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
Affiliations
- Rivers Fragneau
- Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Assistance Publique–Hôpitaux de Paris, Ambroise-Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France
- Sylvie Fraitag
- Assistance Publique–Hôpitaux de Paris, Necker Hospital, Service de Pathologie, Paris, France
- Paul G. Kemps
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
- Zofia Hélias-Rodzewicz
- Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Assistance Publique–Hôpitaux de Paris, Ambroise-Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France
- Somak Roy
- Division of Pathology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
- Benjamin Bonsang
- Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Assistance Publique–Hôpitaux de Paris, Ambroise-Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France
- Allison L. Bartlett
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Subhra Dhar
- Department of Dermatopathology, Wizderm Clinics, Kolkata, India
- Martin Jankofsky
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Jozef Zlocha
- Department of Pediatrics, Clinic Chemnitz, Chemnitz, Germany
- Karel Svojgr
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
- Lenka Krsková
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic; Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
- Andrica C. H. de Vries
- Sophia Children’s Hospital, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Robert M. Verdijk
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Jan A. M. van Laar
- Department of Internal Medicine, Section Clinical Immunology and Allergology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Roos J. Leguit
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
- Philippe Drabent
- Assistance Publique–Hôpitaux de Paris, Necker Hospital, Service de Pathologie, Paris, France
- Eric D. Carlsen
- Department of Pathology, Duke University Medical Center, Durham, NC; Department of Pathology, Duke University Medical Center, Durham, NC
- Jonhan Ho
- Department of Dermatology, University of Pittsburgh School of Medicine, UPMC, Pittsburgh, PA
- Arivarasan D. Karunamurthy
- Department of Dermatology, University of Pittsburgh School of Medicine, UPMC, Pittsburgh, PA; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Mariarita Santi
- Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA
- Marie-Laure Jullié
- Department of Pathology, University Hospital of Bordeaux, Bordeaux, France
- Florian Babor
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany
- Robert Lorsbach
- Division of Pathology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
- Astrid G. S. van Halteren
- Department of Internal Medicine, Section Clinical Immunology and Allergology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Sébastien Héritier
- French Reference Center for Histiocytosis, Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France
- Eli L. Diamond
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY
- Benjamin H. Durham
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
- Ashish R. Kumar
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Arunaloke Bhattacharya
- Department of Pediatrics, Institute of Child Health, Kolkata, India
- Julien Haroche
- Sorbonne University, Internal Medicine Department 2, Institut E3M, French Reference Centre for Histiocytosis, Pitié-Salpȇtrière Hospital, CIMI INSERM-UMRS 1135, Assistance Publique–Hôpitaux de Paris, Paris, France
- Jean Donadieu
- French Reference Center for Histiocytosis, Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France
- Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany
- Jennifer L. Picarsic
- Division of Pathology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pathology, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA; Correspondence: Jennifer L. Picarsic, Department of Pathology, University of Pittsburgh School of Medicine, UPMC Children’s Hospital, 4401 Penn Ave, Main Hospital-Lab-B 260, Pittsburgh, PA 15224;
- Jean-François Emile
- Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Assistance Publique–Hôpitaux de Paris, Ambroise-Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France; Jean-François Emile, Service de Pathologie, Hôpital Ambroise-Paré, 9 Ave Charles de Gaulle, 92104 Boulogne, France;
- DOI
- https://doi.org/10.1182/bloodadvances.2025016167
- Journal volume & issue
-
Vol. 9,
no. 14
pp. 3617 – 3628
Abstract
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.