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© 2001 American Society for Clinical Oncology Prognostic Factors in Localized Primary Synovial Sarcoma: A Multicenter Study of 128 Adult PatientsFrom the French Federation of Cancer Centers Sarcoma Group, Paris, France. Address reprint requests to Martine Trassard, Laboratoire d’Anatomie et Cytologie Pathologiques, Centre René-Huguenin (Directeur: Pr J. Rouëssé), 35 rue Dailly, 92210 Saint-Cloud, France; email trassardmcrh{at}yahoo.com
PURPOSE: To identify most significant and therapeutically relevant prognostic factors in adults with localized primary synovial sarcomas (SS) and to confirm the usefulness of the French Federation of Cancer Centers (FNCLCC) grading system, the prognostic impact of which has been already proven in soft tissue sarcomas. PATIENTS AND METHODS: Data on 128 patients with nonmetastatic SS collected from a cooperative database by the FNCLCC Sarcoma Group between 1980 and 1994 were studied retrospectively. Immunohistochemistry was performed at diagnosis in 77 cases (61%). The tumors were classified as biphasic (n = 45), monophasic fibrous (n = 72), and poorly differentiated (n = 10) subtypes. Histologic grade was determined according to the FNCLCC method, and vascular invasion was assessed in every case. RESULTS: The 5-year disease-specific survival (DSS) rate for this series of patients with localized SS was 62.9% (± 9.6% [SD]) with a median follow-up time of 37 months (range, 8 to 141 months). In multivariate analysis, the adverse risk factors associated with decreased DSS were International Union Against Cancer/American Joint Committee on Cancer stage III/IVA disease, male sex, and truncal tumor locations. For metastasis-free survival (MFS), disease stage III/IVA, tumor necrosis, and monophasic subtypes were the major factors associated with a less favorable prognosis. Separately, when not using disease stage, tumor necrosis, and mitotic activity, histologic grade became the most significant prognostic factor for both DSS and MFS. In addition, larger tumors and older patients become associated with a significantly worse prognosis. Independent adverse risk factors for local recurrence–free survival included histologic grade 3 and truncal tumor location. CONCLUSION: These data confirm that not all SS present the same severe outcome. High-risk patients identified on the basis of these parameters may qualify for an aggressive treatment approach.
SYNOVIAL SARCOMAS (SS) account for approximately 8% of soft tissue sarcomas (STS) and most frequently occur in adolescents and young adults. SS are relatively rare tumors, which explains that previous reports involve a limited number of cases. Moreover, monophasic fibrous and poorly differentiated SS were probably previously underdiagnosed by standard histologic methods. During the last 20 years, new diagnostic methods such as immunohistochemistry have been used to assess diagnosis in most cases.1 SS has traditionally been considered to present a poor prognosis. However, in recent years, it has emerged that all SS did not share the same severe outcome. Furthermore, cytogenetic techniques have shown that certain molecular genetic features were related to the course of the disease and thus present a prognostic significance of this malignancy.2-4 The Sarcoma Group of the French Federation of Cancer Centers (FNCLCC; 11 participating institutions) initiated a retrospective cooperative study on a database with systematic pathologic reviews. A total of 1,345 adults with STS were studied from 1980 to 1994. In this study, we analyzed all available clinical, pathologic, and therapeutic data on 128 adults with localized SS. The aims were to describe a well-defined population with firm diagnosis of SS, identify independent prognostic factors with clinical value, and evaluate the FNCLCC grading system, the importance of which has been already demonstrated in STS.5-7
Database and Patient Selection Between January 1, 1980, and December 31, 1994, 1,345 adults with an STS were admitted to one of the 11 cancer centers (see Appendix) for the management of a first tumoral event. Clinical and pathologic data were collected by reviewing medical records at each institution and were then entered into a comprehensive database. Of these 1,345 patients, 141 (10.5%) had SS. We excluded 13 patients (9%) with metastatic disease at the time of presentation. The study group thus consisted of 128 patients with localized, primary SS of International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) 19928 stage I to IVA disease. Eighty-eight patients (69%) were referred to these cancer centers after a biopsy had been performed, after surgical removal of the tumor have been attempted. Forty patients were initially treated at one of these referral centers. Follow-up information was available for every patient. Follow-up ranged from 3 to 106 months, with a median of 7.5 years. Histologic slides of all tumors were reviewed by the pathologist subcommittee of the FNCLCC Sarcoma Group. For each tumor, one to eight slides selected by the local pathologist were jointly reviewed and discussed until a consensus was reached. Histologic typing was based on the 1994 World Health Organization9 and 1995 Enzinger and Weiss classification.10 Immunohistochemistry had been used to confirm the diagnosis of SS in 77 cases (61%). Moreover, 10 cases were cytogenetically confirmed as t(X;18) translocation–positive. More recently, using reverse transcriptase polymerase chain reaction on paraffin-embedded specimens, SYT-SSX gene fusion transcripts were detected in 88 cases. The 128 selected cases were subclassified as monophasic fibrous type (72 cases), biphasic type with distinct epithelial and spindle cell components (45 cases), and poorly differentiated round-cell type (11 cases). Histologic grade was determined according to the FNCLCC method based on differentiation, mitotic index, and necrosis.5,6 Regarding tumor differentiation, a score of 3 was automatically attributed to SS. The mitotic rate (m) was determined by counting the number of mitoses in 10 successive high-power (x400) fields (HPF) (m = 1, 0 to 9; m = 2, 10 to 19; m = 3, more than 19 mitoses). Microscopic tumor necrosis was recorded either as present or absent and as less or more than 50%. Only areas of coagulation necrosis, with or without leucocyte infiltration, were taken into account (n = 0, absent; n = 1, < 50%; n = 2, > 50%). The final grade was determined by adding the score of each factor. Three grades were defined as grade 1 (total < 4), grade 2 (total of 4 or 5), and grade 3 (total of 6, 7, or 8). All available slides were reviewed by two pathologists (M.T. and V.L.D.) to evaluate vascular invasion. Vascular invasion was defined as the presence of tumor cells within any space with an endothelial lining. The status of microscopic surgical margins was available in 89 cases (70%) and was unknown in the remaining cases. All clinical, biologic, pathologic, and therapeutic data were entered retrospectively in a single computer database.
Statistical Methods
Continuous variables were transformed into binary variables. For the continuous factor of tumor size, a cut point was determined by the method of Miller and Siegmund,11 and clinical outcome was considered as a dichotomous response variable (no failure v failure). The maximum
Multivariate analyses based on the Cox proportional hazards model14 were used to identify the most significant factors related to outcome. We used a stepwise forward selection procedure that inserts factors in turn until the regression is satisfactory. The order of insertion was determined by using the maximum log-likelihood value as a measure of the importance of factors not yet in the regression equation. The statistical significance of adding factors at each step was assessed by using the The results of the multivariate analyses are expressed in terms of relative risks derived from the estimated regression coefficients along with their 95% confidence intervals. The SAS statistical package (LIFETEST and PHREG procedures; SAS Institute, Cary, NC)15 was used for univariate and multivariate analyses.
Patients and Tumor Characteristics The distribution of clinical, pathologic, and treatment data in the overall study population is listed in Table 1. There were 54 men (42%) and 74 women ranging in age from 15 to 76 years (median, 33 years). The maximal frequency of SS was between 15 and 35 years, 32% of patients were younger than 25 years, 58% were younger than 35 years, 77% were younger than 45 years, and 92% were younger than 55 years.
Tumor locations were as follows: the extremities (97 patients, 76%), the head and neck (seven cases), the trunk and abdomen (10 cases), and the pelvis (14 cases). The lower extremities were more frequently affected than the upper extremities, and the thigh was the most common site involved (27 cases). Clinical tumor size was known in 124 cases. The median tumor size was 6 cm (range, 2 to 26 cm); the tumor was smaller than 5 cm in 37 patients (30%), between 5 and 10 cm in 74 patients (60%), and larger than 10 cm in 13 patients (10%). Six tumors (4%) were superficial, and 122 (96%) were deep (ie, infiltrating or located beneath the superficial aponeurosis). Retroperitoneal, intra-abdominal, and pelvic tumors were automatically considered deep. Neurovascular or bone invasion was present in 29 patients (19 and 10 patients, respectively). According to UICC/AJCC staging criteria, 49 patients (40%) were classified as having stage II disease, 50 (40%) were classified as having stage III disease, and 25 patients (20%) were classified as having stage IVA disease. Stage was unknown in one case. The most frequent histologic subtype was the monophasic fibrous subtype (57%), followed by the biphasic subtype (35%). Ten tumors (8%) were poorly differentiated (in the subsequent analyses, we considered together the monophasic fibrous and the poorly differentiated subtypes). The majority of tumors (55%) were grade 3. None were grade 1. The mitotic rate was high in 80 cases (more than nine per 10 HPF). Necrosis was seen in 60% of tumors. Vascular invasion was present in 15 cases (12%).
Treatment Of the 103 patients (80%) who received radiotherapy, 44 underwent simple local excision. Seventy-three patients (57%) received chemotherapy. Surgery was performed after neoadjuvant chemotherapy in 12 patients (9%) and was followed by adjuvant chemotherapy in 52 patients (41%). Five patients (4%) were treated with neoadjuvant and adjuvant chemotherapy. Four patients (3%) received palliative chemotherapy. All chemotherapy regimens included anthracycline and lasted a median of six cycles. Chemotherapy was mostly given to high-risk patients who were principally selected according to their disease stage and/or their histologic grade. Of the 73 patients treated with chemotherapy, 49 were of stage III/IVA and 50 were histologic grade 3. From 1980 to 1990, the chemotherapy regimen was cyclophosphamide, vincristine, doxorubicin, and dacarbazine. After 1990, the regimen was mesna, doxorubicin, ifosfamide, and dacarbazine, or a combination of doxorubicin and ifosfamide or high-dose ifosfamide. One hundred twenty patients (94%) were free of gross disease at the end of initial treatment, with apparent local tumor control. Forty-nine patients (38%) died as a result of their malignancy. Metastatic disease was observed in 61 patients (48%), local recurrence in 30 patients (24%), and simultaneous local and metastatic recurrence in 25 patients (20%). The median time to local recurrence was 19 months (range, 3 to 106 months), and the median time to metastasis was 20 months (range, 1.5 to 114 months). The metastatic sites observed were the lungs (48 cases), locoregional lymph nodes (nine cases), bone (six cases), brain (three cases), liver, pleura, and peritoneum (one case each); other sites were involved in three cases and 10 had multiple concomitant metastatic sites. The median time to cancer-specific death was 37 months (range, 8 to 141 months).
Relationships Among Tumor Characteristics
Analysis of Prognostic Factors
DSS.
Univariate analysis showed that the adverse prognostic factors individually associated with decreased DSS were male sex, tumor size The overall DSS rates according to histologic grade and vascular invasion are shown in Figs 1 and 2, respectively. The results of the Cox model are listed in Table 2.
The most important adverse prognostic factor was UICC/AJCC stage III or IVA, followed by sex (male sex) and truncal location. The other factors did not provide further significant prognostic information after these factors had been considered. After removing from the set of candidate variables the factors that depend on tumor size and/or histologic grade (eg, UICC/AJCC stage, tumor necrosis, and mitotic activity), the independent risk factors for DSS identified by Cox analysis were histologic grade, tumor location (truncal v distal), sex, age at diagnosis (years), and tumor size (centimeters) ( Table 3).
MFS. Univariate analysis of MFS showed that unfavorable prognostic factors were tumor size (  9 cm), UICC/AJCC stage III or IVA, high histologic grade (3), vascular invasion, tumor necrosis, high mitotic activity (> nine per 10 HPF), invasion of neurovascular structures, and positive surgical margins. Figures 3 and 4 show the overall MFS rates according to histologic grade and vascular invasion, respectively. In Cox analysis, three independent factors were found to adversely affect MFS, namely UICC/AJCC stage III or IVA, tumor necrosis, and the monophasic fibrous subtype (Table 2).
When UICC/AJCC stage, tumor necrosis, and mitotic activity were removed from the set of candidate variables, only histologic grade and tumor size (in centimeters) had a statistically significant impact on MFS after stepwise selection (Table 3). LRFS. Table 4 shows the distribution of local recurrences followed by cancer-specific deaths according to the type of primary surgical local treatment. Simple local excision was followed by more local recurrences (36%) and cancer-specific deaths (30%) than was wide tumor resection (16% and 12%, respectively). The differences between the two types of local treatment were statistically significant, whatever the outcome.
In univariate analysis, the following factors had a significant adverse impact on LRFS: UICC/AJCC stage III or IVA, histologic grade 3, and high mitotic activity (> nine per 10 HPF). Tumor necrosis had borderline significance (P = .06). Surgical margins status showed no significant correlation with LRFS. Figure 5 shows the overall LRFS rates according to histologic grade. In Cox analysis, the independent unfavorable risk factors for LRFS were histologic grade 3 and truncal tumor location (Table 2).
The aim of this study was first to identify classical prognostic factors with clinical relevance in a large series of localized SS in adult patients and then to confirm the usefulness of the FNCLCC grading system, the prognostic impact of which has been already proven in STS by previous reports.5-7 Numerous studies over the years have shown that SS is a high-grade malignancy with a high metastatic rate, with 5- and 10-year survival rates of 24% to 76% and 11% to 56%, respectively.16-30 In our study, the 5-year DSS rate was 62.9% (± 9.6% [SD]). Early local recurrence and distant metastasis were observed at a median of 19 months and 20 months after diagnosis, respectively. As in other types of STS, metastases typically were reported to occur in the lungs, but regional lymph nodes were involved in more than 20% of cases,18 a figure far higher than in most other forms of STS. In our series, the metastatic site was the lungs in 48 cases (37%), followed by the lymph nodes in nine cases (7%). Approximately 30% of SS occur in the first two decades of life. In this series, the median age was 33 years, and the maximal frequency of SS was in the first and second decades of our age range (15 to 76 years). In previous studies, 60% to 70% of cases involved the lower extremities, followed by the head and neck region and the anterior abdominal wall. In the current study, lower extremities were more frequently involved than upper extremities, and the thigh was the more common site (27 cases). The vast majority (96%) of these tumors were deep-seated. Comparison of different prognostic studies, especially older ones, is hindered by the use of different statistical methods and histologic diagnosis criteria and by differences in tumor location, tumor size, histologic grading methods, age distribution, and treatment. The present study clearly demonstrates that the UICC/AJCC stage, tumor size, histologic grade (including tumor necrosis and mitotic activity), vascular invasion, and pathologic resection margins influenced DSS and MFS when taken separately. Age at diagnosis, tumor location, histologic subtype, bone invasion, and type of treatment did not affect outcome when examined singularly without reference to other factors. We also found a significant influence of sex on DSS. LRFS was influenced by stage, histologic grade, and mitotic activity. Tumor size is a well-recognized prognostic factor in STS,5,7,31-33 and this was confirmed by the present study. Previous studies that focused specifically on SS have shown that size is an important predictor of survival.16,17,21,24,27,29,30,34,35 Outside the staging system, tumor size was not an individually significant predictor of LRFS, but it remains nevertheless a valuable prognostic determinant, regardless of the end point, after adjusting for the effects of the other variables, especially histologic grade. Mitotic activity was another individual prognostic factor in our SS series. Patients with tumors presenting more than nine mitoses per 10 HPF were associated with a significantly poorer outcome prognosis than their counterparts with nine or fewer mitoses per 10 HPF. Enzinger et al,10 using a method different from ours, have also found that the mean mitotic activity was an important prognostic factor in SS.25,27,36-38 However, the mitotic rate was not an independent predictor of outcome in our study, as opposed to that observed by El-Naggar et al.34 The significance of the mitotic index is supported by studies on DNA ploidy and proliferation markers (PCNA and Ki67).16,37,39,40 Extensive tumor necrosis is a strong predictor of poor outcome in STS,33,38,41-43 including SS.25,37 In our study, less than 50% tumor necrosis was present in 77 tumors (60%) and reached more than 50% in five tumors (4%). Although tumor necrosis was an individual prognostic factor regardless of the end point (DSS or MFS), our multivariate analysis only confirmed its influence on MFS. Patients with extensive tumor necrosis were more likely to develop distant metastasis, as already shown.16 Histologic grade in this study was based on the mitotic index and tumor necrosis, because the differentiation score remains unchanged (ie, score 3). When examined individually, histologic grade is a valuable prognostic factor whatever the end point (DSS or MFS), and grade 3 lesions had the worst prognosis. This association was not found by Singer et al,28 but he used a different grading method. Our findings corroborate the results of other studies using the same grading method for STS.5,7,44 We found that histologic grade was an independent predictor of DSS, MFS, and LRFS. High grade identifies significantly high-risk patients. Indeed, the 5-year DSS rates were 80% and 50% among patients with grade 2 and grade 3 tumors, respectively, and the difference was even larger beyond 5 years. Clear surgical margins in STS have been found to influence local control of the tumor.33,44,45 In this series, in the subset of 89 patients with histologically well-documented pathologic margins, univariate analysis showed that microscopically positive surgical margins were associated with shorter DSS and MFS, but not with LRFS, confirming a previous study.17 However, the majority of cases treated with local marginal excision with or without positive margins have been, when technically possible, surgically re-excised. Moreover, almost all of these patients have received complementary radiotherapy. Actually, our positive-margin patients were less likely to have tumors exceeding 8 cm and truncal tumor locations. However, when local initial surgical treatment was taken into account, the difference between local excision and wide tumor resection became significant for LRFS (P = .007), as in other forms of STS33 and in other series of SS.16,27 Except for LRFS, vascular invasion (as determined microscopically) was an unfavorable prognostic factor in SS, but its predictive value disappeared in the multivariate analysis. It is noteworthy that some morphologic features, such as the histologic subtype of SS and the proportion of epithelial-like structures (previously considered to be prognostically significant), were not correlated with the outcome in our series. As in several previous studies,17,24,25,27,29,31,37 we failed to find a statistical difference between the biphasic and monophasic fibrous forms of SS in terms of survival. Patients with poorly differentiated round-cell SS, which are generally associated with a dismal prognosis,17,30 were too few in number for statistical analysis in our series. Conflicting data have been reported on the prognostic value of sex, age at diagnosis, tumor location, and type of treatment. We observed a trend toward better DSS in women compared with men. However, this was statistically significant for only DSS in both univariate and multivariate analysis. Other series have shown no significant survival difference according to sex,17,25,32,36,37 with the exception of Moberger et al,24 who reported a more favorable prognosis in women. Several studies have demonstrated better survival with younger age at diagnosis.24-26,29,46 Our univariate analysis showed no statistically significant difference, whatever the end point, when patients 33 years of age or younger (the median age) were compared with those older than 33 years, confirming other reports.17,20,27,36 However, when expressed as a continuous variable, increasing age was an independent adverse prognostic factor for DSS. Some authors explain this age-related unfavorable influence in terms of biologic and immunologic factors, age-dependent resistance to adjuvant chemotherapy, and so on.47 In univariate analysis, although we failed to find a significant difference in survival according to the tumor location (extremities v trunk), we nevertheless observed a trend toward increased survival among patients with distal extremity tumors, in keeping with Moberger et al24 and Roth et al.27 After adjusting for the effects of other factors, tumor location became an independent prognostic indicator for LRFS and DSS. This may be explained by the correlation between tumor location and size (proximal located tumors were usually larger) and the difficulty in achieving tumor-free surgical margins. Our results corroborate the findings of other series of STS, including SS.10,45 As previously reported by others,26,46 we found that radiotherapy did not influenced local control or overall survival in SS. The value of radiotherapy was difficult to assess, as postoperative radiotherapy was not randomized. The role of adjuvant and neoadjuvant chemotherapy in the treatment of SS is controversial. Conflicting objective response rates have been reported. In our series, we failed to observe a significant improvement in patient outcome when chemotherapy was used.17,24,26,27 However, the chemotherapeutic protocols used were heterogeneous and the numbers of patients in each category were too small for statistical analysis. As there were different regimens and drugs used, we have chosen to analyze the patients together rather than to individualize them by their drug protocols. Nevertheless, one study48 has shown that intensive neoadjuvant and/or adjuvant chemotherapy could improve overall survival and DSS in SS. These results may be misleading, and the results of their small series certainly must be confirmed. In conclusion, numerous studies have shown that SS is a high-grade malignancy with a high risk of metastatic dissemination. Many series of SS were too small for multivariate analysis, and in most of them, only a limited number of potential prognostic factors were examined. In our series of 128 SS, UICC/AJCC disease stage is the most important predictive independent variable for both DSS and MFS. After removing stage along with tumor necrosis and mitotic index from the analysis, FNCLCC histologic grade becomes the most powerful discriminant prognostic factor for the three outcomes studied. This grading system, combining two significant parameters, namely tumor necrosis and mitotic index, is able to separate SS adult patients into two groups with clearly different outcomes. We thus confirm that SS patients do not all have the same dismal prognosis. Identification of patients at a high risk of metastasis should allow a better selection for more aggressive treatment.
APPENDIX
Supported by a grant from the Ligue Nationale Contre le Cancer, Hauts de Seine, France. We thank Brigitte Martin for her excellent typing of the manuscript and Véronique Picot for her technical assistance.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 statistic was obtained for a cut point set at 8 cm, with failure taken as relapse. For the test based on the usual 
nine per 10 HPF) were no larger than 8 cm. A borderline link was found between sex and tumor location (lower v upper extremities) (P = .050). Of the 97 tumors located in the extremities, 55 such patients (57%) were women, and 48 of these (87%) had their tumor located in the lower extremities. 
