Blood Advances (Jul 2025)

NTRK1-rearranged histiocytosis: clinicopathologic and molecular features

  • 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

DOI
https://doi.org/10.1182/bloodadvances.2025016167
Journal volume & issue
Vol. 9, no. 14
pp. 3617 – 3628

Abstract

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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.