Comparative Transcriptomic and Immune Profiling Reveals a Shared Molecular Identity Between Clear Cell Odontogenic Carcinoma and Hyalinizing Clear Cell Carcinoma

Clear cell odontogenic carcinoma (CCOC) and hyalinizing clear cell carcinoma (HCCC), rare head-and-neck malignancies with recurrent EWSR1::CREB family fusions, show overlapping morphologic and immunophenotypic features; no standardized systemic therapy for either exists. Given tissue constraints, the molecular relationship of CCOC and HCCC to each other and to relevant head-and-neck cancers remains incompletely defined. We used spatial transcriptomic profiling, multiplex immunofluorescence (mIF), and RNA in situ hybridization (RNA-ISH) to characterize the molecular and immune landscape of CCOC, HCCC, and relevant head-and-neck and fusion-associated comparators. Key transcriptomic findings were validated by RNA-ISH (image-based signal quantification), complemented by mIF-defined immune-cell composition, antigen-presentation features, and architecture. CCOC and HCCC demonstrated highly overlapping transcriptomic profiles; clear cell sarcoma, despite shared EWSR1::CREB family fusion contexts, remained distinct. CCOC and HCCC showed enrichment of a shared epithelial-secretory program, with ductal, luminal, and regulated secretory pathway features. IGF2, among the most enriched shared transcripts, showed strong tumor-cell associated expression. Candidate targets included: TACSTD2 (TROP2), FGFR2, FOLR1, KDR, MSLN, and MUC1. mIF profiling demonstrated low B2M and HLA-I expression, sparse lymphoid infiltration, minimal PD-L1 expression, and an overall immune-cold phenotype, consistent with impaired antigen presentation. Transcriptome-wide evidence showed CCOC and HCCC share a common molecular identity, particularly distinct from myoepithelial carcinoma and squamous cell carcinoma. Implications: This study - the most comprehensive molecular comparison to date of CCOC and HCCC, set against each other and relevant differential diagnoses - establishes a shared molecular framework that may improve diagnostic classification and guide biomarker and therapeutic development for these exceptionally rare tumors.