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1 MD * AND
SARAH M. DRY,
2 MD
Division of Surgical Oncology, University of California Los Angeles, Los Angeles, California 2 Division of Pathology, University of California Los Angeles, Los Angeles, California
Synovial sarcoma accounts about 9% of soft tissue sarcomas, most commonly develops in the extremity of young adults, is considered high grade and contains a characteristic translocation (X;18;p11;q11). While surgery and radiation therapy have achieved excellent local control, distant metastasis remains the principal problem limiting survival. Although ifosfamide based chemotherapy has been associated with an improved survival in patients with synovial sarcoma, the search for less toxic and more targeted systemic therapies is ongoing.
KEY WORDS: synovial sarcoma; distant metastasis; SYT-SSX fusion protein; EGFR inhibitor
EPIDEMIOLOGY
Synovial sarcoma comprises approximately 69% of all adult patients with soft tissue sarcomas. Although relatively rare, synovial sarcoma accounts for 1215% of adult extremity soft tissue sarcomas, making it the third most common extremity soft tissue sarcoma [18]. This unique spindle cell tumor occurs predominately in young adults with a median age of about 35 years [912]. This is notably younger than the median age for most other soft tissue sarcomas, which is typically in the fties [1,4,7]. Synovial sarcoma occurs equally in males and females with no predilection for either sex. Unlike some soft tissue histologies, synovial sarcoma has no identiable etiological agent or genetic condition that predisposes an individual to develop this malignancy [1,2,912].
HISTOPATHOLOGY
Despite its name, synovial sarcoma is no longer thought to derive from synovial tissue. The name stems from the early literature, as a result of the frequent paraarticular location and the microscopic resemblance to developing synovium. Subsequent work, including ultrastructural studies and immunohistochemistry, have instead identied the cells in synovial sarcoma as epithelial in origin [16]. Synovial sarcomas, by denition, have been considered to be high grade sarcomas. This contrasts with most soft tissue sarcomas that tend to have a both a high and low grade version. It is important to appreciate, however, that some groups in Europe and Asia believe that synovial sarcomas can and should be graded as intermediate and/or high grade sarcomas [14,17]. Several recently published articles from these groups do show improved disease-free and metastasis-free survival for patients with intermediate (Grade 2) synovial sarcomas [12,14,1720]. The system typically used to stratify synovial sarcomas into intermediate (Grade 2) and high grade (Grade 3) sarcomas is the French Federation of Cancer Centers Sarcoma Group System (FNCLCC) [18]. Mitotic count and percentage of tumor necrosis are used to stratify tumors in this system [12,19,20]. As this topic remains controversial, it is generally felt that it is it best to consider all synovial sarcomas as high grade sarcomas until the prognostic importance of grading synovial sarcomas is resolved [21,23]. Synovial sarcoma typically presents as one of two histologic subtypes, monophasic or biphasic. Monophasic synovial sarcomas are entirely composed of an ovoid-spindle cell morphology, whereas the biphasic subtypes are composed of both spindle cell elements and epithelial components. Recently a third, poorly differentiated histologic subtype of synovial sarcoma has been described. Poorly differentiated synovial sarcomas are composed of uniform, densely packed, small ovoid blue cells that resemble other small round blue cell tumors. In a pure form, poorly differentiated synovial sarcoma rarely
*Correspondence to: Fritz C. Eilber, MD, UCLA, Division of Surgical Oncology, 10833 LeConte Avenue, Rm 54-140 CHS, Los Angeles, CA 90095-1782. Fax: 310-825-7575. E-mail: fceilber@mednet.ucla.edu Received 27 November 2007; Accepted 4 December 2007 DOI 10.1002/jso.20974 Published online in Wiley InterScience (www.interscience.wiley.com).
SITES OF INVOLVEMENT
Synovial sarcomas can develop in almost any anatomic site, however the extremity is the by far the most common site of primary disease. About 80% of all primary synovial sarcomas arise in the extremity with 20% arising in non-extremity sites [2,1214]. Synovial sarcomas can develop throughout the extremity with essentially an equally distribution between the proximal and distal extremity. Distinctively, synovial sarcomas can arise in the very distal aspect of both the upper (hand, wrist) and lower (foot, ankle) extremities [2,914]. Although synovial sarcomas often develop in paraarticular regions of the extremity, they almost never arise within the joint and are not associated with normal synovial tissue. The most common non-extremity sites of primary disease include the trunk (&8%), retroperitoneal/abdominal (&7%), and head and neck (&5%) [2,1214]. As with other soft tissue sarcoma histologies, synovial sarcomas metastatic pattern is predicated upon the location of the primary disease. Since most primary synovial sarcomas are extremity lesions, the vast majority of synovial sarcomas metastasize to the lung [1014]. Intra-abdominal/hepatic metastasis are as expected, rare. Uniquely, synovial sarcomas have been shown to develop nodal metastases more commonly that most soft tissue sarcomas. Although the exact incidence of lymph node metastasis from synovial sarcoma varies in the literature, the pooled data from available studies puts the incidence at about 1012% compared to about 35% for soft tissue sarcomas in general [15].
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Fig. 2. This case of biphasic synovial sarcoma shows epithelial elements (arrows). Some contain obvious lumina and are readily recognized, while others are present as nests or cords of cells (original magnication 400). [Color gure can be viewed in the online issue, available at www.interscience.wiley.com.] sarcomas, which can cause confusion with Ewings/primitive neuroectodermal tumor, especially in small samples or poorly differentiated synovial sarcomas [16]. S100 has been reported to be positive in up to 40% of synovial sarcomas and can cause confusion with malignant peripheral nerve sheath tumor [24,29]. Other antibodies, including actins (SMA, MSA), desmin, CD34, and CD31 typically are negative in synovial sarcomas. Malignant peripheral nerve sheath tumors are often considered in the differential diagnosis with synovial sarcoma. Biphasic and spindled malignant peripheral nerve sheath tumors can be histologically very similar to synovial sarcomas, however, the spindled cells in malignant peripheral nerve sheath tumors will be negative for epithelial markers. Similar to synovial sarcoma, about 50% of malignant peripheral nerve sheath tumors show focal to patchy staining for S100 [30]. Prominent branching thin walled vessels, forming a so-called hemangioper-
Fig. 1. High power (400) examination of monophasic synovial sarcoma shows ovoid to spindle-shaped cells with scant cytoplasm, darkly staining nuclei, and indistinct cell borders. [Color gure can be viewed in the online issue, available at www.interscience.wiley.com.]
Journal of Surgical Oncology
Fig. 3. CAM 5.2 stain on the same case as that shown in P3 strongly highlights the epithelial elements, and shows weaker, patchy staining in the ovoid to spindle cells (original magnication 400). [Color gure can be viewed in the online issue, available at www.interscience. wiley.com.]
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icytomatous pattern are commonly seen in synovial sarcomas and solitary brous tumors. Fortunately, only about 10% of solitary brous tumors stain for epithelial markers and they typically show strong diffuse positive staining with CD34, a marker uniformly negative in synovial sarcoma [31]. Leiomyosarcomas are malignant spindled cell tumors with abundant eosinophilic cytoplasm, and typically are distinguishable from synovial sarcomas on H&E stains, however, a signicant proportion of leiomyosarcomas (up to 40%) have been reported to show (often patchy) positivity for keratins and EMA [32]. Fortunately, leiomyosarcomas are positive for actins and desmin, which are not expressed in synovial sarcomas. Poorly differentiated synovial sarcoma poses the greatest diagnostic challenge, as it can mimic so many tumors, including poorly differentiated carcinoma, Ewings/primitive neuroectodermal tumor and epithelioid brosarcoma [29]. Similar to Ewings/primitive neuroectodermal tumor, poorly differentiated synovial sarcoma may show strong expression of CD99 as well as some epithelial markers [29,33]. As described above, synovial sarcoma can be very difcult to diagnose correctly by histology and immunohistochemical results alone, even by the most experienced sarcoma pathologist. Small biopsy specimens, especially on tumors arising outside of the usual age-range and anatomic location, are often even more problematic [29]. Fortunately, highly sensitive and specic FISH and RT-PCR tests for synovial sarcoma have been developed that can be used on routinely processed, formalin-xed, parafn embedded tissues. If there is high clinical suspicion for synovial sarcoma that cannot be conrmed by histology and immunohistochemistry, molecular testing should be performed. Molecular testing should also be performed in cases with low to moderate clinical suspicion if histology and immunohistochemical results are equivocal. Conversely, if histological, immunohistochemical and clinical features are consistent with synovial sarcoma, molecular testing is generally non-contributory and not necessary [29].
CLINICAL FEATURES
The rst signicant clinical evaluation of synovial sarcoma was performed in 1942, by Haagenson and Stout. In this review that established the pathologic criteria for this disease, only 3 of 104 cases survived for 5 years [61]. Over the past 60 years many studies have examined the clinical, pathologic, and prognostic factors for synovial sarcoma. Unfortunately most of these studies are difcult to interpret for a number of reasons such as the inclusion of non-extremity disease, pediatric/adolescent patients (<16 years), patients who underwent non-curative surgery and/or patients with recurrent and metastatic disease [914,62]. The cleanest study examining the clinical factors that govern the natural history of adult (!16 years) synovial sarcoma was performed by Lewis et al. [10] from Memorial Sloan-Kettering Cancer Center (MSKCC). In this study the clinical and pathologic factors were examined in a homogenous cohort of 112 patients with localized primary extremity synovial sarcoma. All of these patients underwent surgical resection with curative intent at MSKCC and then were followed prospectively. Patients with recurrent of metastasis disease were excluded from the analysis [10]. Median patient age in this study was 35 years with essentially an equal distribution between males and females. Limb sparing surgery was possible in 78% of the cases with 22% requiring amputations. Fourteen percent of the patients from this study had a microscopically positive margin [10]. Comparable rates of amputation (1525%) and margin positivity (1530%) are reported in the literature [914]. Forty-six of the patients were treated with radiation therapy and 37% with chemotherapy. Unfortunately these treatments were not prospectively or uniformly administered and were thus excluded from the statistical analysis. Eleven of the 112 patients developed a local recurrence for an actuarial 5-year local recurrence rate of 12% [10]. This local recurrence rate is lower than reported in historical series, presumably because of better surgery and the employment of radiation therapy. This local recurrence rate is also lower than several contemporary studies (1830%), however, these studies include marginal excisions and are thus difcult to interpret [11,12]. Forty-three of the 112 patients developed a distant recurrence for an actuarial 5-year distant recurrence rate of 39%. Of the 43 distant recurrences, 34 were to the lung. Thirty-one of the patients that developed distant recurrence died of disease for a 5-year actuarial tumor related mortality of 25% [10]. The 5-year disease specic survival of 75% for localized primary disease in this study is slightly better that other studies (6071%) that were able to separate the outcomes of localized disease from that of locally recurrent and metastatic disease [914]. An important study by Singer et al. [9] demonstrated the relatively high incidence of late metastasis in synovial sarcoma. In this analysis of 31 patients with localized disease and a median follow-up time for surviving patients of 82 months, the 5-year survival rate was 60% and the 10-year survival rate was 34%. Thus, almost 50% of the observed deaths occurred between 5 and 10 years emphasizing the importance of long-term follow-up in patients with synovial sarcoma [9].
MOLECULAR GENETICS
In virtually all cases (>90%), synovial sarcomas contain a characteristic translocation between chromosomes X and 18, which in approximately one-third of cases is the only cytogenetic abnormality [34,35]. This translocation, t(X;18) (p11.2;q11.2) involves the SYT gene on chromosome 18 and one of several highly homologous genes (SSX1, SSX2, and SSX4) on the X chromosome. Approximately twothirds of cases have a SYT/SSX1 fusion and one-third have a SYT/ SSX2 fusion, with only very rare cases reporting a fusion between SYT and SSX4 [35,36]. Yang et al. [37] at the Karolinska Institute have reported that up to 10% of synovial sarcoma may contain both a SYT/ SSX1 and SYT/SSX2 translocation in the same tumor. Interestingly, biphasic synovial sarcoma usually show a SYT/SSX1 translocation, whereas monophasic synovial sarcoma and poorly differentiated synovial sarcoma may contain either the SSX1 or SSX2 translocation partner, without a clear predominance of either one [14,3847]. These ndings suggest that SSX1 may promote epithelial differentiation, or that SSX2 may repress it. Recent ndings that the SYT/SSX fusion proteins are involved in aberrant derepression of E-cadherin (a prerequisite for epithelial differentiation), also support this concept [48]. Females are signicantly more likely to have SSX2 fusions and synovial sarcoma arising in the extremities is more likely to harbor a SSX1 fusion, however, the reason for these observations is not clear [14,49]. The SYT/SSX fusion protein is present in both spindled and epithelial elements and the specic SSX fusion partner remains consistent between primary tumors and metastases [14,5053]. Cytogenetics, interphase FISH, conventional RT-PCR and real-time RT-PCR have all been used to diagnose synovial sarcoma [36,5456]. As the X;18 translocation is unique to synovial sarcoma, its detection provides a denitive diagnosis, even in cases with unusual clinical or histologic features [46,47,50,54,57,58]. While cytogenetic analysis can
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the initial treatments also may account for the divergent ndings. Different laboratory testing methods for identifying the synovial sarcoma fusion transcripts are another potential source, and should be considered given the recent report that both SSX1 and SSX2 translocation partners may be seen in the same tumor in up to 10% of synovial sarcomas [37,67]. Another possible difference is the grading system used. Guillou et al. [14] stratied synovial sarcomas into intermediate and high grade tumors, as described by the FNCLCC grading scheme. Earlier studies assumed all synovial sarcomas were all high grade tumors [41,49]. While the association between fusion type and clinical outcome was statistically signicant in earlier studies, it was not vary strong. Thus, it is possible that the effect of histologic grade may overpower that of fusion type it when examined in ner detail [14,49]. Regardless, it is clear that further studies are needed to determine if a particular translocation partner is clinically signicant in synovial sarcomas.
CLINICAL MANAGEMENT
Surgery
The cornerstone of treatment for synovial sarcomas, as with other soft tissue sarcomas, is complete surgical resection. The primary surgical principle is en bloc resection of the tumor with dissection being carried out through normal adjacent tissue planes. If present, an incisional biopsy site should be resected en bloc with the specimen [1,68]. Synovial sarcomas are often positioned very close to neurovascular structures. It is not unusual to have to perform a neurovascular dissection when removing these tumors from the upper (shoulder/axilla) and lower (groin/knee) extremity [2]. Sacrice of these structures is usually not necessary. By attaining exposure of the neurovascular structures both proximally and distally, meticulous dissection can be carried along the neurovascular bundle and if necessary the adventitia of the artery and vein or perineurium can be removed. At a minimum the pathologic specimen needs to be free of tumor at the margin, ideally with a margin of normal tissue. There is no role for non-curative surgery such as an incomplete gross resection or intra-lesional excisions [1,2,68]. Similar to primary disease, surgery is the mainstay of treating locally recurrent disease. Although the amputation rate increases in the setting of locally recurrent disease, the majority of patients are able to undergo limb sparing surgery and amputation is still considered a last resort [7,69]. A large local recurrence that develops in a short interval indicates a biologically aggressive tumor with a high tumor specic mortality. Patients that develop such recurrences should be treated with neoadjuvant systemic therapy [69]. Surgery has a much more limited role in the treatment of metastatic synovial sarcoma and requires careful patient selection. Patients are best selected by extent of disease, longer disease free interval, and favorable response to systemic chemotherapy. For pulmonary metastasis, only complete resection can improve survival beyond that seen for non-surgical therapy [2,70].
PROGNOSTIC FACTORS
Multiple studies have identied a number of prognostic factors associated with disease specic survival such as age, size, margin, mitotic activity, bone or neurovascular invasion, histologic subtype, p53 overexpression, Ki67 proliferative index and SYT-SSX fusion type [914,21,22,49,65]. The relative predictive value of each these prognostic factors remains controversial and is constantly evolving. As stated above, many of these studies are difcult to interpret for a number of reasons such as inclusion of non-extremity disease, pediatric patients, and patients with recurrent and metastatic disease. Despite the heterogeneity of study populations within many of these analyses, large tumor size has consistently proven to be associated with the development of distant metastasis and decreased disease specic survival [914,21,49,65]. In most studies, the prognostic factors for distant recurrence parallel those for disease specic survival. A number of prognostic factors for local recurrence have also been identied such as proximal location, positive margin and as might be expected poor surgery [1012]. As discussed above the cleanest study examining the prognostic factors for adult primary extremity synovial sarcoma was performed by Lewis et al. In this study tumor size greater than 5 cm and tumor invasion of bone, nerve or vascular structures were the only independent adverse prognostic predictors for the development of metastasis and a decreased disease specic survival [10]. Age, which has been commonly noted to be a signicant variable affecting survival in synovial sarcoma, was not an independent predictor of tumor related mortality in this study. Although a number of large studies have found that younger age is associated with an improved disease specic survival on univariate analysis, its signicance has not held up on multivariate analysis [914]. Much has been written about the prognostic signicance of the molecular genetics of synovial sarcoma. Until recently, all studies indicated a worse prognosis for patients with the SYT/SSX1 translocation, with shorter metastasis-free and overall survival times compared to those with the SYT/SSX2 translocations [41,43,49]. SSX1 tumors were also found to have a statistically signicant increase in the proliferation index in some but not all studies [38,43,66]. Recently, however, a study of 163 synovial sarcoma patients by Guillou et al. [14] did not conrm these earlier ndings. In contrast, this study found a trend for a more aggressive clinical course in patients with SSX2 translocations. There is no immediately clear explanation for these differences. Comparisons between the studies are complicated by variations in study designs, laboratory techniques, statistical analyses, and studied clinical outcomes [67]. Variation among the patient populations and
Journal of Surgical Oncology
Radiation Therapy
The same rationale for the use of adjuvant radiation therapy in soft tissue sarcomas applies to synovial sarcoma. Because synovial sarcomas are all considered high grade sarcomas, adjuvant radiation therapy is used in patients with tumors !5 cm in size [1,2,68]. Adjuvant radiation therapy can be administer in a number of ways such as external beam therapy (neoadjuvant or adjuvant), brachytherapy, and intensity modulated radiation therapy (IMRT). Each modality has its advantages and disadvantages, and no one modality specically has been proven better for synovial sarcoma. Regardless of the type of radiation therapy employed, it has been proven to improve the local
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control rate in patients with high grade sarcomas, such as synovial sarcoma [7174].
Chemotherapy
Synovial sarcoma has been regarded as a particularly chemosensitive soft tissue sarcoma. This was initially based on several studies that demonstrated impressive responses to ifosfamide based chemotherapy in the treatment of metastatic and pediatric synovial sarcomas [7578]. These early ndings have been supported by subsequent studies and thus ifosfamide based chemotherapy (/ doxorubicin) is generally considered the rst line treatment for patients with metastatic synovial sarcoma [13,63,7981]. Although ifosfamide based chemotherapy has been shown to produce notable responses in the treatment of metastatic synovial sarcomas, its effect on the survival of adult patients with primary disease has been unclear [8284]. While surgery and radiation therapy have achieved excellent local control, distant metastasis remains the principal problem limiting survival. In patients with primary extremity synovial sarcoma that are !5 cm in size, distant metastasis occur in over 50% of the patients with a resultant 5-year tumor related mortality of almost 40% [10]. Over the past several decades adjuvant and neoadjuvant chemotherapy has been used in an attempt to improve the survival of patients with high-risk primary extremity soft tissue sarcomas. Due to the toxicity of these treatments and limited impact on survival, their use in patients with primary disease has been controversial [85,86]. Ifosfamide based chemotherapy for patients with primary soft tissue sarcomas was introduced in the early 1990s. The few randomized controlled clinical trials performed with ifosfamide have inconsistent results and are difcult to interpret due to small sample sizes, the inclusion of nonextremity tumor sites and heterogeneity of histologic types [82 84,87]. The most encouraging of these studies by Frustaci et al. [84] found a signicant survival benet at 4 years in patients treated with ifosfamide based chemotherapy. Several retrospective analyses have also found that ifosfamide based chemotherapy is associated with an improved survival in patients with high-risk primary extremity soft tissue sarcomas [8890]. Eilber et al. [88] found that patients with treated with neoadjuvant, ifosfamide based chemotherapy had an increased pathologic response and improved survival compared to patients treated with doxorubicin based protocols (containing no ifosfamide). Grobmyer et al. [89] analyzed patients who were treated with surgery only or neoadjuvant chemotherapy containing doxorubicin/ifosfamide/mesna (AIM). Adjusting for known prognostic factors, AIM chemotherapy was associated with a signicantly improved disease specic survival. Although these studies suggest that ifosfamide based therapy offers a survival benet to some high-risk patients with primary extremity soft tissue sarcomas, the benet may well be histology specic. Unfortunately due to the diversity and rarity of soft tissue sarcomas, no single institution has been able to accrue an adequate number of high-risk patients at a pace that would allow for histology specic randomized treatment comparisons. In an effort to circumvent this problem, several investigators have begun to examine the impact of chemotherapy in a histology specic manner through the use of large sarcoma databases [13,91]. Because synovial sarcoma has been held to be such a chemosensitive histology, it has been the focus of several initial studies. Ferrari et al. performed a retrospective analysis of synovial sarcomas of all ages. Although this analysis uses a historical control and only examines the inuence of chemotherapy on a small number of high-risk adult patients; they do demonstrate a signicant improvement in metastasis free survival with treatment [13]. Eilber et al. has also examined the impact of chemotherapy on the survival of patients with high-risk, primary, extremity synovial sarcoma. In this contemporary cohort analysis, ifosfamide based chemotherapy was
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FUTURE THERAPIES
The need for more effective, less toxic systemic therapies for synovial sarcoma is clear. Although there are many unanswered questions about the biology, function, and prognostic signicance of the SYT-SSX fusion protein, it is an attractive target for a histology specic therapy. Cytotoxic CD8 T-lymphocytes specic to the SYTSSX protein have been identied in patients with synovial sarcoma [93]. Recently, a phase I trial of an SYT-SSX derived peptide vaccine in six patients with synovial sarcoma was performed. The treatment was well tolerated and one patient was shown to have stabilization of disease [94]. Members of the epidermal growth factor family are another interesting target in synovial sarcoma. Epidermal growth factor receptors (EGFR) clustered with SSX genes in a microarray analysis [95]. This nding is supported by the specicity of EGFR immunohistochemical staining in synovial sarcoma compared with other soft tissue sarcomas [96]. A phase II trial of an EGFR inhibitor for patients with locally advanced or metastatic synovial sarcomas that overexpresses EGFR is being performed [97].
REFERENCES
1. Brennan MF, Singer S, Maki RG, et al.: Sarcomas of the soft tissues and bone. In: DeVita VT, Hellmann S, Rosenberg SA, editors. Cancer principles and practice of oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005; vol. 35. p 1584. 2. Brennan MF, Lewis JJ, editors. Diagnosis and management of soft tissue sarcoma. London, United Kingdom: Martin Dunitz Ltd; 2002. pp 123128. 3. Singer S, Corson JM, Gonin R, et al.: Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma. Ann Surg 1994;219:165173. 4. Pisters PWT, Leung DHY, Woodruff J, et al.: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:16791689. 5. Coindre JM, Terrier P, Bui NB, et al.: Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study on 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869877. 6. Lewis JJ, Leung D, Casper ES, et al.: Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma. Arch Surg 1999;134:190194. 7. Eilber FC, Rosen G, Nelson S, et al.: High grade extremity soft tissue sarcomas: Factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg 2003;237:218226. 8. Koea JB, Leung D, Lewis JJ, et al.: Histopathologic type: An independent prognostic factor in primary soft tissue sarcoma of the extremity? Ann Surg Oncol 2003;10:432440. 9. Singer S, Baldini EH, Demetri GD, et al.: Synovial sarcoma: Prognostic signicance of tumor size, margin of resection and mitotic activity for survival. J Clin Oncol 1996;14:12011208. 10. Lewis JJ, Antonescu CR, Leung DHY, et al.: Synovial sarcoma: A multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremity. J Clin Oncol 2000; 18:20872094. 11. Spillane AJ, AHern R, Judson IR, et al.: Synovial sarcoma: A clinicopathologic, staging, and prognostic assessment. J Clin Oncol 2000;18:37943803. 12. Trassard M, Le Doussal V, Hacene K, et al.: Prognostic factors in localized primary synovial sarcoma: A multicenter study of 128 adult patients. J Clin Oncol 2001;19:525534. 13. Ferrari A, Gronchi A, Casanova M, et al.: Synovial sarcoma: A retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 2004;101:627634.
319
43.
44.
45.
46. 47.
48.
49.
50.
51.
52.
itive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors. Am J Surg Pathol 1998;22:673682. Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Synovial sarcoma. Cancer Genet Cytogenet 2002;133:123. Mitelman F, Johansson B, Mertens B. Mitelman Database of Chromosome Aberrations in Cancer. 2006. dos Santos NR, de Bruijn DR, Geurts van Kessel A: Molecular mechanisms underlying human synovial sarcoma development. Genes Chromosomes Cancer 2001;30:114. Yang K, Lui WO, Xie Y, et al.: Co-existence of SYT-SSX1 and SYT-SSX2 fusions in synovial sarcomas. Oncogene 2002;21: 41814190. 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 2000;9:18. Crew AJ, Clark J, Fisher C, et al.: Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma. EMBO J 1995;14:23332340. Inagaki H, Murase T, Otsuka T, et al.: Detection of SYT-SSX fusion transcript in synovial sarcoma using archival cytologic specimens. Am J Clin Pathol 1999;111:528533. Kawai A, Woodruff J, Healey JH, et al.: SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 1998;338:153160. Lasota J, Jasinski M, Debiec-Rychter M, et al.: Detection of the SYT-SSX fusion transcripts in formaldehyde-xed, parafnembedded tissue: A reverse transcription polymerase chain reaction amplication assay useful in the diagnosis of synovial sarcoma. Mod Pathol 1998;11:626633. Nilsson G, Skytting B, Xie Y, et al.: The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. Cancer Res 1999;59: 31803184. Shipley J, Crew J, Birdsall S, et al.: Interphase uorescence in situ hybridization and reverse transcription polymerase chain reaction as a diagnostic aid for synovial sarcoma. Am J Pathol 1996; 148: 559567. Tsuji S, Hisaoka M, Morimitsu Y, et al.: Detection of SYT-SSX fusion transcripts in synovial sarcoma by reverse transcriptionpolymerase chain reaction using archival parafn-embedded tissues. Am J Pathol 1998;153:18071812. van de Rijn M, Barr FG, Collins MH, et al.: Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma. Am J Clin Pathol 1999;112:4349. Willeke F, Mechtersheimer G, Schwarzbach M, et al.: Detection of SYT-SSX1/2 fusion transcripts by reverse transcriptasepolymerase chain reaction (RT-PCR) is a valuable diagnostic tool in synovial sarcoma. Eur J Cancer 1998;34:20872093. Saito T, Nagai M, Ladanyi M: SYT-SSX1 and SYT-SSX2 interfere with repression of E-cadherin by snail and slug: A potential mechanism for aberrant mesenchymal to epithelial transition in human synovial sarcoma. Cancer Res 2006;66: 69196927. Ladanyi M, Antonescu CR, Leung DH, et al.: Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: A multiinstitutional retrospective study of 243 patients. Cancer Res 2002; 62:135140. Hiraga H, Nojima T, Abe S, et al.: Diagnosis of synovial sarcoma with the reverse transcriptase-polymerase chain reaction: Analyses of 84 soft tissue and bone tumors. Diagn Mol Pathol 1998; 7:102110. Kasai T, Shimajiri S, Hashimoto H: Detection of SYT-SSX fusion transcripts in both epithelial and spindle cell areas of biphasic synovial sarcoma using laser capture microdissection. Mol Pathol 2000;53:107110. Nishio J, Iwasaki H, Ishiguro M, et al.: Identication of syt-ssx fusion transcripts in both epithelial and spindle cell components of biphasic synovial sarcoma in small tissue samples isolated by membrane-based laser microdissection. Virchows Arch 2001; 439:152157.
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53. Ladanyi M: Fusions of the SYT and SSX genes in synovial sarcoma. Oncogene 2001;20:57555762. 54. Guillou L, Coindre J, Gallagher G, et al.: Detection of the synovial sarcoma translocation t(X;18) (SYT;SSX) in parafnembedded tissues using reverse transcriptase-polymerase chain reaction: A reliable and powerful diagnostic tool for pathologists. A molecular analysis of 221 mesenchymal tumors xed in different xatives. Hum Pathol 2001;32:105112. 55. Hill DA, Riedley SE, Patel AR, et al.: Real-time polymerase chain reaction as an aid for the detection of SYT-SSX1 and SYT-SSX2 transcripts in fresh and archival pediatric synovial sarcoma specimens: Report of 25 cases from St. Jude Childrens Research Hospital. Pediatr Dev Pathol 2003;6:2434. 56. Hostein I, Menard A, Bui BN, et al.: Molecular detection of the synovial sarcoma translocation t(X;18) by real-time polymerase chain reaction in parafn-embedded material. Diagn Mol Pathol 2002;11:1621. 57. Poteat HT, Corson JM, Fletcher JA: Detection of chromosome 18 rearrangement in synovial sarcoma by uorescence in situ hybridization. Cancer Genet Cytogenet 1995;84:7681. 58. Yang P, Hirose T, Hasegawa T, et al.: Dual-colour uorescence in situ hybridization analysis of synovial sarcoma. J Pathol 1998; 184:713. 59. Nikiforova MN, Groen P, Mutema G, et al.: Detection of SYTSSX rearrangements in synovial sarcomas by real-time one-step RT-PCR. Pediatr Dev Pathol 2005;8:162167. 60. Thorson JA, Weigelin HC, Ruiz RE, et al.: Identication of SYT-SSX transcripts from synovial sarcomas using RT-multiplex PCR and capillary electrophoresis. Mod Pathol 2006;19:641 647. 61. Haagenson CD, Stout AP: Synovial sarcoma. Ann Surg 1944;120: 826842. 62. Hajdu SI, Shiu MH, Fortner JG: Tendosynovial sarcoma: A clinicopathological study of 136 cases. Cancer 1977;39:1201 1217. 63. Spurrell EL, Fisher C, Thomas M, et al.: Prognostic factors in advanced synovial sarcoma: An analysis of 104 patients treated at the Royal Marsden Hospital. Ann Oncol 2005;16:437444. 64. Kattan MW, Leung DH, Brennan MF: Postoperative nomogram for 12-year sarcoma-specic death. J Clin Oncol 2002;20:791 796. 65. Antonescu CR, Leung DH, Dudas M, et al.: Alterations of cell cycle regulators in localized synovial sarcoma. Am J Pathol 2000;156:977983. 66. Inagaki H, Nagasaka T, Otsuka T, et al.: Association of SYT-SSX fusion types with proliferative activity and prognosis in synovial sarcoma. Mod Pathol 2000;13:482488. 67. Oliveira AM, Fletcher CD: Molecular prognostication for soft tissue sarcomas: Are we ready yet? J Clin Oncol 2004;22:4031 4034. 68. Eilber FC, Eilber FR: Soft tissue sarcoma. In: Cameron JL, editor. Current surgical therapy. 7th edition. MS, Mosby: St. Louis; 2001. pp 12131218. 69. Eilber FC, Brennan MF, Riedel E, et al.: Prognostic factors for survival in patients with locally recurrent extremity soft tissue sarcomas. Ann Surg Oncol 2005;12:228236. 70. Gadd MA, Casper ES, Woodruff JM, et al.: Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218:705712. 71. OSullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359:22352241. 72. Pisters PW, Harrison LB, Leung DH, et al.: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859868. 73. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benet of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16: 197203. 74. Hong L, Alektiar KM, Hunt M, et al.: Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh. Int J Radiat Oncol Biol Phys 2004;59:752759.
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