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Originally published as JCO Early Release 10.1200/JCO.2004.11.093 on September 13 2004 © 2004 American Society of Clinical Oncology. Histologic Grade, But Not SYT-SSX Fusion Type, Is an Important Prognostic Factor in Patients With Synovial Sarcoma: A Multicenter, Retrospective AnalysisFrom the University Institutes of Pathology of Lausanne, Geneva, Berne, and Basel, Switzerland; Bergonié Institute and University of Bordeaux II, Bordeaux; Gustave Roussy Institute, Villejuif; François-Baclesse Cancer Center, Caen; Léon-Bérard Cancer Center, Lyon; Georges-François-Leclerc Cancer Center, Dijon; René-Huguenin Cancer Center, Saint-Cloud, France; and Jules-Bordet Institute, Brussels, Belgium Address reprint requests to Louis Guillou, MD, Institut Universitaire de Pathologie, rue du Bugnon 25, 1011 Lausanne, Suisse; e-mail: louis.guillou{at}chuv.hospvd.ch
PURPOSE: To assess the prognostic value of SYT-SSX fusion type, in comparison with other factors, in a population of 165 patients with synovial sarcoma (SS). PATIENTS AND METHODS: Data on 165 patients with SS (141 with localized disease at diagnosis) were studied retrospectively. The following parameters were examined for their potential prognostic value: age at diagnosis, sex, tumor site (extremities v proximal/truncal), size, histology, mitotic count, necrosis, histologic grade (Fédération Nationale des Centres de Lutte Contre le Cancer system), stage (1997 tumor-node-metastasis system classification), surgical margin status (assessed histologically), and fusion type (SYT-SSX1 v SYT-SSX2). Median follow-up time was 37 months (range, 2 to 302 months).
RESULTS: Among those patients with localized disease at diagnosis, median and 5-year disease-specific survivals (DSS) for the SYT-SSX1 and SYT-SSX2 subgroups were 126 months and 67.4% versus 82 months and 63.2%, respectively (P = .12). Median and 5-year metastasis-free survivals (MFS) were 84 months and 54.2% for SYT-SSX1 versus 50 months and 47.6% for SYT-SSX2 (P = .76). Univariate analyses showed that high histologic grade (grade 3), high mitotic count ( CONCLUSION: For patients with localized SS, histologic grade but not SYT-SSX fusion type is a strong predictor of survival.
Most synovial sarcomas (SS), regardless of their histologic appearance, bear the translocation t(X;18) (SYT-SSX), which is specific for this tumor type.1 ,2 This translocation, which involves almost always the SSX1 or SSX2 gene, two closely related genes from chromosome Xp11, and the SYT gene from chromosome 18q11, results in the formation of a chimeric gene that encodes a transcription-activating protein.1-3 In a recent study,4 we showed that, using reverse transcriptase polymerase chain reaction (RT-PCR) and consensus primers for SSX1 and SSX2, fusion gene transcripts could be detected in formalin-fixed, paraffin-embedded material with an overall sensitivity of 96% and specificity of 100%. Similar results were obtained by other teams.1 ,2 ,5 In addition to its diagnostic utility, fusion type (SYT-SXX1 v SYT-SSX2) has also been proposed to be of prognostic value. In a pilot study performed in 1998 that included 45 patients with SS (of whom 39 had a localized tumor at presentation), Kawai et al6 showed that patients with SYT-SSX1 fusion type had a significantly shorter metastasis-free survival (MFS) than patients with SYT-SSX2. In addition, these authors observed that biphasic SS were almost never associated with SYT-SSX2 fusion transcripts. Those preliminary results were confirmed recently by the same team in a large multi-institutional analysis of 243 patients.7 In a recent study examining factors of prognostic relevance in SS,8 we failed to find any correlation between fusion type and patient outcome (unpublished data). Because only a limited number of cases were examined at that time, the aim of the present study was to include a larger number of patients and to compare the prognostic value of fusion type, if any, to other factors already acknowledged to be of prognostic significance in SS.
One hundred sixty-five t(X;18)-positive, nonconsecutive patients with SS were retrieved from the database of the French Federation of Cancer Centers Sarcoma Group (Fédération Nationale des Centres de Lutte Contre le Cancer; FNCLCC) and from the files of the Bergonié Institute (Bordeaux, France), the University Institutes of Pathology of Basel, Bern, Geneva, and Lausanne, Switzerland, and the files of the Jules Bordet Institute (Brussels, Belgium). Only patients for whom information on the clinicopathologic characteristics and treatment modalities of the primary tumor and for whom follow-up data were available were enrolled onto this study. Data including patient age at diagnosis, sex, the presence or absence of metastases at diagnosis, tumor site, tumor size, tumor depth, tumor histology, mitotic activity, amount of tumor necrosis, histologic grade (using the FNCLCC grading system9), American Joint Committee on Cancer/International Union Against Cancer (UICC) stage (UICC/tumor-node-metastasis system classification of malignant tumors, fifth edition, 1997),10 treatment modalities, and surgical margin status, when available, were obtained by reviewing medical records at each institution (see Acknowledgments). Limb-based tumors were defined as neoplasms of extremities only; tumors from limb girdles (eg, inguinal region, hip, buttock, shoulder, and axillary region) were considered non–limb-based.
Histologic typing and subtyping was performed on hematoxylin and eosin–stained sections, using the 2002 WHO classification of tumors of soft tissue and bone.11 Histologic slides of all tumors were viewed initially by pathologists trained in soft tissue tumor pathology (see author list). In addition, to avoid interobserver variation, between one and 15 sections per tumor event (median, two slides) were reviewed by one pathologist (L.G.). Biphasic SSs were defined as any tumor showing evidence of glandular formation, regardless of the quantity of glands. Predominantly epithelial (glandular) SSs were classified as biphasic. Monophasic SSs consisted mainly of spindle cells, round cells, or a mixture of both. Poorly differentiated morphology corresponded to areas of high cellularity, high-grade nuclear features, numerous mitoses ( RNA extraction and RT-PCR analysis were performed as previously described.4 For subtyping SYT-SSX fusion transcripts, 3 µL of each PCR product was enzymatically hydrolyzed at 65°C for 1 hour with 5 U of the restriction enzyme TaqI (Roche Diagnostics, Basel, Switzerland) in a final volume of 10 µL. The digestion patterns of the PCR products were analyzed on 2% agarose gels and visualized by ethidium bromide staining. The size of digested products were 65 and 32 base pairs for the SYT-SSX1 fusion gene transcripts, but remained at 97 base pairs for SYT-SSX2. Subtyping was determined in parallel by single-strand conformation polymorphism analysis. Aliquots of 5 µL of PCR products were mixed with 5 µL of denaturing buffer (0.1 mol/L of NaOH and 2 mmol/L of EDTA), heated at 50°C for 10 minutes. After addition of 1 µL of formamide dye, the samples were immediately loaded onto a 40% MDE gel (FMC BioProducts, Rockland, ME) and electrophoresed in 0.5 x Tris-borate EDTA buffer at 20°C and 300 V (20 V/cm) for 5 hours. The gels were stained with a SYBR Gold gel stain (Molecular Probes, Eugene, OR) diluted 1:10,000 in 1 x Tris-borate EDTA buffer and visualized under ultraviolet light using a charge-coupled device camera.
Statistical Analysis Multivariate analyses based on the stepwise Cox proportional hazards model14 were used to identify the most significant factors related to outcome. A stepwise forward selection procedure was used, and a significance level of 5% was chosen as the criterion for entering factors in the multivariate model. The results of the multivariate analyses were expressed in terms of relative risks derived from the estimated regression coefficients, along with their 95% CIs. SPSS statistical software (SPSS Inc, Chicago, IL) was used for univariate and multivariate analyses.
Patient and Tumor Characteristics Patient and tumor characteristics are listed in Table 1. Five patients were 10 years of age or younger; 18 patients were age 60 years or older. One hundred forty-one patients had localized disease at diagnosis. Non–limb-based tumors included lower limb girdle (n = 12), upper limb girdle (n = 3), trunk and abdominal walls (n = 15), head and neck (n = 6), and internal trunk (n = 17). Tumors of the internal trunk subgroup were situated in the lungs, pleura, mediastinum, peritoneum, retroperitoneum, pelvis, and perineum. Ten tumors measured  2 cm; 33 tumors were greater than 10 cm. Thirty-eight SSs (23%), including 37 monophasic and one biphasic, contained areas of poorly differentiated morphology. All neoplasms were deep-seated except one, which was 2 cm in diameter and was situated in the subcutaneous tissue of the thigh. Breakdown according to grade, stage, fusion type, and surgical margin status is shown in Table 1. Treatment modalities for 163 patients (data missing for two patients) included surgery alone (n = 43, including 16 amputations), various combinations of surgery and radiotherapy (n = 33), combinations of surgery, radiotherapy, and chemotherapy (n = 57), combinations of surgery and chemotherapy (n = 23), combinations of radiotherapy and chemotherapy (n = 3), and chemotherapy alone (n = 4). Follow-up intervals ranged from 2 to 302 months (median, 37 months; mean, 60.8 months).
Fusion transcripts were detected in 142 primary tumors (including five cases after chemotherapy and one case after radiotherapy), 14 local recurrences, and four metastases. In five additional cases, fusion gene transcripts were detected in both the primary tumor and local recurrences (n = 3), primary and metastases (n = 1), and local recurrences and subsequent metastases (n = 1); in these cases, SYT-SSX fusion types were always concordant between the different locations. SYT-SSX2 transcripts were detected in nine (19.5%) of 46 biphasic and 44 (37%) of 119 monophasic SSs (Table 2).
Relationship Between Variables Associations between SYT-SSX fusion type and other factors are listed in Table 2. A significant association between fusion type and patient sex was observed. For patients with localized disease, the male to female ratio of SYT-SSX1 cases was 1.15:1, whereas for SYT-SSX2 cases it was 1:2. SSX1 tumors tended to localize in free limbs and to be less necrotic and smaller ( 7 cm) than SSX2 SSs. Biphasic SSs were predominantly SSX1 tumors when considering all patients (P = .04).
Tumor size (
Patient Outcome and Statistical Analysis: All Patients
Patient Outcome and Statistical Analysis: Patients With Localized Disease at Presentation Fifty-eight (41%) of 141 patients with nonmetastatic disease at diagnosis died as a result of their malignancy, and 47 (34%) of 138 patients developed at least one local recurrence independently of the presence of metastases. Among the 75 patients who were considered tumor-free (ie, with microscopically negative margins by the end of the treatment of their primary tumor), 11 patients (14.6%) developed at least one local recurrence 3 to 181 months after diagnosis (median, 44 months). Sixty-five patients (46%) developed at least one metastatic event in the course of their disease. Breakdowns of survivals according to patient and tumor characteristics are reported in Table 3. SYT-SSX1 tumors tended to behave less aggressively than SYT-SSX2 SSs, although the difference was not significant (P = .12; Fig 3). This trend was no longer observed when the subpopulation of patients with free limb tumors was specifically examined (n = 99; P = .95 for DSS; P = .96 for MFS). There was no impact of fusion type on MFS (P = .76; Fig 4; Table 3).
Patients with SYT-SSX2 SS showed a significantly reduced LRFS than those with SYT-SSX1 tumors (P = .0025). Tumors with microscopically positive margins, non–limb-based tumors, and advanced-stage lesions (tumor-node-metastasis system stages II and III) were also associated with reduced LRFS (Table 3). When those patients who developed one or several metastatic events in the course of their disease were examined (n = 65), there was no difference in terms of DSS and MFS between SSX1 and SSX2 tumors (P = .83 for DSS; P = .51 for MFS). Univariate Cox proportional hazards regression models showed that high mitotic rate, presence of tumor necrosis, high histologic grade (FNCLCC grade 3), presence of areas of poorly differentiated morphology, UICC/tumor-node-metastasis system stage III, tumor size greater than 7 cm, and the presence of metastases at diagnosis were significantly associated with cancer-specific death (Table 4). Age greater than 35 years at diagnosis and non–limb-based tumor location were also, although less strongly, significantly associated with death. Fusion type (P = .087), sex, histologic subtype (monophasic v biphasic), and surgical margin status on microscopic examination were not significantly associated with disease-specific death. DSS proportions according to tumor grade, tumor size, and tumor-node-metastasis system stage are shown in Figures 5, 6, and 7 (patients with localized disease at diagnosis).
Multivariate survival analyses showed that, for patients with localized disease at diagnosis for whom information on all factors was available (n = 130), high tumor grade (FNCLCC grade 3) was the most important independent prognostic factor that adversely affected DSS and MFS (Table 5). Age greater than 35 years, which ranked second (P = .12 for DSS; P = .259 for MFS), fusion type, tumor size, tumor-node-metastasis system stage, non–limb-based location, and histology (biphasic v monophasic) were not significant prognostic factors. Poorly differentiated morphology, by definition, overlaps with histologic grade, mitotic count, and tumor necrosis (see Results under Relationship Between Variables). If histologic grade and poorly differentiated morphology were omitted from the set of variables and replaced with tumor necrosis and mitotic count, the latter was the most important predictor of reduced DSS (P = .0001), followed by free-limb location (P = .044). Tumor necrosis (P = .17), tumor-node-metastasis system stage, and age greater than 35 years were not significant risk factors. Mitotic count was the sole significant adverse risk factor associated with decreased MFS (P < .0001). By comparison, when multivariate survival analyses were performed on all patients (patients with localized and metastatic disease at diagnosis) for whom information on all factors was available (n = 152), advanced stage (stage IV; P < .0001), age greater than 35 years (P = .0019), and grade 3 disease (P = .012) were the major adverse risk factors associated with decreased DSS.
SS has traditionally been viewed as a high-grade, deep-seated sarcoma of poor prognosis. However, it has progressively become apparent that not all SSs actually share this outcome. Low-grade variants do exist,15 and many factors actually modulate patient outcome.8 ,16-18 As illustrated in this series, patients with distant metastases at presentation (stage IV) almost always have a poor prognosis, as 75% of such patients are dead within 2 years of diagnosis.7 ,15 For patients with localized disease at presentation (80% to 90% of cases), several factors have been shown to be variably associated with rapid tumor-related death, including older patient age (> 20 years19 ,20 or  25 years16), large tumor size,8 ,16 ,20-26 vascular invasion (ie, tumor inside vessels),8 invasion of bone and neurovascular structures,8 ,21 poorly differentiated histology,16 ,17 ,20 ,24 high mitotic rate ( 10 per 10 high-power fields),8 ,17 ,19 ,20 ,22-24 ,27 presence of tumor necrosis,8 ,16 ,17 ,19 ,23 ,24 male sex, and truncal tumor location.8 Alterations of some cell cycle regulators (p53, Rb, p27,28 cyclin A and D1), high Ki-67 proliferative indices, and expression of growth factors (eg, insulin-like growth factor-129) have also been shown to be correlated with reduced survival (see review in Sandberg and Bridge2). Our results, showing a strong association between death from malignancy and age greater than 35 years, large tumor size (> 7 cm), poorly differentiated histology, high mitotic rate, tumor necrosis, high histologic grade (grade 3), and advanced stage at diagnosis, are in keeping with data from the literature. The prognostic impact of vascular invasion and invasion of bone and neurovascular structures could not be evaluated in the present series because of inconsistencies in data retrieval. In the last few years, several studies have suggested that fusion type could be of prognostic value in SS.6 ,7 ,30-32 In a multi-institutional retrospective analysis of 243 patients with SS, Ladanyi et al7 showed that tumors with SSX1 fusion transcripts were significantly more aggressive than tumors with SSX2 transcripts, and that biphasic SSs were rarely SSX2, confirming their preliminary results published in 19986 and results from Nilsson et al published in 1999.33 The results of our study are at variance with these data. We were unable to find a significant correlation between fusion type and DSS and MFS, whether all patients, patients with localized tumors, or patients with metastatic disease at diagnosis were specifically examined. In fact, we even observed a trend for tumors bearing SYT-SSX2 transcripts to behave more aggressively than SYT-SSX1 SS (P = .087 in Cox univariate analysis for DSS on 165 patients), a finding that is at odds with other studies. Likewise, and in contrast to Mezzelani et al,31 we found no difference in DSS and MFS between SSX1 and SSX2 tumors in the metastatic patient cohort (ie, those patients developing one or several metastases in the course of their disease). Patient and tumor characteristics in our series are comparable to those of other series,7 ,15 ,16 ,19-21 suggesting that the relative lack of prognostic value for fusion type cannot be attributed to biases in patient or tumor selection. If a P value of 5% or less is required for statistical significance, then data from the literature in fact show that survival differences between SSX1 and SSX2 patients are often marginally significant7 if not nonsignificant,30 ,31 suggesting that fusion type is, in all likelihood, not an important prognostic factor in patients with SS. In their Cox regression analysis, Ladanyi et al7 noted that SYT-SSX fusion type emerged as the only independent significant factor (P = .04) for overall survival within the subset of 133 patients with localized disease at diagnosis. However, with the exception of tumor size, other potentially important prognostic factors (eg, mitotic activity, tumor necrosis, foci of poorly differentiated morphology, and so on) were omitted in their Cox model, even though these parameters have been shown to be of prognostic value in sarcomas in general34-37 and SS in particular.8 ,16-25 ,36 ,38 We suspect that, had these factors been included, fusion type would have never emerged as an independent prognostic factor. Some authors7 ,21 believe that histologic grade is not a prognostic factor for SS, which should be considered uniformly high grade. This study demonstrates that this is not the case. When the FNCLCC grading system is applied, patients with grade 2 SS do significantly better than those with grade 3 tumors in terms of DSS and MFS, an observation already put forward by our group8 and others.24 ,27 Similar results were obtained using a four-grade system.17 ,18 If a two-grade system is used, which separates sarcomas only into low-grade or high-grade lesions, it is clear that all SS will fall in the high-grade tumor category, hence lumping together aggressive and less aggressive tumors, resulting in a loss of prognostically relevant information. A two-grade system for grading sarcomas (including SS) cannot be recommended for this reason, despite the fact that this system has been adopted by the new 2002 UICC classification of malignant tumors.39 For patients with localized disease, high histologic grade (FNCLCC grade 3) was the most important predictor of reduced survival (both in terms of overall survival and MFS) in our multivariate analysis. When mitotic activity and tumor necrosis were included in Cox models (and histologic grade and poorly differentiated morphology removed from the set of variables), high mitotic rate emerged as the most important prognostic factor, as already described.8 ,17 ,19 ,20 ,22-24 ,27 Fusion type never emerged as a significant prognosticator in the present multivariate analysis. The finding that patients whose tumors contained the SYT-SSX2 fusion had a significantly increased risk for local recurrence (P = .0046 in Cox univariate association analysis) was unexpected. Many factors are involved in sarcoma recurrences, of which inadequate surgical excision (ie, microscopically positive margins), lack of adjuvant radiotherapy, large tumor size, high histologic grade, and axial tumor location are the most important.8 ,15 ,16 ,21 ,22 ,34 The relatively small proportion of long-term follow-ups and the fact that treatment modalities were neither randomly assigned nor standardized in the present study are potential biases that might explain this apparent relationship between fusion type and local recurrence risk. Additional studies are needed to ascertain whether this relationship really exists independently of other factors. Many authors have observed a significant relationship between fusion type and morphology, SYT-SSX2 fusion transcripts rarely being observed in biphasic SS.6 ,7 ,31 ,40 We made the same observation in our series, with, however, a weaker association (P = .04) than usually reported. This might be explained by the criteria used to define biphasic and monophasic variants of SS. Furthermore, for some tumors, the diagnosis was established on incisional or Tru-Cut biopsy specimens, which might have not always been representative of the complete morphologic spectrum of the lesion. We also observed a significant association between patient sex and fusion type (P = .03), the female to male ratio of SYT-SSX2 cases being twice that of SYT-SSX1 cases. Because Ladanyi et al7 made the same observation, this association is unlikely to be fortuitous and probably reflects differences in the mechanism of the SSX1 and SSX2 gene rearrangements, although without any apparent impact on survival according to our results. Another intriguing association was that of fusion type and site. In our study, SYT-SSX1 tumors tended to arise in free limbs (P = .052), and this was also observed in the series of Ladanyi et al.7 We have no rational explanation for this. In conclusion, this study shows that FNCLCC histologic grade but not SYT-SSX fusion type is of prognostic value in SS in terms of DSS and MFS. This study also confirms the association between fusion type and morphology, biphasic SSs being essentially SYT-SSX1 neoplasms, and between fusion type and patient sex.
The authors indicated no potential conflicts of interest.
We thank Dr Rougier, Noumea, New Caledonia; Drs Khamlu and Petitjean, Besançon; Dr Hofman, Nice; Dr Batt, Vannes; Dr Cousin-Maignan, Nantes; Dr Hainry, Lorient; Dr Bertrand, Angers, France; Dr Weintraub, Geneva; Dr Bode-Lesniewska, Zurich; Drs Levi, Gloor, and Anani, Lausanne; and Dr Baumann, Neuch  tel, Switzerland, for providing clinical and follow-up information.
Supported by a grant from the Fondation Pour La Lutte Contre Le Cancer, Zürich, Switzerland. Presented in part at the US and Canadian Academy of Pathology meeting, Washington, DC, March 22-28, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test where appropriate. Univariate Cox proportional hazards regression models were used to assess the associations of the clinical, surgical, and pathologic features with cancer-related death. Disease-specific survival (DSS) and MFS curves were computed by the Kaplan and Meier method.
