Transcriptomic comparative study between canalicular adenoma and HMGA2::WIF1 canalicular-like pleomorphic adenoma

Canalicular adenoma (CA) is a benign salivary gland tumor predominantly affecting the upper lip and is characterized by monomorphic epithelial cells arranged in branching cords within a loose and vascularized stroma. Unlike pleomorphic adenoma (PA), CA lacks a chondroid matrix and exhibits specific histological features, such as high cuboidal to columnar cells arranged in one to two cell layers. A recently identified PA subtype, named 'HMGA2-canalicular-like PA', mimics the morphology of CA but affects major salivary glands, and harbors the HMGA2::WIF1 fusion. Immunohistochemical markers including SOX10 positivity and p40/p63 negativity are shared between these entities, raising questions about their molecular differences. Therefore, the current study aimed to extensively compare the molecular profiles of CAs and HMGA2-canalicular-like PAs to better understand the mechanisms underlying their oncogenesis. In the present study, CAs and the HMGA2-canalicular-like PAs mostly shared similar histology and immunostaining, while the clinical presentations regarding tumor site and transcriptomic profiles were different. A novel finding was the overexpression of SOX2 in patients diagnosed with CA, in comparison to those diagnosed with HMGA2-canalicular-like PA. The CAs displayed significantly higher enrichment of hallmarks for Hedgehog signaling, IL2/STAT5 signaling, and apical surface, and significantly lower enrichment of hallmarks for apoptosis and mitotic spindle. Additionally, Gene Ontology enrichment analysis displayed significant enrichment of biological process for CAs in comparison to HMGA2-canalicular-like PAs for myofibril assembly, muscle filament sliding, actin-myosin filament sliding, and sarcomere organization. CAs and HMGA2-canalicular-like PAs exhibited similar histology and immunostaining but differed significantly in tumor site and transcriptomic profiles. The latter revealed significant activation of muscle-related transcriptional pathways, and overexpression of SOX2 in CAs. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.