GLI1 fusions involving ACTB, MALAT1, PTCH1 and FOXO4 genes have been reported in a subset of malignant mesenchymal tumors with a characteristic nested epithelioid morphology and frequent S100 positivity. Typically, these multilobulated tumors consist of uniform epithelioid cells with bland nuclei and are organized into distinct nests and cords with conspicuously rich vasculature. We herein expand earlier findings by reporting a case of a 34-year-old female with an epithelioid mesenchymal tumor of the palate. The neoplastic cells stained positive for S100 protein and D2-40, whereas multiple other markers were negative. Genetic alterations were investigated by targeted RNA sequencing, and a PTCH1-GLI1 fusion was detected. Epithelioid mesenchymal tumors harboring a PTCH1-GLI1 fusion are vanishingly rare with only three cases reported so far. Due to the unique location in the mucosa of the soft palate adjacent to minor salivary glands, multilobulated growth, nested epithelioid morphology, focal clearing of the cytoplasm, and immunopositivity for S100 protein and D2-40, the differential diagnoses include primary salivary gland epithelial tumors, in particular myoepithelioma and myoepithelial carcinoma. Another differential diagnostic possibility is the ectomesenchymal chondromyxoid tumor. Useful diagnostic clues for tumors with a GLI1 rearrangement include a rich vascular network between the nests of neoplastic cells, tumor tissue bulging into vascular spaces, and absence of SOX10, GFAP and cytokeratin immunopositivity. Identifying areas with features of GLI1-rearranged tumors should trigger subsequent molecular confirmation. This is important for appropriate treatment measures as PTCH1-GLI1 positive mesenchymal epithelioid neoplasms have a propensity for locoregional lymph node and distant lung metastases.

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czech Republic

Department of Oral and Maxillofacial Surgery University Hospital Olomouc Olomouc Czech Republic

Department of Pathology Bioptical Laboratory Ltd Mikulášské náměstí 4 326 00 Pilsen Czech Republic

Department of Pathology Bioptical Laboratory Ltd Pilsen Czech Republic

Department of Pathology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Plastic and Aesthetic Surgery St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Brno Czech Republic

Institute of Biomedicine Pathology University of Turku and Turku University Hospital Turku Finland

Molecular and Genetic Laboratory Bioptical Laboratory Ltd Pilsen Czech Republic

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