Salivary gland carcinomas with BRAF fusions - an exceedingly rare and yet poorly characterized group of tumors, with potentially targetable molecular alteration.

Alterations of BRAF, most commonly the V600E point mutation, are uncommon in salivary gland tumors, while BRAF fusions are exceptionally rare. We report four salivary gland tumors harboring BRAF fusions. The cohort included three males and one female aged 30-67 years (median, 46 years), all with tumors arising in the parotid gland. Two tumors were classified as intraductal carcinoma of oncocytic and mixed oncocytic-intercalated duct subtype, harboring AGK::BRAF and PAPSS1::BRAF fusions. In both cases, tumor cells were positive for S100, SOX10, and mammaglobin, and negative for androgen receptor. One tumor was diagnosed as low-grade acinic cell carcinoma with an SND1::BRAF fusion; tumor cells expressed SOX10, DOG1, and NR4A2 (Nurr1), but were negative for S100 and NOR1. The fourth tumor, classified as high-grade salivary adenocarcinoma, not otherwise specified, harbored an AGK::BRAF fusion and showed unusual morphology, including monolayered tubules and trabeculae, and focal papillary formations. Tumor cells were columnar with enlarged, overlapping vesicular nuclei and pale cytoplasm, expressing GATA3, S100, SOX10, and DOG1, while lacking mammaglobin expression. Focal p63/p40 positivity suggested a possible preexisting in situ component. BRAF fusions are exceedingly rare in salivary gland tumors and may occur across different histologic types. Given their potential sensitivity to MEK or next-generation RAF inhibitors, comprehensive molecular testing is essential for identifying patients who may benefit from targeted therapies.