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.

  • SS18
  • Synovial Sarcoma
  • Translocation
  • Neoplasm Proteins
  • Biomarkers, Tumor
  • Childhood Cancer
  • TLE1
  • Immunohistochemistry
  • Chromosome 18
  • Messenger RNA
  • Chromosome Mapping
  • Oncogene Fusion Proteins
  • Proto-Oncogene Proteins
  • DNA Sequence Analysis
  • Proteins
  • Oligonucleotide Array Sequence Analysis
  • EGFR
  • Molecular Sequence Data
  • Chromosome Aberrations
  • Soft Tissue Cancers
  • X Chromosome
  • Polymerase Chain Reaction
  • Cancer DNA
  • Cancer RNA
  • Cancer Gene Expression Regulation
  • Adolescents
  • DNA Primers
  • Base Sequence
  • Chromosome X
  • Amino Acid Sequence
  • Immunoenzyme Techniques
  • SS18L1
  • SSX1
  • Survival Rate
  • Karyotyping
  • Gene Expression Profiling
  • Lung Cancer
  • Paraffin Embedding
  • Repressor Proteins
  • FISH
  • Bone Cancer
  • Differential Diagnosis
  • Gene Expression
  • RTPCR
Tag cloud generated 10 March, 2017 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

Olofson AM, Linos K
Primary Intraprostatic Synovial Sarcoma.
Arch Pathol Lab Med. 2017; 141(2):301-304 [PubMed] Related Publications
Primary intraprostatic synovial sarcoma is a rare presentation of an otherwise well-studied disease, and it is one of the few primary sarcomas to occur in the prostate. Ancillary diagnostic techniques including immunohistochemistry and molecular genetics are useful to establish a definitive diagnosis. Despite its unorthodox location, it shares histologic and molecular genetic characteristics with tumors found elsewhere in the body. Most notably, the chromosomal translocation t(X;18)(p11;q11) encodes a chimeric transcription-activating protein, SS18-SSX, which has been identified as the primary driver mutation. The SS18-SSX fusion gene provides a consistent and dependable means of establishing a definitive diagnosis via reverse transcription-polymerase chain reaction or fluorescence in situ hybridization. Recent studies have continued to provide insight into the oncogenesis of this disease. The goal of this review is to elaborate on the clinicopathologic characteristics and underline those techniques that best facilitate the diagnosis of primary intraprostatic synovial sarcoma.

Imura Y, Nakai T, Yamada S, et al.
Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma.
Cancer Sci. 2016; 107(12):1867-1876 [PubMed] Free Access to Full Article Related Publications
Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c-MET signaling in SS. Both HGF and c-MET were highly expressed in Yamato-SS cells, resulting in activation of c-MET and its downstream AKT and extracellular signal-regulated kinase signaling pathways, whereas c-MET was expressed but not activated in SYO-1 or HS-SY-II cells. c-MET-activated Yamato-SS cells showed higher anchorage-independent growth ability and less sensitivity to chemotherapeutic agents than did c-MET-inactivated SYO-1 or HS-SY-II cells. INC280, a selective c-MET inhibitor, inhibited growth of Yamato-SS cells both in vitro and in vivo but not that of SYO-1 or HS-SY-II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c-MET and its downstream effectors in Yamato-SS cells. Co-expression of HGF and c-MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c-MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c-MET-activated SS. HGF/c-MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c-MET inhibitors.

Lan T, Chen H, Xiong B, et al.
Primary pleuropulmonary and mediastinal synovial sarcoma: a clinicopathologic and molecular study of 26 genetically confirmed cases in the largest institution of southwest China.
Diagn Pathol. 2016; 11(1):62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary pleuropulmonary and mediastinal synovial sarcomas (PPMSSs) are extremely rare. The authors present the largest series in an Asian population.
METHODS: Between 2000 and 2015, 26 genetically confirmed PPMSSs were included. The clinicopathologic features of all of the cases were reviewed. Immunohistochemical staining was carried out using the following antibodies: TLE1, cytokeratin (AE1/AE3), EMA, CD99, Bcl-2, CK7, CD34, S-100 protein, and Ki-67. The chromosomal translocation t(X;18)(p11.2;q11.2) was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). We compared the clinical, pathologic, immunohistochemical, and molecular features of this series with that of the previous series and soft tissue synovial sarcomas.
RESULTS: This series included 17 males and nine females. The median age was 36.5 years (range, 16-72 years). The tumors involved the lung (76.9 %), pleura (15.4 %), and mediastinum (7.7 %). The median tumor size was 6 cm (range 2.3 ~ 24 cm). The majority of the tumors were well-circumscribed. The tumors were classified as monophasic (84.6 %), biphasic (3.8 %), and poorly differentiated (11.5 %) types. The tumors were graded as French Federation of Cancer Centers (FNCLCC) grade 2 (62.5 %) and FNCLCC 3 (37.5 %). Diffuse immunostaining for TLE1, BCL-2, and CD99 was identified in 91.7, 95.7, and 56.0 % of the tumors, respectively. Focal positivity was seen with EMA (84.6 %), CK7 (55.6 %), cytokeratin (AE1/AE3) (68.0 %), CD34 (5.0 %), and S-100 protein (21.7 %). A high Ki-67 index (≥10 %) was observed in 91.3 % of the tumors. The fusion transcripts included SS18-SSX1 (15/22, 68.2 %), SS18-SSX2 including variants (6/22, 27.3 %), and SS18-SSX4 (1/22, 4.5 %) fusions. The remaining four cases showed positivity for SS18 rearrangement by FISH. Surgical excision of tumors or lobectomy were performed in 20 patients, and seven of the patients underwent adjuvant therapy. Clinical follow-up was available in 73.1 % cases, with a median follow-up of 12.0 months. The median survival time was 14.5 months. Tumor resection (p = 0.024) and no residual tumor (p = 0.004) were associated with an improved overall survival time.
CONCLUSIONS: PPMSS is a highly aggressive neoplasm. Extensive surgical resection of the tumor and more effective adjuvant therapy should be advocated. PPMSS must be differentiated from similar diseases.

Yamasaki H, Miyamoto M, Yamamoto Y, et al.
Synovial sarcoma cell lines showed reduced DNA repair activity and sensitivity to a PARP inhibitor.
Genes Cells. 2016; 21(8):852-60 [PubMed] Related Publications
Synovial sarcoma is a soft-tissue sarcoma and a rare type of cancer. Unfortunately, effective chemotherapies for synovial sarcomas have not been established. In this report, we show that synovial sarcoma cell lines have reduced repair activity for DNA damage induced by ionizing radiation (IR) and a topoisomerase II inhibitor (etoposide). We also observed reduced recruitment of RAD51 homologue (S. cerevisiae; RAD51) at sites of double-strand breaks (DSBs) in synovial sarcoma cell lines that had been exposed to IR. These findings showed that synovial sarcoma cell lines are defective in homologous recombination (HR) repair. Furthermore, we found that a poly-(ADP-ribose) polymerase (PARP) inhibitor (AZD2281; olaparib) effectively reduced the growth of synovial sarcoma cell lines in the presence of an alkylating agent (temozolomide). Our findings offer evidence that treatment combining a PARP inhibitor and an alkylating agent could have therapeutic benefits in the treatment of synovial sarcoma.

Norlelawati AT, Mohd Danial G, Nora H, et al.
Detection of SYT-SSX mutant transcripts in formalin-fixed paraffin-embedded sarcoma tissues using one-step reverse transcriptase real-time PCR.
Malays J Pathol. 2016; 38(1):11-8 [PubMed] Related Publications
BACKGROUND: Synovial sarcoma (SS) is a rare cancer and accounts for 5-10% of adult soft tissue sarcomas. Making an accurate diagnosis is difficult due to the overlapping histological features of SS with other types of sarcomas and the non-specific immunohistochemistry profile findings. Molecular testing is thus considered necessary to confirm the diagnosis since more than 90% of SS cases carry the transcript of t(X;18)(p11.2;q11.2). The purpose of this study is to diagnose SS at molecular level by testing for t(X;18) fusion-transcript expression through One-step reverse transcriptase real-time Polymerase Chain Reaction (PCR).
METHOD: Formalin-fixed paraffin-embedded tissue blocks of 23 cases of soft tissue sarcomas, which included 5 and 8 cases reported as SS as the primary diagnosis and differential diagnosis respectively, were retrieved from the Department of Pathology, Tengku Ampuan Afzan Hospital, Kuantan, Pahang. RNA was purified from the tissue block sections and then subjected to One-step reverse transcriptase real-time PCR using sequence specific hydrolysis probes for simultaneous detection of either SYT-SSX1 or SYT-SSX2 fusion transcript.
RESULTS: Of the 23 cases, 4 cases were found to be positive for SYT-SSX fusion transcript in which 2 were diagnosed as SS whereas in the 2 other cases, SS was the differential diagnosis. Three cases were excluded due to failure of both amplification assays SYT-SSX and control β-2-microglobulin. The remaining 16 cases were negative for the fusion transcript.
CONCLUSION: This study has shown that the application of One-Step reverse transcriptase real time PCR for the detection SYT-SSX transcript is feasible as an aid in confirming the diagnosis of synovial sarcoma.

Ogino H, Hanibuchi M, Takizawa H, et al.
Primary Pulmonary Synovial Sarcoma Showing a Prolonged Survival with Multimodality Therapy.
Intern Med. 2016; 55(4):381-7 [PubMed] Related Publications
A 54-year-old man was referred to our hospital due to a mass shadow noted on a chest X-ray. Thoracoscopic lobectomy yielded a diagnosis of primary pulmonary synovial sarcoma according to the histology and SYT-SSX1 gene analyses. Five months after the thoracic surgery, he developed brain metastasis; therefore, we performed resection of the brain metastatic focus followed by radiotherapy. As a local recurrence in the thoracic cavity concurrently emerged, systemic chemotherapy was also administered. These observations indicated that a multidisciplinary approach may be useful against primary pulmonary synovial sarcoma, although there is presently no established therapeutic strategy due to its rarity and highly aggressive nature.

Taylor M, Srinivasan L, Abid Q
Primary pulmonary monophasic synovial sarcoma: Evading diagnosis.
Asian Cardiovasc Thorac Ann. 2016; 24(2):214-7 [PubMed] Related Publications
Primary pulmonary synovial sarcoma is a very rare tumor, thus there is no consensus as to the most appropriate management. A 78-year-old man presented with nonspecific symptoms of weight loss and shortness of breath. Imaging confirmed a large right-sided mass and accompanying pleural effusion. Strong 18F-fluorodeoxyglucose uptake was found on positron-emission tomography. The preoperative work-up and intraoperative frozen section were inconclusive. Immunohistochemistry and molecular analysis confirmed the diagnosis of primary pulmonary monophasic synovial sarcoma.

Ito J, Asano N, Kawai A, Yoshida A
The diagnostic utility of reduced immunohistochemical expression of SMARCB1 in synovial sarcomas: a validation study.
Hum Pathol. 2016; 47(1):32-7 [PubMed] Related Publications
Synovial sarcoma is a malignant mesenchymal neoplasm of uncertain histogenesis, characterized by a specific SS18-SSX fusion. The diagnosis of synovial sarcoma can be challenging based on morphology and conventional immunohistochemistry alone, and identification of the fusion gene by molecular genetics may be necessary for diagnosis. Several recent studies have demonstrated the diagnostic utility of the reduced expression of SMARCB1 in synovial sarcomas as measured using immunohistochemistry. Therefore, we undertook a validation study using synovial sarcomas and other spindle or round cell tumors that could enter differential diagnosis of monophasic or poorly differentiated synovial sarcomas. Among 36 synovial sarcomas that were successfully evaluated, the expression of SMARCB1 was diffusely reduced in 33 cases (92%) at variable degrees. In contrast, the expression of SMARCB1 was not reduced in any of the 93 evaluable non-synovial sarcoma tumors (5 thymomas, 5 sarcomatoid mesotheliomas, 10 schwannomas, 9 mesenchymal chondrosarcomas, 20 solitary fibrous tumors, 19 Ewing sarcomas, and 25 malignant peripheral nerve sheath tumors). A few schwannomas and malignant peripheral nerve sheath tumors showed mosaic or complete loss of SMARCB1 expression. Reduced expression of SMARCB1 immunoreactivity was therefore found to be highly sensitive and specific for synovial sarcoma, and can be useful for rapidly and accurately confirming the diagnosis of synovial sarcoma. This reduction in SMARCB1 expression likely reflects the BAF47 ejection mechanism of the SS18-SSX fusion product and can therefore be viewed as an indirect visualization of this fusion product.

Qi Y, Wang N, Pang LJ, et al.
Identification of potential mutations and genomic alterations in the epithelial and spindle cell components of biphasic synovial sarcomas using a human exome SNP chip.
BMC Med Genomics. 2015; 8:69 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Synovial sarcoma (SS) is one of the most aggressive soft-tissue sarcomas and is noted for late local recurrence and metastasis. It is of uncertain histological origin and exhibits a biphasic histopathological form involving both the mesenchyme and epithelium. Thus, its diagnosis and therapy remain a huge challenge for clinicians and pathologists. This study aimed to determine whether differential morphological-associated genomic changes could aid in ascertaining the histogenesis of SS and to determine whether these sarcomas showed some specific mutated genes between epithelial and spindle cells that would promote tumor invasion and metastasis.
METHODS: We conducted a comprehensive genomic analysis of mesenchymal and epithelial components in 12 formalin-fixed paraffin-embedded biphasic SS samples using the Illumina human exon microarray. Exome capture sequencing was performed to validate the single nucleotide polymorphism (SNP)-chip data, and de novo data were generated using a whole-exome chip with the Illumina exon microarray. Fisher's exact test based on PLINK analysis of the SNP-chip data.
RESULTS: Here, the SNP-chip data showed that 336 SNPs had association P-values of less than 0.05 by chi-square test. We identified 23 significantly mutated genes between epithelial and spindle cell regions of SSs. Fifteen gene mutations were specific for the spindle cell component (65.2 %) and eight for the epithelial cell component (34.8 %). Most of these genes have not been previously reported in SS, and neuroguidin (NGDN), RAS protein activator like 3 (RASAL3), KLHL34 and MUM1L1 have not previously been linked to cancer; only one gene (EP300) has been reported in SS. Genomic analyses suggested that the differential SNPs in genes used for functional enrichment are mainly related to the inflammatory response pathway, adhesion, ECM-receptor interactions, TGF-β signaling, JAK-STAT signaling, phenylalanine metabolism, the intrinsic pathway and formation of fibrin.
CONCLUSIONS: This study investigated novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for SS. The identified pathways may be closely correlated with the pathogenic mechanisms underlying SS, and SS development is associated with morphological features.

Schaffer LR, Caltharp SA, Milla SS, et al.
Rare presentation of four primary pediatric cardiac tumors.
Cardiovasc Pathol. 2016 Jan-Feb; 25(1):72-7 [PubMed] Related Publications
Pediatric cardiac tumors are extremely rare and usually benign. We selected four unique cases of pediatric cardiac tumors from a 15-year period at our institution. The four chosen cases represent unique, rare primary tumors of the heart. Our selection includes a case of Rosai Dorfman disease without systemic involvement, which is, to our knowledge, the second case of isolated cardiac Rosai Dorfman disease in a child. We present a case of subtotal replacement of myocardium by granulocytic sarcoma with minimal bone marrow involvement, representing the first reported case in a child manifested as hypertrophic cardiomyopathy, as well as a case of a primary synovial sarcoma arising from the atrioventricular (AV) node, representing the fourth reported pediatric case of a cardiac synovial sarcoma, and it is the first to arise from the AV node. Finally, we present a primary congenital infantile fibrosarcoma of the heart, which is, to our knowledge, the first confirmed cardiac congenital infantile fibrosarcoma. These four cases represent the need for continued inclusion of rare cardiac conditions in a clinician's differential diagnosis. Furthermore, they present the need for more in-depth molecular and genomic analysis of pediatric cardiac tumors in order to identify their etiopathogenesis.

Vlenterie M, Hillebrandt-Roeffen MH, Flucke UE, et al.
Next generation sequencing in synovial sarcoma reveals novel gene mutations.
Oncotarget. 2015; 6(33):34680-90 [PubMed] Free Access to Full Article Related Publications
Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults.

Mishra S, Awasthi N, Hazra SP, Bera MK
Primary synovial sarcoma of the kidney.
Saudi J Kidney Dis Transpl. 2015; 26(5):996-9 [PubMed] Related Publications
Primary synovial sarcoma (SS) of the kidney is a very rare disease as well as a diagnostic dilemma. Here, we present a case of a 60-year-old male clinically diagnosed as renal cell carcinoma. The radical nephrectomy specimen showed a well-circumscribed renal mass of approximately 13 cm × 9 cm × 7 cm. The cut-surface of the mass was tawny and firm, with cystic areas, and also showed focal hemorrhage and necrosis. Histologically, the tumor was composed of spindle cells arranged in the intersecting fascicles, alternating with hypocellular areas suggestive of monophasic synovial sarcoma. Morphological and immunohistochemical features were compatible with the diagnosis of SS of the kidney.

Sista F, Penna AD, Abruzzese V, et al.
Intestinal Intussusception by Monophasic Synovial Sarcoma: Case Report and Literature Review.
Chirurgia (Bucur). 2015 Jul-Aug; 110(4):391-5 [PubMed] Related Publications
INTRODUCTION: Synovial sarcomas are rare malignant tumors of soft tissues, arising mainly from periarticular structures. Gastrointestinal localizations are unusual presentation of these rare sarcomas.
METHODS: We present the case of a 56- years old man with monophasic synovial sarcoma, arising primarily from the ileum, and causing intussusception. A review of the literature was conducted to gather information about this rare sarcoma.
RESULTS: We found that the criteria normally used to determine the prognosis in patients with monophasic synovial sarcoma of soft tissue are poorly applicable for gastrointestinal localizations.
CONCLUSIONS: A better characterization of these tumors could identify them as a distinct entity, compared with monophasic synovial sarcomas of soft tissues.

Zöllner SK, Rössig C, Toretsky JA
Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer.
Cancer Metastasis Rev. 2015; 34(3):417-28 [PubMed] Related Publications
Patients afflicted with synovial sarcoma share the fate of other translocation positive sarcomas; the driver mutation for this cancer is known, yet no means to target the fusion protein SS18-SSX directly exist. Current chemotherapeutic regimens are minimally beneficial, particularly in patients with metastatic disease. SS18-SSX putatively promotes its oncogenic activity through protein-protein interactions that alter genetic programs through chromatin remodeling. This review discusses the functional protein network of SS18-SSX, both wild-type and fusion protein, considers its intrinsically disordered nature, and provides insights into potential therapeutic strategies. A comprehensive overview of the clinical characteristics reveals the need for newly targeted therapeutics based upon oncogenic transformation by the fusion protein SS18-SSX. The wild-type, non-fused proteins SS18 and SSX are presented including their molecular structure and biological function with regard to protein-protein interactions. The interactions of the wild-type proteins inform the oncogenic changes of the fusion protein. The SS18-SSX fusion protein and its protein interactions are described and evaluated for their biological consequences that lead to oncogenesis. This review illustrates the key protein interactions of SS18-SSX that may qualify as primary targets for small molecule-based disruption leading to the development of SS18-SSX-specific drugs. These novel targeted therapeutics may provide a specificity that ultimately improves survival while reducing morbidity of patients with synovial sarcoma.

Barrott JJ, Illum BE, Jin H, et al.
β-catenin stabilization enhances SS18-SSX2-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition.
Oncotarget. 2015; 6(26):22758-66 [PubMed] Free Access to Full Article Related Publications
β-catenin is a master regulator in the cellular biology of development and neoplasia. Its dysregulation is implicated as a driver of colorectal carcinogenesis and the epithelial-mesenchymal transition in other cancers. Nuclear β-catenin staining is a poor prognostic sign in synovial sarcoma, the most common soft-tissue sarcoma in adolescents and young adults. We show through genetic experiments in a mouse model that expression of a stabilized form of β-catenin greatly enhances synovial sarcomagenesis. Stabilization of β-catenin enables a stem-cell phenotype in synovial sarcoma cells, specifically blocking epithelial differentiation and driving invasion. β-catenin achieves its reprogramming in part by upregulating transcription of TCF/LEF target genes. Even though synovial sarcoma is primarily a mesenchymal neoplasm, its progression towards a more aggressive and invasive phenotype parallels the epithelial-mesenchymal transition observed in epithelial cancers, where β-catenin's transcriptional contribution includes blocking epithelial differentiation.

Fricke A, Ullrich PV, Heinz J, et al.
Identification of a blood-borne miRNA signature of synovial sarcoma.
Mol Cancer. 2015; 14:151 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Synovial sarcoma account for approximately 10 % of all soft-tissue tumors and occur most frequently in young adults. A specific translocation in this sarcoma induces fusion of the SYT gene on chromosome 18 to the SSX genes on chromosome X, leading to proliferation of the tumor cells. The need for non-invasive biomarkers indicating recurrence and activity of this disease has sparked research into short non-coding RNA known as microRNA (miRNA).
METHODS: Blood samples of patients with active synovial sarcoma and of synovial sarcoma patients in complete remission as well as of healthy donors and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma were collected. Whole blood RNA was extracted and samples of patients with active synovial sarcoma and of healthy donors were analyzed using an Affymetrix GeneChip miRNA Array v. 4.0. qRT-PCR was carried out to confirm a panel of miRNAs which where differentially expressed in the miRNA array. This miRNA-panel was further evaluated in patients with synovial sarcoma in complete remission and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma as well as in an independent cohort of synovial sarcoma patients.
RESULTS: Unsupervised hierarchical clustering of the miRNA arrays separated patients with active synovial sarcoma from healthy controls. A panel of seven miRNAs (miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p) was further validated by qRT-PCR to be significantly upregulated in synovial sarcoma patients. Moreover, most of the analyzed miRNAs were shown to be significantly upregulated in synovial sarcoma patients compared to leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma patients. Validation of the miRNA panel in an independent cohort of synovial sarcoma patients confirmed higher expression levels compared to healthy controls and patients in complete remission.
CONCLUSION: Our results have identified a specific whole blood miRNA signature that may serve as an independent biomarker for the diagnosis of local recurrence or distant metastasis of synovial sarcoma. It even distinguishes synovial sarcoma from other sarcoma subtypes, thus potentially serving as a specific biomarker for synovial sarcoma.

Ito J, Suzuki S, Yoshida A, Mori T
Primary intraocular synovial sarcoma in the post retinal detachment operative state.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
Synovial sarcoma generally arises in the deep soft tissue, although it has been described at virtually every anatomic site except in the eyeball. We report the case of a 48-year-old woman who had a history of retinal detachment surgery and who had undergone vitrectomy and the insertion of a solid silicon explant 24 years previously. She reported a visual field defect. Funduscopy and MRI revealed a tumour just behind the iris in the left eyeball, and enucleation was performed. Microscopic examination of the tumour revealed uniform spindle cells in a fascicular arrangement with frequent mitotic figures. Immunohistochemistry showed that the tumour was positive for TLE1 and epithelial membrane antigen and fluorescent in situ hybridisation revealed that the tumour had a rearrangement of the SYT gene. Reverse transcription (RT)-PCR confirmed the presence of a SYT-SSX2 fusion transcript. On the basis of these histomorphological and molecular features, the diagnosis of poorly differentiated synovial sarcoma was rendered.

Huo Z, Lu H, Mao Q, et al.
Primary synovial sarcoma of the right heart involving the tricuspid valve in an elderly Chinese woman: a case report.
Diagn Pathol. 2015; 10:80 [PubMed] Free Access to Full Article Related Publications
Described herein is a 51-year-old woman with abdominal discomfort who was found to have a pericardial effusion and a large mass in her right heart by computed tomography scan and who then underwent tumour resection surgery. The tumour was so extensive that it involved the right atrium, the right ventricle and the tricuspid valve, and encompassed the right coronary artery. The patient had no significant medical history, and no tumour was found at any other site. The morphology of the tumour mimicked carcinosarcoma, exhibiting mixed epithelioid and spindle elements and it was difficult to differentiate the diagnosis even by immunohistochemical stains. Then, the final diagnosis of primary biphasic synovial sarcoma of the heart was established based on the finding of SS18 rearrangement. This is a highly intriguing rare case that may represent a diagnostic pitfall, particularly regarding frozen section. The patient will receive chemotherapy, and we will pursue follow-up.

Vlenterie M, Jones RL, van der Graaf WT
Synovial sarcoma diagnosis and management in the era of targeted therapies.
Curr Opin Oncol. 2015; 27(4):316-22 [PubMed] Related Publications
PURPOSE OF REVIEW: Synovial sarcomas are a distinct soft tissue sarcoma subtype, with a predilection for young adults. Despite its common translocation, there is substantial heterogeneity in patient outcome. This review discusses recent developments in diagnosis, prognostication, and treatments, together with the role of targeted agents and immunotherapy in patients with synovial sarcoma.
RECENT FINDINGS: Tumor behavior of synovial sarcomas remains inexplicable and is therefore poorly predictable. Although many variables seem to contribute to and influence patient outcome, no underlying pathophysiology accounting for the variability in behavior has been unraveled. As prognosis remains poor, there is a wistful search for new therapies. In preclinical testing, several receptor tyrosine kinases have been suggested as therapeutic targets with interesting results in vitro or in vivo. However, translating interesting preclinical outcome to clinical results is difficult, to a large extent due to limited patient numbers available to participate in clinical trials.
SUMMARY: By defining predictive variables, researchers try to understand the underlying cause of this tumor's biologic behavior and develop new therapeutic targets. Owing to the minimal number of prospective studies usually with small patient numbers, the strength of improving patient outcome will be in collaborative international studies in this rare tumor type.

Tajima S, Takahashi T, Itaya T, et al.
Cystic synovial sarcoma of the pleura mimicking a cystic thymoma: a case report illustrating the role of decreased INI-1 expression in differential diagnosis.
Int J Clin Exp Pathol. 2015; 8(3):3262-9 [PubMed] Free Access to Full Article Related Publications
Less than 40 cases of primary pleural synovial sarcoma (SS) have been reported to date. Furthermore, only three cases of cystic SS have been documented in the English literature, including cases originating from sites other than the pleura. Herein, we present an exceedingly rare case of cystic SS originating from the mediastinal side of the visceral pleura in an asymptomatic 47-year-old man, which was detected during a checkup. On contrast-enhanced computed tomography, distinguishing between cystic SS and cystic thymoma was difficult because the tumor was attached to the anterior mediastinum where the latter type of malignancy is more often detected. Histopathological examination showed tumor cells with spindled morphology showing hypercellularity and moderate nuclear atypia, with less than one mitotic figure per high-power field. As these features are associated with both monophasic fibrous SS and type A thymoma, more data was required to determine proper diagnosis, and therefore, immunohistochemistry was performed. Along with a conventional panel of markers, the SS-specific marker integrase interactor 1 (INI-1) was applied and found to be decreased; decreased expression of INI-1 is characteristic of SS. A diagnosis of SS was confirmed by detection of the SYT-SSX fusion gene via fluorescence in situ hybridization. Given the relatively common availability of INI-1 testing in departments of pathology, this protein would be helpful incorporated into the standard panel of markers for diagnosing SS.

Abbas M, Dämmrich ME, Braubach P, et al.
Role of immunohistochemistry and fluorescence in-situ hybridization (FISH) in the diagnosis of spindle and round cell tumors of the kidney.
J Egypt Natl Canc Inst. 2015; 27(3):173-8 [PubMed] Related Publications
UNLABELLED: Spindle cell/mesenchymal tumors of the kidney are rare. The diagnosis is supported mainly by the application of ancillary techniques such as immunohistochemistry (IH) and in-situ hybridization (FISH). An accurate diagnosis is essential because early management by complete resection and adjuvant chemotherapy improves the prognosis dramatically. Synovial sarcoma and primitive neuroectodermal tumor/Ewing sarcoma are infrequent malignancies which usually present in soft tissues but rarely in the kidney. The challenge for the pathologists is to histologically differentiate between different types of sarcomas such as PNET/Ewing's sarcoma, sarcomatous dedifferentiated renal cell carcinoma, metastasis, non-Hodgkin's lymphoma, nephroblastoma and angiomyolipoma.
METHODS: We report from our experience six exemplary rare cases that presented in the kidney as spindle/round cell tumors.
RESULTS: We have arrived at the accurate diagnosis after performing a large panel of IH and FISH.
CONCLUSION: In summary we advise an immunohistochemical panel for round/spindle cell tumors of the kidney and for unclear cases we advise to add (FISH) to get the correct diagnosis, as they are completely different regarding surgical approach and post-operative adjuvant therapy.

Mikami T, Kurose A, Javed F, Takeda Y
Detection of Rare Variant of SS18-SSX1 Fusion Gene and Mutations of Important Cancer-Related Genes in Synovial Sarcoma of the Lip: Gene Analyses of a Case and Literature Review.
J Oral Maxillofac Surg. 2015; 73(8):1505-15 [PubMed] Related Publications
Synovial sarcoma (SS) accounts for 5 to 10% of soft tissue sarcomas; however, intraoral SS is rare. Histopathologically, SS shows a biphasic pattern with epithelial and spindle cell components or a monophasic pattern with only spindle cells. The precise diagnosis of SS, especially at an unusual site, is often a challenge to pathologists and clinical oncologists, because the differential diagnosis of SS includes a broad range of tumors, such as soft tissue sarcomas and carcinomas. In the present case, the patient was a 50-year-old woman who presented with the chief complaint of swelling and a slowly enlarging mass of the lower lip in the mucolabial fold region. The mass was covered with intact mucosa and intraoral examination showed no malignant findings. The clinical diagnosis was a benign tumor and a probable salivary gland tumor. Macroscopically, the excised mass also indicated a benign tumor; however, histopathologic findings suggested the diagnosis of SS. For definitive diagnosis, genetic analyses were performed with conventional polymerase chain reaction and next-generation sequencing. As a result, a rare variant of the SS18-SSX1 fusion transcript, which could not be identified by routine procedures for genetic diagnosis, was detected. In addition, 8 missense mutations of cancer-related genes were confirmed. Detection of the fusion transcript is widely used in the diagnosis of SS; however, reported cases of transcript variants of each fusion gene type are limited. Reports of mutational analysis of cancer-related genes on SS also are rare. The accumulation of rare transcript variants and the cytogenetic characters of SS are suggested to be necessary for assuming a genetic diagnosis of SS.

Maekura T, Shimizu S, Kawaguchi T, et al.
Intravascular synovial sarcoma of the pulmonary artery with massive pleural effusion: report of a case with a favorable response to Ifosfamide chemotherapy and palliative radiation therapy.
Intern Med. 2015; 54(9):1095-8 [PubMed] Related Publications
Synovial sarcoma (SS) commonly arises in the para-articular soft tissue; however, very few cases of intravascular SS have so far been reported. We herein describe a case of pulmonary artery SS with massive pleural effusion. A biopsy of the pleural lesions showed uniform short spindle cell proliferation, while the SYT-SSX fusion gene, which is preceded by chromosomal translocation t(X;18)(p11;q11), was detected using reverse transcription-polymerase chain reaction. Treatment with ifosfamide chemotherapy and palliative radiation therapy was effective in reducing the growth of the tumor in the pulmonary artery and pleural lesions, indicating that this regimen may be useful for the treatment of unresectable SS in the pulmonary artery.

Rekhi B, Vogel U
Utility of characteristic 'Weak to Absent' INI1/SMARCB1/BAF47 expression in diagnosis of synovial sarcomas.
APMIS. 2015; 123(7):618-28 [PubMed] Related Publications
Recently, very few studies have shown value of immunohistochemical (IHC) expression of INI1/SMARCB1 in diagnosis of synovial sarcomas (SSs). This study was aimed at testing reproducibility and utility of this finding. Sixty-eight SSs and 147 other tumours, in the form of various biopsies, were tested for IHC expression of INI1. Twenty-six SSs were further confirmed with positive SS18 rearrangement. Forty monophasic spindle cell type (58.8%), 13 biphasic (19.1%), 12 poorly differentiated (17.6%) and three calcifying SSs (4.4%) were positive for epithelial membrane antigen (EMA) (46/62) (74.1%), pan cytokeratin (AE1/AE3) (31/47) (65.9%), cytokeratin (CK7) (20/31) (64.5%), BCL2 (62/66) (93.9%), MIC2 (61/63) (96.8%), transducin-like enhancer of split 1 (TLE1) (29/31) (93.5%) and CK19 (14/24) (58.3%). INI1 expression was 'weak to absent' in 60/68 (88.2%) SSs; in 1/3 atypical ossifying fibromyxoid tumours (AOFMTs) and in 3/10 (30%) malignant peripheral nerve sheath tumours (MPNSTs) of various types. INI1 was completely absent in 10/10 (100%) epithelioid sarcomas (ESs), 4/4 (100%) malignant rhabdoid tumours, single paediatric undifferentiated sarcoma, 5/19 (26.3%) myoepithelial carcinomas and in 2/4 (50%) epithelioid-subtype of MPNSTs. Remaining 100 tumours, including 12 Ewing sarcomas, 15 carcinomas, eight solitary fibrous tumours (SFT), seven extraskeletal myxoid chondrosarcomas, three fibrosarcomas and other tumours retained INI1 expression. A unique 'weak to absent' IHC expression of INI1 is highly sensitive (88.2%) and specific (97.3%) for a SS, irrespective of its subtypes and types of biopsies. This can be considered useful in diagnosing SSs, especially in settings lacking molecular and/or cytogenetic analysis. A similar INI1 expression is shared by certain AOFMTs and MPNSTs.

Hirose M, Mizuno K, Kamisawa H, et al.
Clear cell sarcoma of the kidney distinguished from synovial sarcoma using genetic analysis: a case report.
BMC Res Notes. 2015; 8:129 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The most common pediatric renal neoplasm is Wilms tumor, but clear cell sarcoma of the kidney or synovial sarcoma of the kidney are also sometimes encountered. Accurate pathological diagnosis is important, because adjuvant therapies including chemotherapy and radiotherapy differ according to the pathological type.
CASE PRESENTATION: A 9-year-old boy presented with a headache, and ultrasonography, computed tomography, and magnetic resonance imaging revealed a heterogeneous enhancement of soft tissue originating from the upper pole of the left kidney, measuring approximately 11.0 × 10.0 × 8.0 cm. A left radical nephrectomy was performed using an intraperitoneal approach through an anterior subcostal incision. Pathological examination suggested clear cell sarcoma of the kidney or synovial sarcoma of the kidney based on morphological and immunohistological features. Using genetic analysis, a final diagnosis of spindle cell pattern clear cell sarcoma of the kidney was made based on the absence of the SYT-SSX fusion gene. After adjuvant chemo-radiotherapy was administered, no recurrence or metastasis has been identified as of 60 months postoperatively.
CONCLUSION: In this case, it was difficult to discriminate clear cell sarcoma of the kidney from synovial sarcoma of the kidney based on histopathological examination alone, and genetic analysis was required. Accurate pathological diagnosis of pediatric renal tumor is important for determining optimal treatment and preventing recurrence and metastasis.

Nielsen TO, Poulin NM, Ladanyi M
Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy.
Cancer Discov. 2015; 5(2):124-34 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Oncogenesis in synovial sarcoma is driven by the chromosomal translocation t(X,18; p11,q11), which generates an in-frame fusion of the SWI/SNF subunit SS18 to the C-terminal repression domains of SSX1 or SSX2. Proteomic studies have identified an integral role of SS18-SSX in the SWI/SNF complex, and provide new evidence for mistargeting of polycomb repression in synovial sarcoma. Two recent in vivo studies are highlighted, providing additional support for the importance of WNT signaling in synovial sarcoma: One used a conditional mouse model in which knockout of β-catenin prevents tumor formation, and the other used a small-molecule inhibitor of β-catenin in xenograft models.
SIGNIFICANCE: Synovial sarcoma appears to arise from still poorly characterized immature mesenchymal progenitor cells through the action of its primary oncogenic driver, the SS18-SSX fusion gene, which encodes a multifaceted disruptor of epigenetic control. The effects of SS18-SSX on polycomb-mediated gene repression and SWI/SNF chromatin remodeling have recently come into focus and may offer new insights into the basic function of these processes. A central role for deregulation of WNT-β-catenin signaling in synovial sarcoma has also been strengthened by recent in vivo studies. These new insights into the the biology of synovial sarcoma are guiding novel preclinical and clinical studies in this aggressive cancer.

Palmerini E, Benassi MS, Quattrini I, et al.
Prognostic and predictive role of CXCR4, IGF-1R and Ezrin expression in localized synovial sarcoma: is chemotaxis important to tumor response?
Orphanet J Rare Dis. 2015; 10:6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. The role of adjuvant chemotherapy is debated. New prognostic and predictive factors are needed.
METHODS: We reviewed patients with localized SS; SS18-SSX fusion transcript presence was confirmed by FISH and RT-PCR. Expression of CXCR4, IGF-1R and Ezrin were evaluated by immunohistochemistry.
RESULTS: Tumor samples from 88 SS patients (45 female; 43 male) with median age 37 years (range 11-63) were selected. The size of the lesion was > 5 cm in 68% of patients and 34% of cases presented biphasic histotype. All patients underwent surgery, 56% adjuvant radiotherapy (RT), 65% adjuvant chemotherapy. A positive stain for IGF-1R was detected in 55 patients, with nucleus expression in 21 patients. CXCR4 was expressed in 74 patients, nuclear pattern in 31 patients. 80 SS were positive to Ezrin, 48 had cytoplasmatic location, 32 membrane location. With a median follow-up of 6 years (1-30 years), the 5-year overall survival (OS) was 70% (95% CI 60-81). 5-year OS was 63% (95% CI 41-85%) for patients with positive IGF-1R/nuclear expression, and 73% (95% CI 61-85%; P = 0.05) in negative patients. 5-year OS was 47% (95% CI 27-66%) in patients with positive CXCR4/nuclear staining, and 86% (95% CI 76-96%, P = 0.0003) in negative cases. No survival difference was found according to Ezrin expression. By multivariate analysis, nuclear expression of CXCR4 and IGF-1R was confirmed independent adverse prognostic factor for SS patient survival linked to the use of chemotherapy.
CONCLUSIONS: Our findings have important potential implications demonstrating that together with clinical prognostic factors such as radiotherapy and age, CXCR4 and IGF-1R negatively influences survival in patients with localized SS. We believe that further studies addressed to the effects of CXCR4 and IGF-1R inhibitors on cell viability and function are needed to plan new and more appropriate SS treatments.

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] Free Access to Full Article 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.

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