Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries

Abstract

Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. The discovery of recurrent activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a critical step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations affecting the sonic hedgehog (SHH) pathway, specifically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implications of these discoveries.

Keywords: BRAF; MAPK; RAS; ameloblastoma; odontogenic tumor; therapy.

Figure 1

Histopathology of ameloblastoma. (A) The follicular pattern with islands of odontogenic epithelium within fibrous stroma. The epithelium consists of peripheral palisading cells showing reverse polarization and central loosely arranged cells resembling the stellate reticulum. H&E staining (×100). (B) The plexiform pattern with anastomosing strands of basal cells, delicate stroma, and inconspicuous stellate reticulum. H&E staining (×100).

Figure 2

Schematic of the mitogen activated protein kinase (MAPK) pathway with mutation frequencies in ameloblastoma based on all studies in which each gene was evaluated.–

Figure 3

Summary of BRAF, KRAS, HRAS, NRAS, FGFR2, SMO, PIK3CA, CTNNB1, and SMARCB1 mutations in ameloblastoma based on two studies in which all of these genes were evaluated., Colored boxes indicate the presence of mutations in the indicated genes (rows) and samples (columns). The histologic pattern (plexiform versus non-plexiform) is also indicated (if known).

Figure 4

Relationship between the anatomic location and mutation frequency in ameloblastoma based on all studies in which BRAF, RAS, FGFR2, and SMO were evaluated.–,

Figure 5

Clinical and prognostic significance of the BRAF V600E mutation in ameloblastoma adapted from Brown et al. (A) Box plot showing a statistically significant difference in age distribution for BRAF V600E-mutated and BRAF wild-type ameloblastomas (P = 0.0007). Diamond indicates the mean, middle horizontal line indicates the median, box indicates 25th and 75th percentiles, and whiskers indicate minimum and maximum. (B) Recurrence-free survival (in years) for BRAF V600E-mutated and BRAF wild-type ameloblastomas using the Kaplan–Meier method.