Histomolecular Features of a Rare Subtype of Pleomorphic Adenoma Characterised by Abundant Lymphoid Stroma and HMGA2 Rearrangements

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AIMS: To describe the morphological features and explore the molecular profiles of pleomorphic adenomas (PA) with abundant lymphoid stroma and HMGA2 rearrangements, and to compare them with classic lymphadenomas, in order to identify a potential molecular and morphological overlap. METHODS: Four cases of PA with abundant lymphoid stroma and HMGA2 rearrangements were identified from four different institutions in France and Japan. Their characterisation was performed through a detailed pathological, immunohistochemical, and molecular analysis. RESULTS: All tumours were well-circumscribed and encapsulated, predominantly composed of ductal and tubular structures with scattered myoepithelial cells embedded within a dense lymphoid stroma rich in non-atypical lymphocytes. Immunohistochemistry was positive for CK7, p63, p40, SOX10, S100, and HMGA2, and negative for PLAG1. The Ki67 proliferation index was low. Molecular analyses revealed no MDM2 amplification and excluded EBV infection. Clonality studies confirmed a polyclonal lymphoid infiltrate. Targeted DNA and RNA sequencing found no mutation; however, three cases harboured HMGA2::WIF1 fusions and one harboured HMGA2::RPSAP52 fusion. In the transcriptomic analysis, these tumours clustered together with classic lymphadenomas, separated from other salivary gland neoplasms. CONCLUSIONS: The present study reports four cases of pleomorphic adenoma characterised by abundant lymphoid stroma and HMGA2 rearrangements, for which transcriptomic analysis found that the lymphoid stroma shared a profile similar to that observed in lymphadenomas. Given this distinctive morphological and molecular feature, we propose the designation "lymphadenoma-like" for this novel subtype of pleomorphic adenoma.

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