Histology and immunophenotype of NTRK1-rearranged histiocytosis. Low magnification photomicrographs of 2 exemplary skin lesions with either a well-limited pushing nodule in the dermis (A; AP30) or a more infiltrative lesion with finger-like borders (B; AP16). Histiocytes were medium sized with eosinophilic cytoplasm in early type lesions (C; AP11), whereas mature lesions contained larger mononucleated cells with a foamy cytoplasm (D; AP30) and multinucleated Touton giant cells (E; AP17). Some multinucleated cells demonstrated emperipolesis (arrow). Case AP25 was early type in the upper part and mature in the deep dermis (F). (A-F) Hematoxylin and eosin staining. Immunohistochemistry with pan-TRK (G-K) showing strong expression of multinucleated cells (G; AP19) and mononucleated spindle cells (H; AP31) and milder expression in an early type lesion (I; AP32). Positive cells were detectable within the epidermis in a few cases (J; AP12). In this early type lesion, only a fraction of the mononucleated histiocytes expressed pan-TRK (K; AP09). Cells were positive with histiocyte markers, such as PU.1 (L; AP10), and some also expressed S100 (M; AP24). Frequent positivity for cyclin D1 (N; AP30) and phosphorylated extracellular signal-regulated kinase (phophoERK) (O; AP32) confirmed the activation of the MAPK pathway in these neoplasms with NRTK1 fusions.