TLE1 as a Diagnostic Immunohistochemical Marker for Synovial Sarcoma Emerging From Gene Expression Profiling Studies

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
American Journal of Surgical Pathology (Impact Factor: 5.15). 03/2007; 31(2):240-6. DOI: 10.1097/01.pas.0000213330.71745.39
Source: PubMed


Synovial sarcoma is a soft tissue malignancy defined by the SYT-SSX fusion oncogene. Demonstration of the t(X;18) by cytogenetics, fluorescence in situ hybridization or reverse-transcriptase polymerase chain reaction has become the gold standard for diagnosis, but practical considerations limit the availability of these methods. Gene expression profiling studies performed by several independent groups have consistently identified TLE1 as an excellent discriminator of synovial sarcoma from other sarcomas, including histologically similar tumors such as malignant peripheral nerve sheath tumor. TLE proteins (human homologues of Groucho) are transcriptional corepressors that inhibit Wnt signaling and other cell fate determination signals, and so have an established role in repressing differentiation. We examined the expression of TLE proteins in synovial sarcoma and in a broad range of mesenchymal tumors using tissue microarrays to assess the value of anti-TLE antibodies in the immunohistochemical confirmation of synovial sarcoma. We demonstrate that TLE expression is a consistent feature of synovial sarcoma using both a well-characterized monoclonal antibody recognizing the TLE family of proteins and a commercially available polyclonal antibody raised against TLE1. Both antibodies gave intense and/or diffuse nuclear staining in 91/94 molecularly confirmed synovial sarcomas. Moderate staining is occasionally seen in schwannoma and solitary fibrous tumor/hemangiopericytoma. In contrast, TLE staining is detected much less frequently and at lower levels, if at all, in 40 other mesenchymal tumors. Our findings establish TLE as a robust immunohistochemical marker for synovial sarcoma, and may have implications for understanding the biology of synovial sarcoma and for developing experimental therapies for this cancer.

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    • "Among the differential diagnosis of synovial sarcoma, TLE1 positivity was noted in 16.6 per cent MPNSTs, 40 per cent Ewing sarcomas, while its negativity was observed in epithelioid sarcomas and in a single case of a solitary fibrous tumour and adult fibrosarcoma, respectively. Terry et al17 documented TLE1 positivity in 5 per cent MPNSTs; in 8 per cent of Ewing sarcomas/PNETs; in none of the epithelioid sarcomas and in 30 per cent of solitary fibrous tumors, Kosemehmetoglu et al24 observed TLE1 positivity in 30 per cent MPNSTs; in 33 per cent epithelioid sarcomas; in 20 per cent solitary fibrous tumours, but in none of the Ewing sarcomas. The reason for much lesser staining in the former study was usage of tissue array, instead of standard tissue sections. "
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    ABSTRACT: Background & objectives: Logistic and financial constraints limit application of several available immunohistochemical (IHC) markers and molecular analysis in every case of synovial sarcoma, diagnosed in our settings. Recently, TLE1 has been recognized as a robust IHC marker for diagnosing a synovial sarcoma. Here, we present IHC features of synovial sarcomas, including TLE1 expression in these cases and in some other tumours. Methods: Conventional sections from 42 synovial sarcomas (30 retrospective & 12 prospectively diagnosed) were subjected to TLE1 IHC staining, including 21 tumours confirmed with molecular testing. TLE1 immunostaining was graded from 0, 1+, 2+, 3+, with 2+ or 3+ grades interpreted as positive staining. Results: Of the 42 tumours, 26 (61.9%) were of monophasic spindle cell type, 13 biphasic type (30.9%), two (4.7%) calcifying type and remaining one (2.3%) was a poorly differentiated synovial sarcoma. On immunohistochemistry (IHC), tumours were positive for epithelial membrane antigen (EMA) (26/34, 76.4%), cytokeratin (CK)7 (6/10, 60%), CK/MNF116 (6/21, 28.6%), B cell lymphoma 2 (BCL2) (36/37, 97.3%), cluster of differentiation molecule 99 (MIC2) (23/31, 74.1%) and transducin-like enhancer of split 1 (TLE1) (40/42, 95.2%), while negative for CD34 in all 21 tumours, wherever performed. TLE1 was also positive in tumour controls, including schwannomas (5/5, 100%), neurofibromas (2/2, 100%), malignant peripheral nerve sheath tumors (2/12, 17%) and Ewing sarcomas (4/10, 40%). TLE1 sensitivity for diagnosis of synovial sarcomas was 95.2 per cent. Its overall specificity was 63.7 per cent, whereas with regards to tumors forming its closest differential diagnoses, its specificity was 72 per cent. Interpretation & conclusions: Although molecular confirmation is the diagnostic gold standard for synovial sarcoma, TLE1, in view of its high sensitivity may be a useful marker within the optimal IHC panel comprising EMA, BCL2, MIC2, CD34 and CK7, especially on small biopsy samples, for substantiating a diagnosis of synovial sarcoma. Awareness of TLE1 expression in other tumours and its correct interpretation are necessary.
    The Indian Journal of Medical Research 11/2012; 136(5):766-75. · 1.40 Impact Factor
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    • "Expression profiling of 5520 genes at the mRNA level using microarrays has revealed distinct molecular signatures for 41 sarcomas, thereby providing new markers with potential diagnostic value [6]. Furthermore, expression microarrays have identified robust, novel sarcoma-specific immunohistochemical markers [7–10]. These results are expected to lead to novel therapeutic modalities in the near future. "
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    ABSTRACT: Soft tissue sarcomas are rare and account for less than 1% of all malignant cancers. Other than development of intensive therapies, the clinical outcome of patients with soft tissue sarcoma remains very poor, particularly when diagnosed at a late stage. Unique mutations have been associated with certain soft tissue sarcomas, but their etiologies remain unknown. The proteome is a functional translation of a genome, which directly regulates the malignant features of tumors. Thus, proteomics is a promising approach for investigating soft tissue sarcomas. Various proteomic approaches and clinical materials have been used to address clinical and biological issues, including biomarker development, molecular target identification, and study of disease mechanisms. Several cancer-associated proteins have been identified using conventional technologies such as 2D-PAGE, mass spectrometry, and array technology. The functional backgrounds of proteins identified were assessed extensively using in vitro experiments, thus supporting expression analysis. These observations demonstrate the applicability of proteomics to soft tissue sarcoma studies. However, the sample size in each study was insufficient to allow conclusive results. Given the low frequency of soft tissue sarcomas, multi-institutional collaborations are required to validate the results of proteomic approaches.
    06/2012; 2012(1):876401. DOI:10.1155/2012/876401
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    • "However, the other component TLE1 is a Groucho corepressor that usually interacts with transcriptional activators and functions as a competitive inhibitor to repress transcription (Ali et al., 2010). TLE1 is known to be highly expressed in synovial sarcoma (Terry et al., 2007) and has recently been demonstrated to be a robust diagnostic marker for synovial sarcoma, although its biological function in this disease has been unclear (Foo et al., 2011; Jagdis et al., 2009; Knö sel et al., 2010). "
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    ABSTRACT: Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.
    Cancer cell 03/2012; 21(3):333-47. DOI:10.1016/j.ccr.2012.01.010 · 23.52 Impact Factor
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