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Lasota J, Chłopek M, Kaczorowski M, Natálie K, Ryś J, Kopczyński J, Sulaieva O, Michal M, Kruczak A, Harazin-Lechowska A, Szczepaniak M, Koshyk O, Hałoń A, Czapiewski P, Abdullaev Z, Kowalik A, Aldape KD, Michal M, Miettinen M. Utility of Immunohistochemistry With Antibodies to SS18-SSX Chimeric Proteins and C-Terminus of SSX Protein for Synovial Sarcoma Differential Diagnosis. Am J Surg Pathol 2024; 48:97-105. [PMID: 37899499 DOI: 10.1097/pas.0000000000002144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Synovial sarcoma is a relatively common soft tissue tumor characterized by highly specific t(X;18)(p11;q11) translocation resulting in the fusion of SS18 with members of SSX gene family. Typically, detection of SS18 locus rearrangement by fluorescence in situ hybridization or SS18 :: SSX fusion transcripts confirms the diagnosis. More recently, immunohistochemistry (IHC) for SS18-SSX chimeric protein (E9X9V) and C-terminus of SSX (E5A2C) showed high specificity and sensitivity for synovial sarcoma. This study screened a cohort of >1000 soft tissue and melanocytic tumors using IHC and E9X9V and E5A2C antibodies. Three percent (6/212) of synovial sarcomas were either negative for SS18-SSX or had scattered positive tumor cells (n=1). In these cases, targeted RNA next-generation sequencing detected variants of SS18 :: SSX chimeric transcripts. DNA methylation profiles of 2 such tumors matched with synovial sarcoma. A few nonsynovial sarcoma tumors (n=6) revealed either focal SS18-SSX positivity (n=1) or scattered positive tumor cells. However, targeted RNA next-generation sequencing failed to detect SS18 :: SSX transcripts in these cases. The nature of this immunopositivity remains elusive and may require single cell sequencing studies. All synovial sarcomas showed positive SSX IHC. However, a mosaic staining pattern or focal loss of expression was noticed in a few cases. Strong and diffuse SSX immunoreactivity was also seen in epithelioid sclerosing osteosarcoma harboring EWSR1 :: SSX1 fusion, while several sarcomas and melanocytic tumors including cellular blue nevus (5/7, 71%) revealed focal to diffuse, mostly weak to intermediate SSX staining. The SS18-SSX and SSX IHC is a useful tool for synovial sarcoma differential diagnosis, but unusual immunophenotype should trigger molecular genetic testing.
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Affiliation(s)
- Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
| | - Małgorzata Chłopek
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
- Department of Molecular Diagnostics, Holycross Cancer Center
| | - Maciej Kaczorowski
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
- Department of Clinical and Experimental Pathology, Wrocław Medical University, Wrocław
| | - Klubíčková Natálie
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Janusz Ryś
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Cracow Branch, Krakow, Poland
| | | | - Oksana Sulaieva
- Department of Clinical Pathology, Medical Laboratory Care and Safe Diagnostics (CSD), Kyiv, Ukraine
| | - Michael Michal
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Anna Kruczak
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Cracow Branch, Krakow, Poland
| | - Agnieszka Harazin-Lechowska
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Cracow Branch, Krakow, Poland
| | | | | | - Agnieszka Hałoń
- Department of Clinical and Experimental Pathology, Wrocław Medical University, Wrocław
| | - Piotr Czapiewski
- Department of Pathology, Staedtisches Klinikum Dessau, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau
- Institute of Pathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Zied Abdullaev
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holycross Cancer Center
- Division of Medical Biology, Institute of Biology Jan Kochanowski University, Kielce
| | - Kenneth D Aldape
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
| | - Michal Michal
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
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Ogino S, Konishi H, Ichikawa D, Hamada J, Shoda K, Arita T, Komatsu S, Shiozaki A, Okamoto K, Yamazaki S, Yasukawa S, Konishi E, Otsuji E. Detection of fusion gene in cell-free DNA of a gastric synovial sarcoma. World J Gastroenterol 2018; 24:949-956. [PMID: 29491688 PMCID: PMC5829158 DOI: 10.3748/wjg.v24.i8.949] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 01/11/2018] [Accepted: 01/19/2018] [Indexed: 02/06/2023] Open
Abstract
Synovial sarcoma (SS) is genetically characterized by chromosomal translocation, which generates SYT-SSX fusion transcripts. Although SS can occur in any body part, primary gastric SS is substantially rare. Here we describe a detection of the fusion gene sequence of gastric SS in plasma cell-free DNA (cfDNA). A gastric submucosal tumor was detected in the stomach of a 27-year-old woman and diagnosed as SS. Candidate intronic primers were designed to detect the intronic fusion breakpoint and this fusion sequence was confirmed in intron 10 of SYT and intron 5 of SSX2 by genomic polymerase chain reaction (PCR) and direct sequencing. A locked nucleic acid (LNA) probe specific to the fusion sequence was designed for detecting the fusion sequence in plasma and the fusion sequence was detected in preoperative plasma cfDNA, while not detected in postoperative plasma cfDNA. This technique will be useful for monitoring translocation-derived diseases such as SS.
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Affiliation(s)
- Shinpei Ogino
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Junichi Hamada
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Katsutoshi Shoda
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Sanae Yamazaki
- Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Satoru Yasukawa
- Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Eiichi Konishi
- Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
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Carmody Soni EE, Schlottman S, Erkizan HV, Uren A, Toretsky JA. Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma. Clin Orthop Relat Res 2014; 472:874-82. [PMID: 23716114 PMCID: PMC3916608 DOI: 10.1007/s11999-013-3065-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
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.
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Affiliation(s)
- Emily E. Carmody Soni
| | - Silke Schlottman
| | - Hayriye V. Erkizan
| | - Aykut Uren
| | - Jeffrey A. Toretsky
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Recurrent and novel SS18-SSX fusion transcripts in synovial sarcoma: description of three new cases. Tumour Biol 2012; 33:2245-53. [PMID: 22976541 PMCID: PMC3501176 DOI: 10.1007/s13277-012-0486-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 08/09/2012] [Indexed: 12/30/2022] Open
Abstract
Synovial sarcoma (SS) is an aggressive type of tumor, comprising approximately 10 % of soft tissue sarcomas. Over 90 % of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of oncogenic SS18-SSX1 or SS18-SSX2 fusions. In a typical SS18-SSX fusion transcript, exon 10 of SS18 is fused to exon 6 of SSX1/2. However, several variant fusion transcripts have been already described. In the present study, we examined the fusion transcript type in a series of 40 primary untreated SS tumor specimens using reverse transcription polymerase chain reaction and fluorescence in situ hybridization assay. We detected SS18-SSX1 transcript in 22 (55 %) patients and SS18-SSX2 transcript in 17 (42.5 %) patients, while in one patient, none of SS18-SSX1/2 fusion transcripts were identified. Among the cases under study, two tumors carried novel SS18-SSX1 and SS18-SSX2 variant translocations that were allegedly created by an alternative splicing, and in additional case, an unusual translocation variant previously described by other group was found. Our data suggest that alternative splicing may play an important role in novel fusion transcript formation, and additionally we show that it may be a recurrent event in SS. Furthermore, we describe the first case of a complex rearrangement possibly linking SS to REPS2 gene.
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Abdelkrim SB, Trabelsi A, Hammedi F, Boudagga MZ, Bdioui A, Jomaa W, Mokni M. Synovial Sarcoma: A Clinicopathological and Radiological Study of 12 Cases Seen Over 18 Years. World J Oncol 2010; 1:14-18. [PMID: 29147174 PMCID: PMC5649729 DOI: 10.4021/wjon2009.12.1201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Background Synovial sarcoma is a rare malignant soft tissue tumor characterized by a poor outcome. We report herein our experience concerning synovial sarcoma and review its diagnosis, histology, treatment and prognosis. Methods This is a retrospective review, from 1990 to 2007, of cases of synovial sarcoma diagnosed at the Department of Pathology, Farhat Hached hospital, Sousse, Tunisia. The clinical, radiological and pathological features as well as treatment modalities and patient's outcome were recorded. Results From 1990 to 2007, 12 cases of synovial sarcoma have been diagnosed in our department. Patients' mean age at the time of diagnosis was 21 years. There was no sex predominance and the lower extremity was the most commonly involved. A painful tumefaction was the most common presenting symptom. The duration of symptoms ranged from 6 months to 6 years. Malignancy was suspected on radiological findings in only 2 cases. Ten patients underwent surgery, in association with adjuvant chemotherapy in 4 cases, one of whom underwent post-operative radiotherapy. Histological subtypes included monophasic synovial sarcoma in 8 cases, biphasic synovial sarcoma in 3 cases and poorly differentiated synovial sarcoma in one case. At the time of analysis, 6 patients were dead with an average follow-up of 18 months. Conclusions Synovial sarcoma is a rare malignancy with a propensity for young adults and a poor prognosis. Its symptomatology is non-specific and it is characterized by histopathological diversity. Diagnosis can be suggested by radiology and definitive diagnosis is achieved after pathological analysis.
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Affiliation(s)
| | - Amel Trabelsi
- Department of Pathology, Farhat Hached Hospital, Sousse, Tunisia
| | - Faten Hammedi
- Department of Pathology, Farhat Hached Hospital, Sousse, Tunisia
| | | | - Ahlem Bdioui
- Department of Pathology, Farhat Hached Hospital, Sousse, Tunisia
| | - Wafa Jomaa
- Department of Pathology, Farhat Hached Hospital, Sousse, Tunisia
| | - Moncef Mokni
- Department of Pathology, Farhat Hached Hospital, Sousse, Tunisia
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Dimitriadis E, Rontogianni D, Kyriazoglou A, Takou A, Frangia K, Pandis N, Trangas T. Novel SYT-SSX fusion transcript variants in synovial sarcoma. ACTA ACUST UNITED AC 2009; 195:54-8. [PMID: 19837269 DOI: 10.1016/j.cancergencyto.2009.06.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2009] [Revised: 06/09/2009] [Accepted: 06/10/2009] [Indexed: 11/15/2022]
Abstract
Synovial sarcoma (SS) is characterized by the t(X;18)(p11.2;q11.2) chromosomal translocation detected in >95% of cases. Through this translocation, one of the SYT genes, SYT4 on chromosome 18, is fused to one of the SSX genes on chromosome X. SYT4-SSX1 is the most common fusion subtype, present in approximately two thirds of the cases, followed by SYT4-SSX2 and, very rarely, SYT4-SSX4. Variant fusion transcripts occur less often, and most of the reported cases are the result of small insertions. Described here is a novel fusion variant containing a small deletion resulting in an alternative reading frame of the SSX part of the fusion gene. This fusion transcript may provide further insight into the oncogenic function of the SSX partner of the fusion gene.
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Iwasaki H, Nabeshima K, Nishio J, Jimi S, Aoki M, Koga K, Hamasaki M, Hayashi H, Mogi A. Pathology of soft-tissue tumors: Daily diagnosis, molecular cytogenetics and experimental approach. Pathol Int 2009; 59:501-21. [DOI: 10.1111/j.1440-1827.2009.02401.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Fisher C. Soft tissue sarcomas with non-EWS translocations: molecular genetic features and pathologic and clinical correlations. Virchows Arch 2009; 456:153-66. [DOI: 10.1007/s00428-009-0776-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Revised: 03/27/2009] [Accepted: 04/14/2009] [Indexed: 12/15/2022]
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