Abstract
Background: The role of neoadjuvant chemotherapy for localized synovial sarcoma is still controversial. This study aimed to explore the influence of neoadjuvant chemotherapy combined with surgery in localized synovial sarcoma through analysis of our hospital's patient records. Patients and Methods: A total of 122 patients diagnosed with synovial sarcoma were enrolled in this study from January 1980 to December 2016 at the Cancer Institute Hospital of The Japanese Foundation for Cancer Research. The impact of neoadjuvant chemotherapy on overall survival was assessed to show how clinicopathological factors (e.g. age, tumor size, treatment, dose intensity, pathological pattern and histological grading) influenced patient prognosis. Results: Among 106 patients, 76 (71.7%) received neoadjuvant chemotherapy and 30 (28.3%) did not. The median follow-up was 39.2 (range=12-286) months. The 5-year and 10-year overall survival rates were 65.4% and 58.4% respectively. The tumor size and histological grade influenced the patient's overall survival (p<0.05). Among the patients with grade 2 tumor, tumor size did not influence prognosis. Neoadjuvant chemotherapy improved the overall survival of patients who had grade 3 tumors. Conclusion: Treatment with neoadjuvant chemotherapy proved beneficial for high-risk patients with grade 3 synovial sarcoma but was not effective for those with low-risk and grade 2 tumor. Tumor size and histological grade were important factors in patient prognosis but had no connection with pathological patterns.
Synovial sarcoma is a high-grade malignant tumor, it accounts for approximately 5-10% of all soft-tissue sarcomas, and mainly develops in the para-articular regions in adolescents and young adults (1). The combination of surgery and chemotherapy has resulted in about a 60% 5-year survival rate (2, 3), but the 10-year survival rate remain surprisingly low. Therefore, identification of appropriate therapy for this sarcoma type is urgently needed. Neoadjuvant chemotherapy is commonly performed for high-grade soft-tissue sarcoma to reduce the risk of local and metastatic recurrence (4). Compared with other soft-tissue sarcomas, synovial sarcoma is considered to be a chemosensitive tumor. As evidenced by the results of clinical trials conducted on adult (5-8) and pediatric (9, 10) patients. However, in previous studies, it has been reported that several factors influenced the prognosis of patients with synovial sarcoma. Treatment using neoadjuvant chemotherapy in patients with resectable synovial sarcoma remains controversial.
Synovial sarcoma is characterized by a chromosomal translocation between chromosomes 18 and X, generating oncoproteins such as synovial sarcoma translocation, chromosome 18–synovial sarcoma X chromosome breakpoint 1 and 2 (SS18–SSX1 and SS18–SSX2) (11, 12). This translocation is present in greater than 95% of cases and is likely to be the oncogenic driving event in the development of this tumor (6). Pathologically, synovial sarcoma is mainly divided into two types: monophasic and biphasic. According to The French Federation of Comprehensive Cancer Centers (FNCLCC) grading system, by tumor differentiation score, this tumor is classified either as histological grade 2 or 3 (13).
Our study sought to clarify the prognostic factors or the influence of neoadjuvant chemotherapy for patients with resectable synovial sarcoma. To analyze the influencing factors for the prognosis of patients with this tumor type, 106 patients with resectable synovial sarcoma were enrolled in a single-center study over 35 years and the overall survival rate was assessed.
Patients and Methods
A total of 122 patients diagnosed with synovial sarcoma were enrolled in this study from January 1980 to December 2016 at the Cancer Institute Hospital of The Japanese Foundation for Cancer Research. Clinical and pathological data were collected retrospectively by reviewing medical records at our Institution, with the last follow-up conducted in January 2018. The inclusion criterion confirmed pathological diagnosis by a pathologist from our Institution through histological characteristics of the biopsy specimen and immunohistochemistry. Sixteen patients were excluded due to the following criteria: Metastatic disease at the time of diagnosis; no surgical treatment of the primary region. The histological grade was determined according to the FNCLCC grading system (13). The tumors were classified as either grade 2 or grade 3, and the histological grade depended on the mitotic rate and the existence of necrosis. This research was approved by the Institutional Review Boards of the affiliated institutions. Informed consent was given by patients for use of their medical records and all patient data were anonymized.
chemotherapy drugs, dosage and administration used in this study.
Treatment. The treatment implemented for synovial sarcoma was wide resection and neoadjuvant chemotherapy. When the tumor had infiltrated important nerves and vessels, and wide resection would not guarantee the patient's safety after surgery, amputation was the preferred treatment. The patients receiving neoadjuvant chemotherapy received one to two treatment courses prior to surgery, and one to six treatment courses after surgery. The specific methodology of the chemotherapy course was made according to the tolerance of the patients to medications or response of the tumor after chemotherapy. The patients were treated using adriamycin or ifosfamide; the dose, administration method, and administration time of these chemotherapy drugs were principally based on the protocol shown in Table I.
Statistical analysis. The data from medical records was collected from January 1980 to 28 December 2016, from the Cancer Institute Hospital of The Japanese Foundation for Cancer Research. Comparisons between groups of measurement data with normal distributions were analyzed by the chi-squared test. Survival rates were estimated from the day of surgery for those who did not undergo neoadjuvant chemotherapy, and the date of starting such therapy for those who did, with the use of Kaplan–Meier survival curves and log-rank test. All statistical tests were bilateral. The data was analyzed by SPSS 21.0 (IBM, Armonk, NY, USA).
Results
Baseline information of patients. There were 106 patients, with an average age of 39.1 (range=12-77) years in this study. The average size of the tumors was 5.9 (range=1.0-22.5) cm. Overall, 48 patients had tumors smaller than 5 cm. The tumor sites of involvement were mostly in the lower limb (61.7%). Of the 106 patients, 71.7%) received neoadjuvant chemotherapy and most (94.3%) underwent wide resection, although six patients (5.7%) underwent amputation due to the tumors invading important vessels and nerves. Baseline information of patients is shown in Table II.
Baseline information of study patients.
Treatment outcome. The median follow-up time was 39.2 months (range=12-286 months). At the last follow-up, 74 patients were still alive and 32 patients had died. Among those who had died, 30 died due to pulmonary metastasis and the remainder due to other reasons. The 5- and 10-year OS rates were 65.4% and 58.4% respectively (Figure 1).
Kaplan–Meier curve of overall survival for the whole patient cohort. The 5- and 10-year overall survival rates were 65.4% and 58.4%, respectively.
Influencing factor for prognosis. Tumor size and histological grade significantly influenced OS (p<0.05). The 5- and 10-year OS rates of those with tumors of 5 cm or more in size were worse than those of patients with tumor less than 5 cm (51.9% and 41.0% vs. 82.1% and 78.4%, respectively (p=0.0001; Figure 2A). A larger tumor size resulted in poor prognosis in patients with grade 3 tumor (p=0.043; Figure 2B), but had no influence on the prognosis of those with grade 2 tumor (Figure 2C). The OS of patients with grade 3 tumor was significantly worse than that of those with grade 2 tumor (Figure 3A). Neoadjuvant chemotherapy did not improve the 5- and 10-year OS of patients with grade 2 tumor but did improve that of those with grade 3 tumor, although not statistically significantly (Figure 3B and C). Moreover, although neoadjuvant chemotherapy did not improve the OS of those with monophasic-type tumor, in patients with grade 3 tumor, OS was improved for those with monophasic-type disease (Figure 4). Furthermore, neoadjuvant chemotherapy improved the prognosis of patients with a smaller grade 3 tumors (Figure 5), which indicated that patients with grade 3 tumor benefited from the use of neoadjuvant chemotherapy regardless of the tumor size.
Discussion
The most common treatment for synovial sarcoma that results in favorable prognosis is considered to be a surgery. However, the information on surgery-combined treatment is not available. To elucidate whether clinicopathological characteristics and neoadjuvant chemotherapy are correlated with survival in patients with synovial sarcoma is the reason this study was performed. This study clearly found that in the 106 patients with synovial sarcoma, factors such as histological grade, tumor size and neoadjuvant chemotherapy influenced the patients' prognoses. Furthermore, neoadjuvant chemotherapy for synovial sarcoma with histological grade 3 was found to be beneficial for patients.
Kaplan–Meier curve of overall survival according to tumor size (A) and in combination with tumor grade 2 (B) and 3 (C). Considering the whole cohort, tumor of more than 5 cm in size resulted in poor survival duration. Tumor size influenced the prognosis of patients with grade 3 tumor, but not that of those with grade 2 tumor.
In the 1990s, the 5-year OS of patients with synovial sarcoma was 40-76% (14-16). There were many recent studies on local synovial sarcoma without metastasis. Shi et al. reported that the 5-year OS was 61% in a single-institution follow-up study (17); Ferrari et al. reported corresponding OS of 64.3% (8). In this study, the 5-year OS was 65.4%, which was consistent with those of the previous studies.
Kaplan–Meier curve of overall survival of patients with grade 2 or 3 tumor (A) and in those in combination with neoadjuvant chemotherapy (B and C). Patients with grade 3 tumor had a significantly worse prognosis. Neoadjuvant chemotherapy tended to improve the prognosis of patients with grade 3 tumor but not that of those with grade 2 tumor.
Although synovial sarcoma is considered a chemosensitve disease (5-8), the role of neoadjuvant chemotherapy in local synovial sarcoma is still controversial. Eilber et al. reported that the 4-year OS of patients receiving chemotherapy was 88%, compared with 67% of patients who did not (18). However, a recent pooled analysis of the two largest randomized trials which assessed the role of adjuvant chemotherapy in sarcoma (EOTOC 62771 and 62931) showed that no benefit of adjuvant chemotherapy was observed in the group of 108 patients with synovial sarcoma (19). A large Italian single-institution study also showed that neoadjuvant chemotherapy did not improve survival in patients with local synovial sarcoma despite the use of high-dose combination regimen (9 g/m2 ifosfamide, 80 mg/m2 doxorubicin) in the majority of treated patients (20). In our study, neoadjuvant chemotherapy improved OS in those with grade 3 tumor, although the difference was not significant. In patients with grade 2 tumor, neoadjuvant chemotherapy did not improve the survival time. Moreover, the tumor size had no influence on prognosis in patients with grade 2 tumor. These results show that neoadjuvant chemotherapy tended to be especially beneficial for high-risk patients with histological grade 3 synovial sarcoma and improved their prognosis and controlled distant metastasis.
Kaplan–Meier curve of overall survival of patients with monophasic type tumor (A) and in combination with neoadjuvant chemotherapy (B). Neoadjuvant chemotherapy did not improve the overall survival of patients with monophasic-type tumor, however, of the patients with grade 3 tumor, it improved survival of those with monophasic-type disease.
Kaplan–Meier curve of overall survival of patients with grade 3 tumor <5 cm in size. Neoadjuvant chemotherapy improved the prognosis of patients with a smaller grade 3 tumor although not significantly.
Tumor size is one of the important factors influencing prognosis in synovial sarcoma (2, 8, 17, 21, 22). In our study, a larger tumor size resulted in worse prognosis, however, tumor size was not a prognostic factor for low-risk patients with grade 2 tumor.
It is still controversial whether the pathological pattern (monophasic or biphasic type) influences the survival time (16, 23-25). Our study showed that there was no significant difference in survival time between the two groups.
Limitations of this study are as follows: (i) Our study was a retrospective study and the conclusion needs further prospective study; (ii) more cases are needed, therefore, a larger sample would be conducive to further verification. Because this was a single-center study, there might have be inconsistency in treatment and management of the patients. Despite these, we believe that our conclusion has great clinical significance for understanding the prognosis of this rare tumor.
Acknowledgements
The Authors thank members of our Department for helpful discussions.
Footnotes
Authors' contributions
Yusuke Minami designed the study, and wrote the initial draft of the article. Yusuke Minami also contributed to analysis and interpretation of data, and assisted in the preparation of the article. All other Authors have contributed to data collection and interpretation, and critically reviewed the article. All Authors approved the final version of the article, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflicts of Interest
None declared.
- Received November 28, 2019.
- Revision received December 13, 2019.
- Accepted December 17, 2019.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
