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.

Department of Clinical and Experimental Pathology Wrocław Medical University Wrocław

Department of Clinical Pathology Medical Laboratory Care and Safe Diagnostics Kyiv Ukraine

Department of Molecular Diagnostics Holycross Cancer Center

Department of Pathology Holycross Cancer Center

Department of Pathology Staedtisches Klinikum Dessau Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg Dessau

Department of Tumor Pathology Maria Skłodowska Curie National Research Institute of Oncology Cracow Branch Krakow Poland

Division of Medical Biology Institute of Biology Jan Kochanowski University Kielce

Institute of Pathology Otto von Guericke University Magdeburg Magdeburg Germany

Laboratory of Pathology National Cancer Institute Bethesda MD

Medical Laboratory CSD Kyiv Ukraine

Sikl's Institute of Pathology Faculty of Medicine and Teaching Hospital in Plzen Charles University Plzen Czech Republic

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