NTRK1-rearranged histiocytosis: clinicopathologic and molecular features

NTRK1-rearranged histiocytosis: clinicopathologic and molecular features

Abstract: 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...

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Main Authors: Rivers Fragneau, Sylvie Fraitag, Paul G. Kemps, Zofia Hélias-Rodzewicz, Somak Roy, Benjamin Bonsang, Allison L. Bartlett, Subhra Dhar, Martin Jankofsky, Jozef Zlocha, Karel Svojgr, Lenka Krsková, Andrica C. H. de Vries, Robert M. Verdijk, Jan A. M. van Laar, Roos J. Leguit, Philippe Drabent, Eric D. Carlsen, Jonhan Ho, Arivarasan D. Karunamurthy, Mariarita Santi, Marie-Laure Jullié, Florian Babor, Robert Lorsbach, Astrid G. S. van Halteren, Sébastien Héritier, Eli L. Diamond, Benjamin H. Durham, Ashish R. Kumar, Arunaloke Bhattacharya, Julien Haroche, Jean Donadieu, Arndt Borkhardt, Jennifer L. Picarsic, Jean-François Emile
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Blood Advances
Online Access:http://www.sciencedirect.com/science/article/pii/S2473952925002691
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Summary:Abstract: 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 using 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 that required 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 of 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 of 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.
ISSN:2473-9529

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