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Pulmonary metastases from pleomorphic adenoma (PA)-spectrum salivary gland neoplasms are rare and may be difficult to diagnose, particularly in limited pulmonary specimens. We aimed to characterize their clinicopathologic and molecular features and highlight practical diagnostic pitfalls.

We conducted a retrospective single-institution study of three patients with pathologically confirmed pulmonary metastases from PA-spectrum salivary gland neoplasms. Clinical history, histomorphology, immunophenotype, and PLAG1 break-apart fluorescence in situ hybridization findings were reviewed. Targeted next-generation sequencing was performed on the two metastasizing pleomorphic adenoma (MPA) lesions, and a focused literature-based comparison was undertaken.

Two pulmonary lesions were classified as histologically bland MPA, whereas the third was classified as metastatic carcinoma ex pleomorphic adenoma (CXPA) with a myoepithelial carcinoma component. In one MPA, apparent focal TTF-1 and Napsin A immunoreactivity in a core biopsy was attributable predominantly to entrapped pneumocytes rather than convincing expression in the neoplastic component, creating a potential pitfall for misdiagnosis as primary pulmonary adenocarcinoma. PLAG1 rearrangement was detected in all three pulmonary lesions. Targeted sequencing identified an ARID1A loss-of-function alteration and a TSHR variant considered potentially of germline origin in one MPA; the sequencing findings in the other MPA were of uncertain clinical significance.

Pulmonary PA-lineage metastases may be histologically bland or overtly malignant. Entrapped pneumocytes may cause misleading TTF-1 and Napsin A immunoreactivity in limited pulmonary specimens. PLAG1 FISH provides useful support for PA-lineage origin but does not independently distinguish MPA from metastatic CXPA. Integrated assessment of clinical history, morphology, immunophenotype, and molecular findings is essential for accurate classification.