS rate	13.70%
5-year CSS rate	13.20%

NOS: Not other specified, OS: Overall survival, CSS: Cancer-specific survival

Table 2:

Median survival data (month) of patients with limb synovial sarcoma and metastasis at presentation

Category	OS	95% CI	CSS	95% CI
Overall	18.0±1.3	15.5–20.5	19.0±1.5	16.0–22.0
Age (years)
<40	23.0±1.9	19.3–26.7	24.0±2.2	19.6–28.4
≥8	15.0±1.9	11.2–18.8	16.0±1.4	13.3–18.7
Gender
Female	20.0±2.4	15.3–24.7	22.0±2.4	17.3–26.7
Male	18.0±1.3	15.4–20.6	19.0±1.3	16.5–21.5
Tumor grade
Low	22.0±16.0	0.0–53.4	16.0±2.0	12.0–20.0
High	19.0±2.0	15.1–22.9	23.0±3.3	16.4–29.6
Tumor type
Synovial sarcoma, NOS	16.0±1.9	12.3–19.7	16.0±2.0	12.0–20.0
Synovial sarcoma, spindle cell	22.0±3.4	15.3–28.7	23.0±3.3	16.4–29.6
Other	24.0±6.4	11.4±36.6	30.0±5.9	18.4–41.6
Tumor size
<10 cm	29.0±5.2	18.8–39.2	33.0±4.3	24.7–41.3
≥1 cm	16.0±1.1	13.8–18.2	16.0±1.2	13.7–18.3
Surgery
Yes	24.0±3.4	17.3–30.7	25.0±3.8	17.5–32.5
No	6.0±1.4	3.2–8.8	8.0±2.2	3.7–12.3
Radiotherapy
Yes	22.0±2.0	18.0–26.0	22.0±2.8	16.6–27.4
No	17.0±1.7	13.7–20.3	18.0±1.6	14.9–21.1
Chemotherapy
Yes	21.0±1.6	17.8±24.2	22.0±1.7	18.7±25.3
No	9.0±2.8	3.4±14.6	10.0±2.6	5.0±15.0

Discussion

In this study, we included 217 metastatic LSS patients from the SEER database for survival analysis. There are very few cases of metastatic LSS and few studies have documented the findings. In addition, the standard treatment for metastatic LSS is poorly documented. Tumor patients’ survival knowledge will help the clinicians in developing appropriate surgical procedures. This study is the first to reveal clinical features of metastatic LSS patients and ulteriorly explore independent predictors of survival using the public SEER database. The average and median age at diagnosis of this population was 40 years, which is almost similar to that reported by Krieg et al.,^[15] that is, 35.4 years. Therefore, LSS is also prone to affect young people, similar to the overall SS.^[8] Spurrell et al.^[9] reported that there is a slight male predominance in advanced SS from the single-center study. Male predominance was also observed in the metastatic LSS group. Metastasis was common in LSS, and the most common site is lung.^[8] Despite treatment, SS is associated with a high recurrence rate (24–29%) and metastatic rate (47–48%).^{[11, 15, 16]} Further, SS patients with metastasis at diagnosis had significant poorer OS than those with late metastasis.^[15] The 5-year OS rate of this metastatic cohort was 13.7%, which was worse than that reported by Krieg et al.^[15] of 28%. Therefore, it is essential to single out such patients for prognostic analysis. On univariate analysis, age was not a significant potential predictor of OS or CSS. Okcu et al.^[17] also found that age was not associated with survival in young SS patients. We have noted that neither gender nor tumor type was significantly related to survival time. In general, tumor grade was seen as a significant prognostic indicator of SS.^[13,18] However, our univariate analysis showed no obvious difference in either OS or CSS, based on tumor grade. Maybe metastatic LSS has its unique features. Tumor size is one of the most significant factors associated with the survival of SS.^{[8, 17, 19]} Jacobs et al.^[19] reported that the tumor size was an independent risk factor of survival for SS. Moreover, Spillane et al.^[8] reported that the tumor size was associated with the tumor stage in SS patients and hence affected survival. However, they also found that smaller SSs had an unexpectedly poor prognosis. Pappo et al.^[18] found a borderline significant relationship between OS and tumor size (P = 0.09). The present study demonstrated that tumor size ≥10 cm could independently predict worse survival in metastatic LSS patients. Although surgical resection is regarded as the mainstream treatment for LSS, evidence for the role of surgery among metastatic LSS patients still lack. Ferrari et al.^[20] found that the surgery alone is sufficient therapy for patients with adequately resected ≤5 cm SS. We found that surgery was the most significant prognostic factor for both OS and CSS based on multivariate analysis. Spillane et al.^[8] also thought that adequate local treatment might affect the survival of SS patients. Adjuvant radiotherapy is often employed in SS patients with tumor size ≥5 cm.^[17] Ferrari et al.^[21] thought that radiotherapy might improve the local control not only after wide resection but also after narrower resection. Al-Hussaini et al.^[10] showed that surgery combined with radiotherapy could prolong the survival of patients with localized SS. This research first showed the role of radiotherapy to improve metastatic LSS survival. While SS is considered to be chemosensitive, there are still controversy about the use of chemotherapy in SS.^[17] Some studies reported a survival benefit with chemotherapy among SS patients,^[22-25] while others did not observe this evidence.^[26-28] Despite considerable toxicity of high-dose ifosfamide, this regimen translated into a survival benefit among patients with metastatic SS.^[29] In fact, Ferrari et al.^[21] recommended that SS patients with tumor size >5 cm be the first to be considered for chemotherapy. This study preliminarily determined the effect of chemotherapy on prolonging the prognosis of metastatic LSS. There are some limitations to this study. First, details about local or distant recurrence after diagnosis were not documented in the SEER database, which may influence survival time. Second, some other clinical variables, such as surgical margin and chemoradiotherapy program, were not available in this database. Third, this study was a retrospective study with some bias. Despite these limitations, the SEER database is a very useful resource for studying rare tumors, such as LSS patients with metastasis at presentation.

Conclusion

Therefore, this study revealed that LSS patients with metastasis at presentation had a very poor prognosis. Combination therapy of surgery, radiotherapy, and chemotherapy may be beneficial for prolonging their survival time.