New Insights into Ameloblastic Fibromas, Fibrodentinomas, and Fibro-Odontomas: Findings from an International Multicenter Study.

Introduction: Ameloblastic fibroma (AF), ameloblastic fibrodentinoma (AFD), and ameloblastic fibro-odontoma (AFO) are rare mixed odontogenic tumors. While some authors propose that some cases may evolve into odontomas, other tumors with aggressive clinical features suggest a neoplastic origin. A subset of AF and AFD/AFO harbor the pathogenic BRAF p.V600E mutation. SOX9, known for its role in the differentiation of various cell types, particularly in chondrogenesis, has not been previously studied in odontogenic tumors. In this study, we report the clinicopathologic features of a large international cohort of AF and AFD/AFO cases and analyze the immunohistochemical expression of BRAF p.V600E and SOX9.

Materials and methods: Clinical and radiographic data were collected from four Oral and Maxillofacial Pathology service archives spanning from 1991 to 2024. Deidentified slides were reviewed by two independent oral pathologists. Immunohistochemical staining for BRAF p.V600E and SOX9 was performed on non-decalcified tissue samples from cases with available specimens.

Results: A total of 62 tumors were identified, including 30 AF cases and 32 AFD/AFO cases. The cohort consisted of 33 male and 29 female patients, with average ages of 15.3 years for AF and 12.3 years for AFD/AFO. Tumors predominantly affected the posterior mandible and appeared as unilocular or multilocular radiolucent or mixed lesions, often causing tooth impaction and cortical expansion, with an average size of 3.7 cm for AF and 2.5 cm for AFD/AFO. Two cases were classified as peripheral AF/AFD. Microscopically, all cases exhibited cellular mesenchymal components resembling dental papilla, with branching strands and islands of odontogenic epithelium. AFD/AFO cases also displayed dental hard tissue, and occasional chondromyxoid differentiation was observed within the stroma. Rare hybrid tumors were identified, including associations with calcifying odontogenic cysts, cemento-ossifying fibroma and central giant cell granuloma. BRAF p.V600E showed cytoplasmic positivity in the mesenchymal component of AF (81%) and AFD/AFO (54%). SOX9 exhibited diffuse nuclear immunoreactivity in both epithelial and mesenchymal components (92%).

Conclusion: This study represents one of the largest well-documented series of AF and AFO/AFD, providing valuable clinicopathologic and immunohistochemical insights. Additionally, the diffuse expression of SOX9 in both epithelial and mesenchymal components suggests a potential role in odontogenic differentiation, a novel finding that may have implications for understanding the histogenesis of these lesions. The aggressive behavior of some AFs and AFD/AFOs in our study supports their classification as odontogenic neoplasms rather than hamartomas.