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Correlates of SYT-SSX Fusion Type in Synovial Sarcoma: Getting More Complex But Also More Interesting?

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

To the Editor:

The recent paper by Guillou et al¹ is a significant advance in the understanding of prognostic factors in synovial sarcoma (SS). The authors found that histologic grade and patient age, but not SYT-SSX fusion type, were strong predictors of survival by multivariate analysis for patients with localized SS. Thus, they did not confirm the correlation of SYT-SSX fusion type and survival found in the study of 243 patients by our collaborative group.² As retrospective series, both studies suffer from limited data on multiple variables including treatment. It is therefore difficult to judge whether the different conclusions may have been influenced by systematic differences in chemotherapy or surgical management. As Guillou et al point out, the association of SYT-SSX fusion type and survival has not been statistically robust even in the several positive studies published to date. In that sense, their negative results are perhaps not surprising.

Because we and some other groups have considered all SS to be high grade in a two-grade system, the impact of grade (in a three-grade system) on the prognostic analysis of fusion type had not been addressed. Although the study by Guillou et al is an important contribution because it also included three-grade histologic grading in the survival analyses, several special features of their study group merit further comment. In their study, SYT-SSX1 tumors tended to arise in free limbs. Although the P value was marginal (all tumors P = .05; localized tumors P = .04), this observation is notable because in our study² there was also a similar trend (P = .07) for SYT-SSX1 primaries to be more often peripheral (ie, free limb) than SYT-SSX2 tumors (P = .01 for combined data for all tumors in both studies). However, in our study, axial versus peripheral site was not prognostically significant (overall survival: all patients, P = .06; localized tumors, P = .06), whereas it was significant in the Guillou study (localized tumors: disease-specific survival, P = .013), and most of the mortality among axial primary cases appeared as a result of local relapses. This raises the possibility that there may have been general differences in how aggressively axial tumors were surgically managed in their 11 or 12 participating centers compared with the centers in our study. Because there was an excess of SYT-SSX2 tumors among axial primaries in the Guillou study, such differences may have had an impact on the results of the survival analysis according to fusion type. A univariate survival analysis of fusion type in their patientswith nonmetastatic free limb primaries (n = 99) might therefore be of interest.

A second interesting difference between the two studies is that in the Guillou study SYT-SSX2 tumors were more often metastatic than SYT-SSX1 tumors (P = .17), whereas the opposite trend was noted in our study (P = .05). These contradictory trends suggest that the association of SYT-SSX fusion type and stage is unlikely to be significant, but these presumably random differences between the two studies may have had a potentially important effect on the statistical power of the analyses performed in the subsets of patients with nonmetastatic tumors. Our analysis of overall survival in patients with localized tumors included 122 SYT-SSX1 cases and 80 SYT-SSX2 cases. In contrast, the equivalent analysis in the Guillou study included 99 SYT-SSX1 cases but only 42 SYT-SSX2 cases.

It is clear that SYT-SSX fusion type has important effects on the biology of SS, as is evident from other correlations with fusion type. Guillou et al do confirm previous findings regarding associations of fusion type with sex and biphasic histology.^2,3 The reproducible correlation with patient sex, reflecting a 1:1 male-to-female ratio for SYT-SSX1 cases but a 1:2 ratio for SYT-SSX2 cases, suggests that the possibility that SSX1 and SSX2 may not be equally subject to X-inactivation should be re-examined. The interpretation of this correlation may also need to take into account the recent finding that the SSX2 gene exists in two perfect copies in opposite orientation approximately 50 kb from each other.⁴ The striking correlation with histology, with most biphasic cases (ie, cases showing glandular epithelial differentiation in addition to primitive spindle cells) containing the SYT-SSX1 fusion type, suggests that hypothetical subtle functional differences between SYT-SSX1 and SYT-SSX2 may influence tumor differentiation patterns. The newly emerging correlation of SYT-SSX fusion type with primary site suggested by the concordant findings in these two areas in the present study and our previous analysis also raise the possibility that the cells susceptible to transformation by SYT-SSX1 and SYT-SSX2 may differ in subtle ways. Thus, SYT-SSX fusion type remains biologically intriguing as a prognostic factor because it is linked to the etiology of SS. However, in terms of practical clinical use, it may well be overshadowed by phenotypic factors such as grade (as in the Guillou study) or proliferative rate,^5,6 which in a sense reflect a synthesis of genotypic factors such as SYT-SSX fusion type as well as secondary genetic alterations.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Guillou L, Benhattar J, Bonichon F, et al: Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: A multicenter, retrospective analysis. J Clin Oncol 22 : 4040 -4050, 2004[Abstract/Free Full Text]

2. Ladanyi M, Antonescu CR, Leung DH, et al: Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: A multi-institutional retrospective study of 243 patients. Cancer Res 62 : 135 -140, 2002[Abstract/Free Full Text]

3. Antonescu CR, Kawai A, Leung DH, et al: Strong association of SYT-SSX fusion type and morphologic epithelial differentiation in synovial sarcoma. Diagn Mol Pathol 9 : 1 -8, 2000[CrossRef][Medline]

4. Gure AO, Wei IJ, Old LJ, et al: The SSX gene family: Characterization of 9 complete genes. Int J Cancer 101 : 448 -453, 2002[CrossRef][Medline]

5. Skytting BT, Bauer HC, Perfekt R, et al: Ki-67 is strongly prognostic in SS: Analysis based on 86 patients from the Scandinavian Sarcoma group register. Br J Cancer 80 : 1809 -1814, 1999[CrossRef][Medline]

6. Antonescu CR, Leung DH, Dudas M, et al: Alterations of cell cycle regulators in localized synovial sarcoma: A multifactorial study with prognostic implications. Am J Pathol 156 : 977 -983, 2000[Abstract/Free Full Text]

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