Primary Pulmonary Ameloblastoma

Overview

Three solitary peribronchial pulmonary neoplasms (5.4–7.3 cm) exhibiting canonical morphologic and molecular features of ameloblastoma were identified in consultation files from 2022–2025 across three academic centers. Histology demonstrated a predominant stellate reticulum-like component of loosely arranged p40-reactive squamoid-to-spindled cells with long intercellular bridges and streaming architecture, bordered by palisaded columnar cells with focal reverse nuclear polarity. All tumors expressed BRAF V600E by immunohistochemistry and harbored BRAF V600E mutations on molecular testing. Clinical and radiographic evaluation, including panoramic dental radiographs, excluded occult gnathic primaries. No recurrences or metastases have been observed to date.

Methods and approach

Case identification comprised consultation submissions of pulmonary neoplasms between 2022 and 2025 at three academic institutions. Detailed clinicopathologic review included gross pathology, routine histology, and targeted immunohistochemistry (including p40 and BRAF V600E). Molecular characterization employed allele-specific assays and broad next-generation sequencing (NGS) panels in two cases. Clinical correlation entailed review of imaging and dental panoramic radiographs to exclude gnathic primary tumors and follow-up data for outcome assessment.

Results

All three lesions were solitary, peribronchial masses measuring 5.4–7.3 cm. The dominant histologic pattern was stellate reticulum-like cellularity with long intercellular bridges and swirling/streaming architecture, rimmed by palisaded columnar epithelium showing focal reverse polarity adjacent to myxoid stroma. p40 labeled the squamoid-to-spindled cells. BRAF V600E immunohistochemistry was diffusely positive in tumor epithelium in all cases; BRAF V600E mutations were confirmed by molecular assays, including comprehensive NGS in two tumors. Prominent hyperplasia of entrapped pneumocytes created an apparent biphasic pattern in one case, but these entrapped elements were BRAF V600E–negative, supporting non-neoplastic entrapment rather than true biphasia. Comprehensive clinical and radiographic evaluation, including dental panoramic films, failed to identify gnathic primaries. Clinical follow-up to date shows no local recurrence or distant spread.

Implications

These cases constitute the first reported series of primary pulmonary ameloblastomas, demonstrating that pulmonary neoplasms can recapitulate both the histomorphology and BRAF V600E molecular signature of gnathic ameloblastoma. BRAF V600E testing is diagnostically informative for distinguishing true tumor epithelium from entrapped pulmonary epithelium and may inform classification and therapeutic considerations. The findings raise unresolved questions regarding histogenesis—whether these represent odontogenic rests, ectopic ameloblastomatous differentiation, or alternative lineage commitment in respiratory epithelium—necessitating further molecular and developmental investigation. Recognition of this entity is important to avoid misclassification and to guide management, including complete surgical resection and consideration of targeted therapy in appropriate contexts.