Advances in Clinical and Experimental Dentistry 1 . Department of Oral Pathology, Faculty of Dentistry, Horus University in Egypt Correspondence: Prof. Nagla Salama, Email: nsalama@horus.edu.eg DOI: 10.21608/ACED.2023.250605.1025 Research Article A subset of plasmacytoid pleomorphic adenoma showing CTNNB1::PLAG1 fusion Nagla Salama 1 , PhD and Mahmoud Fathy 1 , PhD Abstract Background This study aimed to explore the morphological, clinical, and molecular aspects of pleomorphic adenoma (PA) and myoepithelial salivary gland neoplasms, investigating their behavior and potential diagnostic markers. Objective This article further explores and expands upon this spectrum of molecularly labeled subsets showing specific morphologic features. Method Tissue samples from 25 cases of PA were examined, and RNA next-generation sequencing (NGS) was performed on paraffin-embedded sections using the Illumina TruSight RNA Pan-cancer panel. Cellular characteristics, clinical attributes, and molecular profiles were assessed to identify unique features and potential diagnostic indicators. Results PA, a prevalent benign tumor, exhibited diverse morphologies and posed risks of recurrence and malignant transformation. Notably, specific metaplasias within PA cells hinted at microenvironment changes and potential behavioral variations. Furthermore, plasmacytoid myoepitheliomas, more aggressive than PA, posed challenges in accurate differentiation. In 12 out of 25 cases, the presence of the CTNNB1:PLAG1 fusion gene alongside plasmacytoid cells confirmed the diagnosis of plasmacytoid pleomorphic adenoma. Advances in knowledge The identification of specific metaplasias and fusion genes, notably CTNNB1-PLAG1, provided diagnostic insights, potentially influencing improved diagnostics and targeted treatments in the future. Keywords: Salivary gland tumors, pleomorphic adenoma, plasmacytoid