Spitz tumours with MET gene fusions: 17 cases with identifiable histomorphological and genetic features

The present study reports a series of 17 melanocytic tumours harbouring activating fusions of MET, which encodes a key receptor tyrosine kinase (RTK) implicated in mitogen-activated protein kinase (MAPK) signalling. Tumours were diagnosed as Spitz naevus (n=12, 71%) or melanocytoma (n=5, 29%). No cases of melanoma were identified. Three histopathological patterns emerged. The first, 'plexiform maturing fascicles' (n=7), was characterised by spindle-shaped melanocytes arranged in superficial fascicles maturing into smaller rounded nests embedded in desmoplasia. The second, 'Reed-like' (n=6), featured spindled or epithelioid melanocytes at the dermoepidermal junction with epidermal hyperplasia and scattered melanophages. The third, 'BAP1-inactivated melanocytoma-like' (n=2), showed predominantly intradermal epithelioid melanocytes with pleomorphism and a brisk inflammatory infiltrate. Two cases could not be classified in these pattern categories. Cases classified as melanocytomas more frequently exhibited cellular atypia; for example, prominent nucleoli or giant atypical melanocytes. Moreover, TRIM4::MET fusion genes were identified as a recurring initiating genomic alteration, and tumours with this fusion gene (n=5) showed distinctive features: predominantly intradermal nodular growth, fibromyxoid stroma, intercellular clefting, and nested melanocytes. MET fusion kinases represent targetable genetic alterations, with potential therapeutic implications in melanomas. Recognising these three histopathological patterns provides critical insights for diagnosis and targeted ancillary testing.