Novel Histologic Features in Ameloblastoma With RASQ61R Mutation

Ameloblastoma is characterized histologically by evidence of ameloblastic differentiation and molecularly by MAPK pathway alterations, most frequently BRAFV600E mutation and RAS mutations, as well as by SMO mutations. This mutational profile is present across all histologic variants, including those occasionally lacking overt histologic evidence of ameloblastic differentiation, such as desmoplastic ameloblastoma and granular cell ameloblastoma. Recently, we have come across 4 cases of maxillary ameloblastoma demonstrating peculiar histologic features not accounted for by recognized histologic variants. Three intraosseous tumors were remarkably similar in histologic appearance and demonstrated a proliferation of spindled to basaloid cells in solid/sheet-like, cystic, and ribbon-like growth patterns within dense fibrous connective tissue. One case had numerous squamous morules and only 1 case, focally, demonstrated ameloblastic differentiation, yet all 3 cases harbored NRASQ61R mutation. A fourth case harbored HRASQ61R mutation and arose peripherally, in palatal (maxillary) gingiva, as a follicular-patterned neoplasm with bland squamoid morphology and scattered foci of ameloblastic differentiation. RAS Q61R immunohistochemistry was positive in both the tumor and overlying surface epithelium, in support of surface derivation. These 4 cases demonstrate that ameloblastoma may occasionally present with non-traditional histologic features, lacking categorization into known histologic variants and sometimes lacking any evidence of ameloblastic differentiation. In this setting, the differential diagnosis may be broad and include more indolent odontogenic neoplasms such as adenomatoid odontogenic tumor or squamous odontogenic tumor, odontogenic carcinomas, and non-odontogenic neoplasms. A high index of suspicion, followed by confirmatory molecular testing or mutation-specific immunohistochemistry, is necessary for accurate diagnosis.