Models of Oral Epithelial Dysplasia: A Systematic Review and Temporal Analysis

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck, associated with substantial morbidity and mortality worldwide. Oral epithelial dysplasia (OED) can precede OSCC, offering a critical window for preventive and therapeutic intervention. This review maps the historical and current landscape of in vitro and in vivo models of OED, providing insight into their strengths, limitations, and translational relevance.

A systematic review and temporal analysis were conducted following PRISMA guidelines, with literature searches performed across Medline, EMBASE, EBM Reviews, and Web of Science.

From 4009 records, 292 studies from 26 countries were included, yielding 307 models of OED. Only a minority of studies (17.4%) focused primarily on dysplasia as a precancerous condition. In vivo models predominated (88.9%), while in vitro systems were comparatively scarce and largely limited to 2D cultures. Organoid-based approaches were rarely reported, highlighting a gap in advanced model development. Reproducibility data were available for 125 studies (45.8%). The hamster emerged as the most frequently used animal [n = 96, 35%], and 4-nitroquinoline-1-oxide (4-NQO) remained the most common carcinogen, particularly in murine models. A strong sex bias was observed, with male animals heavily over-represented.

Overall, models of OED remain under-represented and under-developed, particularly in comparison to innovations in other fields of cancer research. Despite the central role of OED in oral carcinogenesis, current models do not adequately reflect clinical diversity or exploit modern 3D and patient-derived technologies. This review provides a critical reference point to guide future studies toward more accurate, reproducible, and clinically relevant models, with the potential to advance prevention, early detection, and targeted therapies for OSCC.