Synovial Sarcoma

Overview

"A malignant neoplasm arising from tenosynovial tissue of the joints and in synovial cells of tendons and bursae. The legs are the most common site, but the tumor can occur in the abdominal wall and other trunk muscles. There are two recognized types: the monophasic (characterized by sheaths of monotonous spindle cells) and the biphasic (characterized by slit-like spaces or clefts within the tumor, lined by cuboidal or tall columnar epithelial cells). These sarcomas occur most commonly in the second and fourth decades of life. (From Dorland, 27th ed; DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1363)" [Source: MeSH, 2014]

A S18-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is characteristic of nearly all synovial sarcomas. This translocation fuses the SS18T (SYT) gene from chromosome 18 to one of three homologous genes at Xp11, SSX1, SSX2 or SSX4.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Gene Expression
  • Cancer DNA
  • Translocation
  • Messenger RNA
  • Cancer RNA
  • Polymerase Chain Reaction
  • X Chromosome
  • Proto-Oncogene Proteins
  • Lung Cancer
  • Immunoenzyme Techniques
  • Repressor Proteins
  • DNA Primers
  • SS18
  • Karyotyping
  • Proteins
  • Base Sequence
  • TLE1
  • Cancer Gene Expression Regulation
  • Chromosome 18
  • SSX1
  • Synovial Sarcoma
  • Oncogene Fusion Proteins
  • Childhood Cancer
  • Adolescents
  • Survival Rate
  • Bone Cancer
  • Neoplasm Proteins
  • Tumor Markers
  • Immunohistochemistry
  • Chromosome Mapping
  • DNA Sequence Analysis
  • Gene Expression Profiling
  • Differential Diagnosis
  • EGFR
  • Chromosome X
  • FISH
  • Chromosome Aberrations
  • Soft Tissue Cancers
  • Oligonucleotide Array Sequence Analysis
  • RTPCR
  • Amino Acid Sequence
  • SS18L1
  • Molecular Sequence Data
  • Paraffin Embedding
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (8)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
TLE1 9q21.32 ESG, ESG1, GRG1 -TLE1 and Synovial Sarcoma
15
EGFR 7p12 ERBB, HER1, mENA, ERBB1, PIG61, NISBD2 Overexpression
-EGFR Overexpression in Synovial Sarcoma
13
SS18L1 20q13.3 CREST, LP2261 -SS18L1 and Synovial Sarcoma
5
FOXC1 6p25 ARA, IGDA, IHG1, FKHL7, IRID1, RIEG3, FREAC3, FREAC-3 -FOXC1 and Synovial Sarcoma
1
SS18 18q11.2 SYT, SSXT Translocation
-t(X;18)(p11.2;q11.2) SS18-SSX1 in Synovial Sarcoma
-t(X;18)(p11.2;q11.2) SS18-SSX2 in Synovial Sarcoma
-t(X;18)(p11.2;q11.2) SS18-SSX4 in Synovial Sarcoma
SSX1 Xp11.23 SSRC, CT5.1 Translocation
-t(X;18)(p11.2;q11.2) SS18-SSX1 in Synovial Sarcoma
SSX2 Xp11.22 SSX, HD21, CT5.2, CT5.2A, HOM-MEL-40 Translocation
-t(X;18)(p11.2;q11.2) SS18-SSX2 in Synovial Sarcoma
SSX4 Xp11.23 CT5.4 Translocation
-t(X;18)(p11.2;q11.2) SS18-SSX4 in Synovial Sarcoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Research Publications

Thway K, Fisher C
Synovial sarcoma: defining features and diagnostic evolution.
Ann Diagn Pathol. 2014; 18(6):369-80 [PubMed] Related Publications
Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation, with a propensity to occur in young adults and which can arise at almost any site. It is generally viewed and treated as a high-grade sarcoma. As one of the first sarcomas to be defined by the presence of a specific chromosomal translocation leading to the production of the SS18-SSX fusion oncogene, it is perhaps the archetypal "translocation-associated sarcoma," and its translocation remains unique to this tumor type. Synovial sarcoma has a variety of morphologic patterns, but its chief forms are the classic biphasic pattern, of glandular or solid epithelial structures with monomorphic spindle cells and the monophasic pattern, of fascicles of spindle cells with only immunohistochemical or ultrastructural evidence of epithelial differentiation. However, there is significant morphologic heterogeneity and overlap with a variety of other neoplasms, which can cause diagnostic challenge, particularly as the immunoprofile is varied, SS18-SSX is not detected in 100% of SSs, and they may occur at unusual sites. Correct diagnosis is clinically important, due to the relative chemosensitivity of SS in relation to other sarcomas, for prognostication and because of the potential for treatment with specific targeted therapies in the near future. We review SS, with emphasis on the diagnostic spectrum, recent immunohistochemical and genetic findings, and the differential diagnosis.

Nishio J, Kamachi Y, Iwasaki H, Naito M
Diffuse-type tenosynovial giant cell tumor with t(1;17)(p13;p13) and trisomy 5.
In Vivo. 2014 Sep-Oct; 28(5):949-52 [PubMed] Related Publications
Diffuse-type tenosynovial giant cell tumor (TSGCT) is a locally aggressive neoplasm that primarily affects the synovium and tendon sheath in young adults. Rearrangement of chromosome band 1p13 is now considered a characteristic genetic feature of TSGCT, with the most frequent chromosomal alteration t(1;2)(p13;q37). Here, we describe a unique cytogenetic finding of diffuse-type TSGCT arising in the ankle of an 18-year-old woman. Magnetic resonance imaging demonstrated an ill-defined juxta-articular mass with decreased signal intensity on both T1- and T2-weighted images. Contrast-enhanced T1-weighted images showed intense enhancement of the mass. Open complete resection was performed. Histologically, the tumor was composed of mononuclear cells admixed with multi-nucleated osteoclast-like giant cells, foam cells, siderophages and inflammatory cells. Cytogenetic analysis revealed a reciprocal translocation involving chromosomes 1 and 17, concomitant with a few other numerical and structural alterations. In addition, trisomy 5 as the sole anomaly was identified in two metaphase cells. To the best of our knowledge, this is the first report of this neoplasm with t(1;17)(p13;p13).

Chakiba C, Lagarde P, Pissaloux D, et al.
Response to chemotherapy is not related to chromosome instability in synovial sarcoma.
Ann Oncol. 2014; 25(11):2267-71 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic complexity and response to chemotherapy.
PATIENTS AND METHODS: The study population included 65 SS patients diagnosed between 1991 and 2013 and with available tissue material. Genomic profiling was carried out by using array-CGH. Forty-five SS out of the 65 patients were treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy. Radiological response was assessed according to RECIST criteria. Histological response was defined by the percentage of recognizable tumor cells on the surgical specimen.
RESULTS: Genomic complexity was significantly associated with MFS. However, there was no statistically significant association between radiological or histological response and genomic complexity.
CONCLUSION: The absence of significant association between response to chemotherapy and genomic complexity suggests that the prognostic value of chromosome instability in SS is independent of response to chemotherapy; mechanisms leading to metastatic relapse of SS are intrinsic to the biology of the tumor and current cytotoxic drugs are only poorly efficient to prevent it.

Minami Y, Kohsaka S, Tsuda M, et al.
SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1.
Cancer Sci. 2014; 105(9):1152-9 [PubMed] Related Publications
MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3'-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma.

Kimura H, Yamamoto N, Nishida H, et al.
Synovial sarcoma in knee joint, mimicking low-grade sarcoma confirmed by molecular detection of SYT gene split.
Anticancer Res. 2014; 34(6):3105-11 [PubMed] Related Publications
A 10-year-old boy underwent arthroscopic curettage for an intra-articular mass in knee joint. The tumor was diagnosed as low-grade fibrous sarcoma. Five years later, the patient presented with a recurrent tumor. The patient underwent a marginal excision with knee joint preservation and without adjuvant therapy. Two years after the last surgery, the patient is thriving with no evidence of recurrent or metastatic disease. The final diagnosis was synovial sarcoma confirmed via a SYT gene split performed with fluorescent in situ hybridization (FISH), although the tumor appeared as a low-grade fibrous type in a hematoxylin-eosin section. The first curetted specimen was also confirmed to bear a SYT gene split. Synovial sarcoma has been conventionally recognized as a high-grade sarcoma. Our patient had a tumor that exhibited the characteristics of both a histologically and clinically low-grade tumor. From the present case, we consider that low-grade variants of synovial sarcoma do exist although their existence remains controversial.

Przybyl J, Sciot R, Wozniak A, et al.
Metastatic potential is determined early in synovial sarcoma development and reflected by tumor molecular features.
Int J Biochem Cell Biol. 2014; 53:505-13 [PubMed] Related Publications
INTRODUCTION: Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized.
MATERIALS AND METHODS: Sixty-four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group).
RESULTS: AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors.
CONCLUSIONS: Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms. This article is part of a Directed Issue entitled: Rare Cancers.

Silverstein D, Klein P
Large monophasic synovial sarcoma: a case report and review of the literature.
Cutis. 2014; 93(1):13-6 [PubMed] Related Publications
Synovial sarcomas account for approximately 8% of all soft tissue tumors. The hallmark tumor marker is the t(X;18) translocation, which results in fusion of the SYT gene of chromosome 18 to the SSX gene of the X chromosome, creating most frequently either an SYT-SSX1 or SYT-SSX2 transfusion transcript. Clinically, synovial sarcomas most often present on the extremities and average roughly 7 cm in diameter. Metastatic spread to regional lymph nodes and/or the lungs is common. Because the incidence of this tumor is low, most studies have been retrospective; therefore, management and prognostic interpretation has remained controversial. We report a case of a patient who presented with a slowly growing, unusually large mass on the left forearm of 10 years' duration. A diagnosis of monophasic synovial sarcoma was confirmed by biopsy. We also review the literature regarding management strategies for synovial sarcomas.

Huang CC, Michael CW, Pang JC
Fine needle aspiration of primary mediastinal synovial sarcoma: cytomorphologic, immunohistochemical, and molecular study.
Diagn Cytopathol. 2014; 42(2):170-6 [PubMed] Related Publications
The cytologic diagnosis of synovial sarcoma (SS) can be difficult when it occurs in unusual locations, atypical age groups, and/or have unusual morphology. We report a case of primary mediastinal SS in a 65-year-old male with a long smoking history who presented with increasing shortness of breath and was found to have a 14.2 cm mediastinal mass. Smears from the endobronchial ultrasound guided fine needle aspiration of the mass were moderately cellular consisting of loosely cohesive clusters, some of which demonstrated nuclear molding, and dispersed single cells. The relatively uniform tumor cells had a high nuclear-to-cytoplasmic ratio, finely granular chromatin, and inconspicuous nucleoli. Some of the single cells had spindled morphology with unipolar wispy tails and naked nuclei. Based on the clinical presentation and the cytomorphologic features, our initial differential diagnoses included atypical carcinoid, small cell carcinoma, basaloid squamous cell carcinoma, sarcoma, and lymphoma. Immunohistochemical studies on the cell block sections revealed that the tumor cells were focally positive for cytokeratin and diffusely positive for CD56, while negative for CD45, synaptophysin and chromogranin. Ultimately, an immunohistochemical stain for TLE-1 demonstrated diffusely strong nuclear positivity and molecular studies showed the presence of the t(X; 18) SYT/SSX1 translocation confirming the diagnosis of SS. In this report, we describe the cytomorphologic features of SS, its diagnostic pitfalls, and potential mimics in the mediastinum.

Chuang HC, Hsu SC, Huang CG, et al.
Reappraisal of TLE-1 immunohistochemical staining and molecular detection of SS18-SSX fusion transcripts for synovial sarcoma.
Pathol Int. 2013; 63(12):573-80 [PubMed] Related Publications
The aim of the present study was to re-evaluate TLE-1 staining and the molecular detection methods of SS18-SSX transcripts for synovial sarcoma. We analyzed TLE-1 expression in 50 molecularly confirmed synovial sarcomas and 85 other soft tissue tumors with three previously published scoring systems. In the present study, 39 to 43 synovial sarcomas showed TLE-1 nuclear staining, whereas 9-15 of 85 other soft tissue tumors showed TLE-1 staining (P < 0.0001). The specificities of strong TLE-1 staining were 100%, 97.6% and 98.8%. The positive likelihood ratio of moderate and strong TLE-1 nuclear expression was >10 in all three scoring systems. There was no difference in TLE-1 staining between different subtypes of synovial sarcoma (P > 0.05). Based on a comparison between conventional reverse transcription (RT)-polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), quantitative RT-PCR is a more sensitive method than conventional RT-PCR and FISH to detect t(X;18). A positive correlation between TLE-1 staining and SS18-SSX translocation was detected by conventional PCR (P < 0.05). In conclusion, although all three scoring systems could differentiate synovial sarcoma from other soft tissue tumors, diffuse moderate to severe intensity tumors showed the highest specificity in the diagnosis of synovial sarcoma.

Saito T
The SYT-SSX fusion protein and histological epithelial differentiation in synovial sarcoma: relationship with extracellular matrix remodeling.
Int J Clin Exp Pathol. 2013; 6(11):2272-9 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Synovial sarcoma (SS) tumor cells, which have the chromosomal translocation t(X;18)(p11.2;q11.2), have an inherently greater propensity for epithelial differentiation than other mesenchymal tumors, especially spindle cell sarcomas. This is caused by de-repression of the transcription of E-cadherin by SYT-SSX1 and SYT-SSX2, which dissociate Snail or Slug, respectively, from the E-cadherin promoter. However, a subset of SS with SYT-SSX1 loses E-cadherin expression despite adequate de-repression because of mutations in E-cadherin, resulting in monophasic histology. The ratio of the expression levels of SYT-SSX1 and Snail is also associated with E-cadherin expression: the lower the SYT-SSX1/Snail ratio, the lower the level of E-cadherin expression, and vice versa, thus affecting tumor histology. In addition, Wnt signal activation caused by mutation of β-catenin, APC, or Axin 1 and 2 is associated with monophasic histology. Remodeling of the extracellular matrix is also important. Only cells that survive all of these steps can finally exhibit biphasic histology. On the other hand, the SYT-SSX2 fusion has a weaker de-repression effect on the E-cadherin promoter than does SYT-SSX1, so it is difficult for SYT-SSX2-expressing tumors to achieve sufficient capacity for epithelial differentiation to form glandular structures. This review provides an interesting model for this epithelial differentiation that shows a possible mechanism for the aberrant mesenchymal to epithelial transition of SS and suggests that it might better be considered an epithelial to mesenchymal transition.

Joseph CG, Hwang H, Jiao Y, et al.
Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas.
Genes Chromosomes Cancer. 2014; 53(1):15-24 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest were mutations in H3F3A, encoding the variant histone H3.3. Mutations in this gene have only been previously observed in gliomas. Loss of heterozygosity of exomic regions was extensive in osteosarcomas but rare in SYN and MLPS. These results provide intriguing nucleotide-level information on these relatively uncommon neoplasms and highlight pathways that help explain their pathogenesis.

Falkenstern-Ge RF, Kimmich M, Grabner A, et al.
Primary pulmonary synovial sarcoma: a rare primary pulmonary tumor.
Lung. 2014; 192(1):211-4 [PubMed] Related Publications
INTRODUCTION: Pulmonary sarcomas overall are very uncommon and comprise only 0.5 % of all primary lung malignancies. The diagnosis is established only after sarcoma-like primary lung malignancies and a metastatic extrathoracic sarcoma have been excluded. Synovial sarcoma accounts for ~8 % of soft-tissue sarcomas. Synovial sarcoma arising from the pleura has rarely been reported.
METHODS: We report a case of a 58-year-old woman who complained of right-sided chest pain and shortness of breath. Chest CT scan revealed a large heterogeneous mass, occupying most of the right hemithorax. Histologic diagnosis was supplemented by interphase cytogenetic (FISH) analysis.
RESULTS: Computed tomography guided Tru-cut biopsy was suspicious for a sarcomatous or fibrous malignancy. However, intraoperative frozen-section diagnostics confirmed the diagnosis of a sarcoma. Immunohistochemistry showed that tumor cells expressed epithelial membrane antigen, CD99 and BCL2. Based on immunohistochemistry, the diagnosis of synovial sarcoma was suspected and was confirmed by FISH analysis. The patient was treated with right upper bilobectomy. Due to R1-resection status, postsurgical systemic chemotherapy was administered.
CONCLUSIONS: Primary pulmonary synovial sarcoma is a rare primary lung tumor. Due to extensive size of the tumor with pleural and mediastinal invasion only a R1-resection status could be achieved by thoracic surgery.

Yoneda Y, Ito S, Kunisada T, et al.
Truncated SSX protein suppresses synovial sarcoma cell proliferation by inhibiting the localization of SS18-SSX fusion protein.
PLoS One. 2013; 8(10):e77564 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Synovial sarcoma is a relatively rare high-grade soft tissue sarcoma that often develops in the limbs of young people and induces the lung and the lymph node metastasis resulting in poor prognosis. In patients with synovial sarcoma, specific chromosomal translocation of t(X; 18) (p11.2;q11.2) is observed, and SS18-SSX fusion protein expressed by this translocation is reported to be associated with pathogenesis. However, role of the fusion protein in the pathogenesis of synovial sarcoma has not yet been completely clarified. In this study, we focused on the localization patterns of SS18-SSX fusion protein. We constructed expression plasmids coding for the full length SS18-SSX, the truncated SS18 moiety (tSS18) and the truncated SSX moiety (tSSX) of SS18-SSX, tagged with fluorescent proteins. These plasmids were transfected in synovial sarcoma SYO-1 cells and we observed the expression of these proteins using a fluorescence microscope. The SS18-SSX fusion protein showed a characteristic speckle pattern in the nucleus. However, when SS18-SSX was co-expressed with tSSX, localization of SS18-SSX changed from speckle patterns to the diffused pattern similar to the localization pattern of tSSX and SSX. Furthermore, cell proliferation and colony formation of synovial sarcoma SYO-1 and YaFuSS cells were suppressed by exogenous tSSX expression. Our results suggest that the characteristic speckle localization pattern of SS18-SSX is strongly involved in the tumorigenesis through the SSX moiety of the SS18-SSX fusion protein. These findings could be applied to further understand the pathogenic mechanisms, and towards the development of molecular targeting approach for synovial sarcoma.

Bozzani A, Arici V, Ragni F, Sagrada PF
Clinical suspicion of bilateral carotid body paraganglioma and an unexpected histologic diagnosis.
Ann Vasc Surg. 2014; 28(1):262.e9-11 [PubMed] Related Publications
Carotid body tumor (CBT) is the most common of the head and neck paragangliomas (PGLs). Conversely, synovial sarcomas are usually located around knee and ankle joint and rare variants occur in the oral cavity. A 68-year-old man presented with a left voluminous painless cervical mass. The diagnosis of CBT of type III Shamblin was suspected. The cervical mass was removed en bloc. Unexpectedly, pathologic examination showed monophasic synovial sarcoma. Excision of PGLs remains the therapy of choice, especially to make a correct histologic diagnosis.

Schoolmeester JK, Cheville JC, Folpe AL
Synovial sarcoma of the kidney: a clinicopathologic, immunohistochemical, and molecular genetic study of 16 cases.
Am J Surg Pathol. 2014; 38(1):60-5 [PubMed] Related Publications
We report the clinicopathologic and immunohistochemical features of 16 cases of genetically confirmed primary synovial sarcoma of the kidney. The cases occurred in 9 men and 7 women ranging in age from 17 to 78 years (mean, 46 y). The tumors were grossly large, solid, and variably cystic (2.2 to 19.0 cm; mean 8.6 cm). Microscopically, all tumors were of the monophasic type and diffusely immunoreactive for TLE1 and BCL-2. Focal pankeratin positivity was found in just under half. Ten cases carried an SS18-SSX2 fusion transcript, and 5 cases showed an SS18-SSX1 transcript by reverse transcription polymerase chain reaction. The remaining case demonstrated SS18 rearrangement by fluorescence in situ hybridization. Clinical follow-up information was available for 12 patients (range, 1 to 77 mo; mean, 32.5 mo). Fourteen patients underwent radical nephrectomy, and 3 patients had lung metastases at presentation. Six patients died of disease within 1 to 58 months (mean, 31 mo) of their diagnosis. Five patients were alive without evidence of disease 12 to 77 months (mean, 39 mos) after surgery. A single patient was alive with metastases to the spine 11 months after surgery. We conclude that renal synovial sarcoma is an aggressive tumor, with adverse patient outcome in >50% of cases. Synovial sarcoma must be distinguished from morphologically similar lesions of the kidney.

Yoshino M, Sekine Y, Koh E, et al.
Pericardial synovial sarcoma: a case report and review of the literature.
Surg Today. 2014; 44(11):2167-73 [PubMed] Related Publications
Primary pericardial synovial sarcoma is a rare disease. We herein report a case of synovial sarcoma that originated in the epicardium. A 13-year-old male visited our hospital with a fever and chest pain. Copious pericardial effusion and a large intrapericardial tumor were detected. An open-chest tumor resection was performed. A solid nodular tumor was observed in the pericardial cavity. The tumor was a polypoid mass that was pedunculated and grew from the inner surface of the pericardium near the origin of the SVC and ascending aorta. Histologically, the tumor cells were uniformly spindle shaped, with an ovoid or oval nucleus, and formed solid, compact sheets and fascicles. A storiform pattern was also observed. Based on the histopathological and immunohistochemical findings, and the fluorescence in situ hybridization detection of rearrangement of the SYT gene, a monophasic synovial sarcoma was diagnosed. We discuss the diagnosis and treatment of this case and review the pertinent literature.

Ren T, Lu Q, Guo W, et al.
The clinical implication of SS18-SSX fusion gene in synovial sarcoma.
Br J Cancer. 2013; 109(8):2279-85 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The aim of this study is to evaluate distribution and clinical impact of the SS18-SSX fusion gene in patients with synovial sarcoma in China.
METHODS: We collected and analysed the clinical data of 88 patients using univariate and multivariate survival analysis. HEK 293T and NIH 3T3 cell lines were transfected with the SS18-SSX1 or SS18-SSX2 gene to determine the respective involvement of these fusion genes in cell proliferation and invasion.
RESULTS: Overall survival was significantly better among SS18-SSX2 cases (P=0.001), FNCLCC grade 2 cases (P<0.001), and UICC stage 1 or 2 (P<0.001) by univariate and multivariate survival analysis. SS18-SSX1-positive cells were more proliferative and invasive than SS18-SSX2-positive cells.
CONCLUSION: SS18-SSX fusion type is a significant prognostic factor for patients with synovial sarcoma.

Kang Y, Pekmezci M, Folpe AL, et al.
Diagnostic utility of SOX10 to distinguish malignant peripheral nerve sheath tumor from synovial sarcoma, including intraneural synovial sarcoma.
Mod Pathol. 2014; 27(1):55-61 [PubMed] Related Publications
Synovial sarcoma and malignant peripheral nerve sheath tumor pose a significant diagnostic challenge given similar histomorphology. The distinction is further complicated by similar immunophenotype and especially by occasional synovial sarcomas that present as intraneural tumors. Although the presence of a t(X;18) rearrangement or expression of TLE1 can help confirm the diagnosis of synovial sarcoma, negative results for these tests are not diagnostic of malignant peripheral nerve sheath tumor. The SOX10 transcription factor, a putative marker of neural crest differentiation, may have diagnostic utility in this differential, but immunohistochemical data are limited. The goal of the present study was to determine the diagnostic utility of SOX10 to discriminate between synovial sarcoma and malignant peripheral nerve sheath tumor. Forty-eight cases of malignant peripheral nerve sheath tumor, all from patients with documented neurofibromatosis, and 97 cases of genetically confirmed synovial sarcoma, including 4 intraneural synovial sarcomas, were immunohistochemically stained for SOX10. The stain was scored for intensity and fraction of cells staining. Thirty-two of 48 malignant peripheral nerve sheath tumors (67%) were SOX10-positive. The majority of malignant peripheral nerve sheath tumors showed ≥2+ staining, but staining did not correlate with grade. By contrast, only 7/97 (7%) synovial sarcomas were SOX10-positive. Only three synovial sarcomas showed ≥2+ staining but, importantly, two of these were intraneural synovial sarcoma. Therefore, SOX10 is a specific (93%), albeit not very sensitive (67%), diagnostic marker to support a diagnosis of malignant peripheral nerve sheath tumor over synovial sarcoma. Furthermore, the stain needs to be interpreted with caution in intraneural tumors in order to avoid a potential diagnostic pitfall. It remains to be determined whether SOX10-positive cells in intraneural synovial sarcoma represent entrapped Schwann cells, synovial sarcoma cells or both.

Barham W, Frump AL, Sherrill TP, et al.
Targeting the Wnt pathway in synovial sarcoma models.
Cancer Discov. 2013; 3(11):1286-301 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
UNLABELLED: Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.
SIGNIFICANCE: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans.

Sahara S, Otsuki Y, Egawa Y, et al.
Primary synovial sarcoma of the stomach--a case report and review of the literature.
Pathol Res Pract. 2013; 209(11):745-50 [PubMed] Related Publications
Synovial sarcoma (SS) is a mesenchymal spindle cell tumor which displays variable epithelial differentiation. It commonly arises around the major joints or tendon sheaths in young adults, but is not commonly seen in the stomach. We experienced a case of primary gastric SS. The patient is a 22-year-old male, who presented with epigastric pain. Upper endoscopy showed an ulcer of 25 mm in diameter with marginal elevation on the posterior mid-gastric body. Biopsy of the ulcer base showed monotonous proliferation of small spindle-shaped cells on HE-stain. On immunohistochemical staining, these cells were positively stained with vimentin, cytokeratin, epithelial membrane antigen, and CD99, but were negative for KIT, CD34, desmin, and S-100 protein. These findings were compatible with SS of monophasic type. Diagnosis of primary gastric SS was made because there were no other primary lesions, nor metastatic lesions. The wedge resection was performed. Reverse transcriptase polymerase chain reaction (RT-PCR), using the RNA from frozen neoplastic tissue of the resected specimen, detected a fusion gene called SYT-SSX1, specific for SS. Though SS arising in the stomach is rare, it should be considered in the differential diagnosis of KIT-negative gastric spindle cell tumor.

Xiong B, Chen M, Ye F, et al.
Primary monophasic synovial sarcoma of the liver in a 13-year-old boy.
Pediatr Dev Pathol. 2013 Sep-Oct; 16(5):353-6 [PubMed] Related Publications
Synovial sarcoma originating in the liver is extremely rare, and thus far only 3 cases have been reported in the English literature. Herein, we report a primary hepatic synovial sarcoma in a 13-year-old Chinese boy. This patient present with a 10-day right upper quadrant pain, and a heterogeneous mass was documented in the right hepatic lobe by computed tomography. Subsequently, the patient underwent right hepatectomy. Histologically, the tumor exhibited classic features of monophasic synovial sarcoma. The diagnosis was confirmed by the presence of SS18 gene rearrangement and identification of SS18-SSX1 fusion transcript. Unfortunately, a relapsing mass was detected 11 months after the surgery. To the best of our knowledge, the current case is the 1st published example in the pediatric population.

Henderson DW, Reid G, Kao SC, et al.
Challenges and controversies in the diagnosis of malignant mesothelioma: Part 2. Malignant mesothelioma subtypes, pleural synovial sarcoma, molecular and prognostic aspects of mesothelioma, BAP1, aquaporin-1 and microRNA.
J Clin Pathol. 2013; 66(10):854-61 [PubMed] Related Publications
Pleural malignant mesothelioma (MM) includes several unusual and even rare but distinctive histological subtypes, in addition to the usual subdivision into epithelioid, biphasic and sarcomatoid MM. Criteria for discrimination between fibrous pleuritis versus desmoplastic mesothelioma include evidence of neoplastic invasion for diagnosis of desmoplastic MM, but this histological assessment is complicated by the recently-described 'fake fat phenomenon' in cases of fibrous pleuritis. The distinction between biphasic and monophasic synovial sarcoma of the pleura versus biphasic and sarcomatoid MM can be problematical and is most cogently based upon molecular detection of the t(X;18) translocation, whereas a clear diagnosis of MM for a pleural tumour histologically resembling synovial sarcoma is favoured by a negative result for this translocation and, probably, microRNA evidence supportive of a diagnosis of MM. Aquaporin-1 (AQP1) is a molecule involved in the growth of MM cells, and yet is a factor reported to correlate with improved survival rates for MM with an epithelioid component, in comparison to AQP1-poor MM, as assessed from AQP1 expression by epithelioid MM cells only (apart from co-expression by stromal endothelial cells in addition to the tumour cells). Recent reports have also focused upon germline mutations in the BRCA1-associated protein 1 (BAP1), not only in cases of familial mesothelioma, but also BAP1 deletion in sporadic MM. Prognostic factors for MM include not only the histological subtypes, but other independent variables that include (among others), AQP1 expression by mesothelioma cells, the clinical status of the patient, the serum neutrophil:lymphocyte ratio and blood thrombocytosis.

Ichimura H, Kikuchi S, Ozawa Y, Matsuzaki K
Primary synovial sarcoma of the lung successfully resected under temporary bypass.
Interact Cardiovasc Thorac Surg. 2013; 17(3):588-90 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
A 48-year old man presented with chest pain and haemoptysis. Chest computed tomography showed a 60-mm mass in the left upper lobe of the lung, adjacent to the distal aortic arch. Bronchoscopic cytology revealed the presence of malignant cells and, in the absence of evidence of distant metastasis, a thoracotomy was performed. Although the tumour was firmly adherent to the distal aortic arch, under temporary bypass from the left subclavian artery to the descending aorta, it was successfully resected en bloc with the section of the aorta attached to it. The tumour was diagnosed as a primary synovial sarcoma of the lung on the basis of histopathological findings and fluorescent chromogenic in situ hybridization, showing SS18 gene rearrangement.

Carmody Soni EE, Schlottman S, Erkizan HV, et al.
Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma.
Clin Orthop Relat Res. 2014; 472(3):874-82 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Most synovial sarcomas contain a chromosomal translocation t(X;18), which results in the formation of an oncoprotein SS18-SSX critical to the viability of synovial sarcoma.
QUESTIONS/PURPOSES: We (1) established and characterized three novel synovial sarcoma cell lines and asked (2) whether inhibition of SS18-SSX1 decreases cell viability in these cell lines; and (3) whether reduction in viability after SS18-SSX1 knockdown is caused by apoptosis. After identifying a specific posttranscriptional splice variant in our cell lines, we asked (4) whether this provides a survival benefit in synovial sarcoma.
METHODS: Cells lines were characterized. SS18-SSX1 knockdown was achieved using a shRNA system. Cell viability was assessed by WST-1 analysis and apoptosis examined by caspase-3 activity.
RESULTS: We confirmed the SS18-SSX1 translocation in all cell lines and identified a consistent splicing variant. We achieved successful knockdown of SS18-SSX1 and with this saw a significant reduction in cell viability. Decreased viability was a result of increased apoptosis. Reintroduction of the exon 8 sequence into cells reduced cell viability in all cell lines.
CONCLUSIONS: We confirmed the presence of the SS18-SSX1 translocation in our cell lines and its importance in the survival of synovial sarcoma. We have also demonstrated that reduction in cell viability is related to an increase in apoptosis. In addition, we have identified a potential mediator of SS18-SSX function in exon 8.
CLINICAL RELEVANCE: SS18-SSX represents a tumor-specific target in synovial sarcoma. Exploitation of SS18-SSX and its protein partners will allow us to develop potent tumor-specific therapeutic agents.

Yin L, Chen M, Ye F, et al.
A poorly differentiated synovial sarcoma arising from the pulmonary valve.
Cardiovasc Pathol. 2013 Nov-Dec; 22(6):501-2 [PubMed] Related Publications
Synovial sarcoma originating in the pulmonary valve is extremely rare. Herein, we report a poorly differentiated synovial sarcoma arising from this peculiar location in a 17-year-old Chinese boy. Histologically, this tumor was entirely poorly differentiated with uniform small round cell morphology, and it exhibited prominent myxoid change in some areas. The diagnosis was confirmed by the presence of SS18 rearrangement and identification of the SS18-SSX1 fusion transcript. To the best of our knowledge, the present case is the first published example of synovial sarcoma occurring in the pulmonary valve. Additionally, this is the first case showing entirely uniform small round cell morphology without classic areas of synovial sarcoma.

Kato K, Tanaka M, Toyoda Y, et al.
A novel fluorescence in situ hybridization assay for synovial sarcoma.
Pathol Res Pract. 2013; 209(5):309-13 [PubMed] Related Publications
Synovial sarcoma, which is difficult to diagnose precisely, is one of the most common childhood nonrhabdomyosarcoma soft-tissue sarcomas. The purpose of this study is to develop new molecular cytogenetic assay. We used two sets of two-color break-apart FISH probes, flanking either the SSX1/SSX4 or SSX2 locus. Each set of probes is composed of differentially labeled DNA fragments complementary to sequences proximal or distal to the break point within the SSX1/SSX4 or SSX2 locus, which are applied separately to histopathological sections. Interphase nuclei containing a translocation that disrupts either SSX1, SSX2, or SSX4 locus will display two single-color signals that have "broken apart" from each other. We applied it to two synovial sarcoma cell lines and clinical samples. This assay can detect translocation at either SSX1/SSX4, or SSX2 locus on interphase spread prepared from synovial sarcoma cell line and histopathological sections, which is sufficient to diagnose as synovial sarcoma. Our new FISH assay has several advantages, including its applicability to paraffin-embedded samples, discrimination of the SS18-SSX1 and SS18-SSX2 translocations particularly in cases with aneuploidy, and potentially detecting translocations in all cases of synovial sarcoma, even with variant translocations. Our strategy will improve the accuracy of diagnoses, thereby facilitating appropriate treatment planning.

Pereira E Silva R, Leitão T, Correia L, et al.
Primary synovial sarcoma of the kidney with unusual follow up findings.
Can J Urol. 2013; 20(2):6734-6 [PubMed] Related Publications
We present a case report of a 17-year-old patient with a large renal mass that was detected on a computed tomography scan during investigation for secondary hypertension. Radical nephrectomy was performed and the morphologic and immunocytochemical findings were compatible with a diagnosis of monophasic synovial sarcoma of the kidney. A cytogenetic search for t(X;18) translocation was performed, which was negative. The patient underwent an ifosfamide-based chemotherapy regimen. During follow up, a positron emission tomography scan showed increased 18F-fluorodeoxyglucose metabolism at the right femur. Although cancer cells were expected in the biopsy specimen, only fibrous dysplasia of the bone was found. The patient was disease free at his 29 month follow up check up.

Michels S, Trautmann M, Sievers E, et al.
SRC signaling is crucial in the growth of synovial sarcoma cells.
Cancer Res. 2013; 73(8):2518-28 [PubMed] Related Publications
Synovial sarcoma is a soft-tissue malignancy characterized by a reciprocal t(X;18) translocation encoding a chimeric transcriptional modifier. Several receptor tyrosine kinases have been found activated in synovial sarcoma; however, no convincing therapeutic concept has emerged from these findings. On the basis of the results of phosphokinase screening arrays, we here investigate the functional and therapeutic relevance of the SRC kinase in synovial sarcoma. Immunohistochemistry of phosphorylated SRC and its regulators CSK and PTP1B (PTPN1) was conducted in 30 synovial sarcomas. Functional aspects of SRC, including dependence of SRC activation on the SS18/SSX fusion proteins, were analyzed in vitro. Eventually, synovial sarcoma xenografts were treated with the SRC inhibitor dasatinib in vivo. Activated phospho (p)-(Tyr416)-SRC was detected in the majority of tumors; dysregulation of CSK or PTP1B was excluded as the reason for the activation of the kinase. Expression of the SS18/SSX fusion proteins in T-REx-293 cells was associated with increased p-(Tyr416)-SRC levels, linked with an induction of the insulin-like growth factor pathway. Treatment of synovial sarcoma cells with dasatinib led to apoptosis and inhibition of cellular proliferation, associated with reduced phosphorylation of FAK (PTK2), STAT3, IGF-IR, and AKT. Concurrent exposure of cells to dasatinib and chemotherapeutic agents resulted in additive effects. Cellular migration and invasion were dependent on signals transmitted by SRC involving regulation of the Rho GTPases Rac and RhoA. Treatment of nude mice with SYO-1 xenografts with dasatinib significantly inhibited tumor growth in vivo. In summary, SRC is of crucial biologic importance and represents a promising therapeutic target in synovial sarcoma.

Soria-Céspedes D, Galván-Linares AI, Oros-Ovalle C, et al.
Primary monophasic synovial sarcoma of the tonsil: immunohistochemical and molecular study of a case and review of the literature.
Head Neck Pathol. 2013; 7(4):400-3 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Synovial sarcoma (SS) arises primarily in the lower extremities with a predilection for sites in proximity to large joints, such as the knee. It rarely occurs in the head and neck region, and the tonsil is an unusual site for the tumor, with only eight previously published cases in this anatomical site. We present a case of a primary monophasic SS arising in the right tonsil in a 63-year-old male. His medical history was noncontributory. Immunohistochemistry showed that cytokeratin OSCAR, EMA, Bcl-2, vimentin, PGP 9.5, and TLE1 were diffusely positive. A molecular analysis using RT-PCR indicated that the patient was positive for the SYT/SSX1 fusion transcript. A diagnosis of monophasic synovial sarcoma of the tonsil was made.

Shelekhova KV, Calonje E, Grossmann P, et al.
Superficial soft tissue biphasic synovial sarcoma with apocrine differentiation in the glandular component: a report of two cases.
Am J Dermatopathol. 2014; 36(10):847-52 [PubMed] Related Publications
: The authors present 2 cases of a subcutaneous biphasic synovial sarcoma with marked apocrine differentiation that potentially may be confused with cutaneous epithelial neoplasms, including malignant apocrine mixed tumor or metaplastic carcinoma with an apocrine glandular component. Microscopically, both neoplasms had a biphasic architecture with the epithelial and spindle cell components. The epithelial component was prominent and consisted of simple glands with round lumina and complex glandular structures with intraluminal bridges forming cribriform areas. The glands were lined by cuboidal to columnar cells with eosinophilic or clear cytoplasm manifesting apical apocrine-like and intraluminal eosinophilic secretions. The spindle cell component was less prominent and was composed of relatively uniform or slightly atypical spindle sells surrounding and merging focally with the glandular structures. Immunohistochemically, the tumor cells in both components were positive for vimentin, AE1/AE3, CK7, and epithelial membrane antigen. Desmin, smooth muscle actin, muscle-specific actin, CD34, and S-100 protein were all negative. SYT-SSX1 gene fusion using fluorescence in situ hybridization and RT-PCR methods was detected in both cases.

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