https://orcid.org/0009-0007-7208-9058
Key Points
NTRK1-rearranged histiocytosis often presents as one or multiple cutaneous xanthogranulomas, but may rarely involve extracutaneous tissues.
Targeted therapy with the TRK-inhibitor larotrectinib is highly effective in patients with severe extracutaneous disease.
Non-Langerhans cell histiocytoses are a diverse group of histiocytic diseases. Different entities are defined based on clinical, histopathologic, and/or molecular characteristics. This study aimed to define NTRK-rearranged histiocytosis. Through international collaboration, we investigated 50 cases of histiocytosis with pan-tropomyosin receptor kinase (pan-TRK) expression and/or in-frame NTRK rearrangement. We also analyzed 45 control xanthogranulomas by pan-TRK immunohistochemistry and targeted RNA sequencing. Slides were centrally reviewed; clinical and molecular data were collected. The 50 cases comprised 30 children and 20 adults, with a median age of 11.5 years (range 0-73 years) and a male predominance (64%). Most patients (88%) had disease limited to the skin, including a single skin nodule in 41 patients and multiple skin lesions in 3 others. Four newborns presented with skin lesions, hepatomegaly, and thrombocytopenia requiring transfusions. The 2 remaining patients had life-threatening lesions of the brain or bronchus. All cases displayed xanthogranuloma histology, often including foamy histiocytes and Touton giant cells. Histiocytes stained positive for pan-TRK in 50/50 cases, whereas all 45 control xanthogranulomas without in-frame NTRK fusions stained negative. NTRK1 fusion partners included IRF2BP2 (23/46), TPM3 (12/46), SQSTM1 (3/46), PRDX1 (3/46), NPM1 (2/46), LMNA (2/46) and ARHGEF2 (1/46). Clinical outcomes were favorable, including spontaneous disease regression in 3/4 newborns with systemic disease, and rapid clinical response in both patients with a brain or bronchial tumor treated with the TRK inhibitor larotrectinib. This study advances the molecular characterization of histiocytoses and may guide the diagnosis and personalized treatment of patients.
