Molecular and Microenvironmental Mechanisms of Malignant Transformation in Benign Salivary Gland Tumors: Implications for Oral Squamous Cell Carcinoma

Malignant transformation of benign salivary gland tumors represents a critical biological process that provides valuable insights into head and neck carcinogenesis, with potential implications for oral squamous cell carcinoma (OSCC). Understanding the molecular, epigenetic, and microenvironmental mechanisms underlying this transition is essential for improving early diagnosis, risk stratification, and personalized management strategies. This study presents a comprehensive narrative review of the current literature focusing on benign salivary gland tumors with malignant potential, particularly pleomorphic adenoma and carcinoma ex pleomorphic adenoma, emphasizing molecular alterations, angiogenesis, and tumor microenvironment dynamics. A structured literature search was conducted across major biomedical databases, including PubMed and Scopus, selecting studies that addressed genetic rearrangements, epigenetic modifications, histopathological features, and clinical connections of malignant transformation. The findings highlight recurrent genetic alterations such as PLAG1 and HMGA2 rearrangements, TP53 mutations, and ERBB2 overexpression, along with epigenetic dysregulation through CpG island hypermethylation. Enhanced angiogenesis, marked by increased expression of CD105 and vascular endothelial growth factor, as well as a “cold” immune microenvironment, emerged as key contributors to tumor progression. These mechanisms demonstrate significant overlap with pathways implicated in OSCC development. Benign salivary gland tumors represent a valuable model for studying malignant transformation in head and neck oncology. Interpreting shared molecular and microenvironmental pathways may facilitate the identification of novel biomarkers and support the development of personalized diagnostic and therapeutic approaches for OSCC.