Since synovial sarcoma constitutes a minority of cases of an already rare disease (STS), it has been difficult to definitively characterize the unique behavior, prognostic factors, and outcome with multimodality therapy among patients with this histology. Of the retrospective studies that have examined the natural history of this disease, size has clearly emerged as the dominant predictor of outcome.5, 7–12
However, controversy exists regarding the relative influence of other prognostic variables, including age7
, neurovascular invasion10
, mitotic rate11
, and type of fusion transcript14, 23
Our study identified size and site as significant predictors of DSS and DRFS on multivariate analysis (although there was only a trend toward statistical significance for lower extremity tumors relative to upper extremity for both DSS and DRFS). Although Trassard13
found truncal location to be adversely associated with DSS but not metastasis-free survival, the current study is the first study to demonstrate that primary tumor location is associated with DSS and DRFS differences even after adjusting for size.
In the current series, SYT-SSX fusion transcript data were available for 52% of patients, and largely reflects the patients who were diagnosed later in the study period and/or those who had their definitive resection performed at our institution, providing sufficient material for molecular analysis. In the subset of patients with available fusion transcript data, SYT-SSX1 was independently associated with an increased risk of early distant recurrence after adjusting for tumor size and location (p=0.02) but was not associated with an increased risk of DSS (p=0.8). In the present study we confirmed a significant association between fusion type and patient sex with SYT-SSX1 and SYT-SSX2 cases having a male to female ratio of 1.7:1 and 0.6:1, respectively. Most large studies have observed that synovial sarcoma among women is twice as likely to contain the SYT-SSX2 fusion type compared to those arising in men.12, 23, 24
Histologic subtype was also associated with fusion type. Biphasic tumors predominantly demonstrated the SYT-SSX1 fusion type. In a prior study from our institution of 45 synovial sarcoma patients (39 localized, 6 metastatic), patients with the SYT-SSX1 fusion type had a significantly shorter DRFS than patients with SYT-SSX2.14
These findings were subsequently confirmed in a large multi-institutional analysis of 243 patients.12
The present study suggests that fusion type is more important in early (<3 year) distant recurrence and that late recurrence is largely dependent on tumor size and location. Other investigators have made different observations. A study of 141 patients with localized synovial sarcoma employing the 3-tier Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system found histologic grade, and not fusion type, to be a significant predictor of DSS and DRFS on multivariate analysis.23
Using a grading system similar to the FNCLCC, Takenaka et al. observed tumor size but not fusion transcript type to be prognostic for both OS and DRFS in 91 patients with localized disease.24
Although retrospective analyses are important to identify factors independently associated with prognosis, they are limited in their ability to provide survival estimates for individual patients. Nomograms are increasingly accepted as models in which identified prognostic factors can be incorporated into a scoring system and used to predict likelihood of DSS. These statistically based tools not only use the factors included in a clinical staging system, but may also incorporate additional factors suspected to have an impact on outcome. A postoperative nomogram calculating 12-year DSS for all patients with resected STS has previously been published with the goal of providing more individualized patient counseling for follow-up scheduling and consideration for additional therapy or clinical trials.20
We provide a synovial sarcoma specific nomogram based on preoperatively known clinical and pathologic variables. Although the only independent determinants of outcome were size and location, we also included depth and histologic variant in the nomogram because of their ability to incrementally enhance the prognostic value of the nomogram. This nomogram demonstrates the magnitude of the risk of sarcoma death as well as the variability in survival estimates that exist among individual patients with synovial sarcoma. For example, with a deep, monophasic tumor of the lower extremity, a 5 cm tumor has a favorable predicted 3-year survival of 85% and 5-year survival of 82%. However, this predicted survival drops significantly to 73% at 3 years and to 64% at 5 years if the tumor increases to 8 cm in size. For a 10 cm tumor, the predicted survival is 65% at 3 years and 55% at 5 years. The generic postoperative sarcoma nomogram provides the same 12-year estimate for DSS of 71% for all these hypothetical patients since tumor size is grouped by increments of 5 cm. Similarly, for a 15 cm deep, biphasic synovial sarcoma of the thorax, the synovial specific nomogram estimates a 3 and 5-year survival of 25% and 15%, while the generic sarcoma nomogram estimates a 12-year DSS of 28%.
We chose to focus on 3- and 5-year time points for this synovial specific nomogram since decisions regarding adjuvant/neoadjuvant chemotherapy are typically based on shorter term estimations of recurrence and death. This makes direct comparisons between the synovial specific and generic sarcoma nomograms difficult. Given the confidence intervals for the respective nomograms, the differences between nomograms may represent less pronounced true differences. Nevertheless, it is noteworthy that the synovial specific nomogram predicts a more favorable survival than the generic sarcoma nomogram for the low risk patient and a worse survival for the higher risk patients. Ultimately, the synovial sarcoma specific nomogram may prove to be a more sensitive tool for predicting outcome, consistent with the idea that sarcomas exhibit unique patterns of recurrence and mortality depending on histologic type.
The synovial sarcoma specific nomogram may also allow more informed decision-making with regard to risk, particularly for the typical size cutpoints clinicians use for consideration of neoadjuvant chemotherapy. For example, most clinicians would consider a young patient with a 5 cm synovial sarcoma a potential candidate for systemic chemotherapy (www.nccn.org/professionals/sarcoma
). From the synovial sarcoma nomogram (), it is evident that the 3-year DSS can vary significantly for a 5 cm tumor. A hypothetical patient with a deep, 5 cm, biphasic synovial sarcoma of the trunk has a total point score of 93. According to the synovial sarcoma nomogram, this corresponds to a 3-year sarcoma-specific survival of 68%. In contrast, another hypothetical patient with a superficial, 5 cm, monophasic synovial sarcoma of the upper extremity has a total point score of 46. This corresponds to an estimated 3-year sarcoma-specific survival that exceeds 90%.
Based on these risk assessments, although both hypothetical patients have 5 cm tumors, it would be reasonable to consider neoadjuvant or adjuvant ifosfamide-based chemotherapy for the first patient, while it would be difficult to justify it for the second since it is difficult to improve significantly on the excellent predicted outcome for this patient by the addition of chemotherapy. Thus, this synovial sarcoma specific nomogram enables the patient and physician to make more informed decisions regarding neoadjuvant/adjuvant chemotherapy based on assessment of predicted risk for an individual patient rather than employing traditional size cutpoints alone.
Our non-randomized data also lend support to the premise that AI-based chemotherapy is associated with improved survival in synovial sarcoma patients resected with curative intent.5
When comparing the DSS predicted by the nomogram constructed from non-AI treated patients to the observed survival for AI-treated patients, controlling for other factors, the DSS for patients treated with AI chemotherapy was greater than that predicted by the preoperative nomogram for the first 3 years following diagnosis (). After 3 years, the nomogram-predicted survival was no longer statistically different from untreated patients, and after 4 years the curves converge and are essentially superimposable. It is conceivable that with longer follow-up of the AI-treated patients (median 40 months, range 8 to 140) statistically significant differences in survival may be extended. However, it may be that there is a time-varying effect to AI-chemotherapy with a loss of DSS benefit over time, as has been observed in other randomized and non-randomized studies of heterogeneous cohorts of STS patients.25, 26
Ultimately, the hypothesis that chemotherapy provides a survival advantage for patients with synovial sarcoma requires confirmation in randomized trials.