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.

Assistance Publique Hôpitaux de Paris Necker Hospital Service de Pathologie Paris France

Department of Dermatology University of Pittsburgh School of Medicine UPMC Pittsburgh PA

Department of Dermatopathology Wizderm Clinics Kolkata India

Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Department of Internal Medicine Section Clinical Immunology and Allergology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Department of Neurology Memorial Sloan Kettering Cancer Center New York NY

Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia Philadelphia PA

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pathology Duke University Medical Center Durham NC

Department of Pathology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Department of Pathology Leiden University Medical Center Leiden The Netherlands

Department of Pathology Memorial Sloan Kettering Cancer Center New York NY

Department of Pathology University Hospital of Bordeaux Bordeaux France

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

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

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty Center of Child and Adolescent Health Heinrich Heine University Düsseldorf Germany

Department of Pediatrics Clinic Chemnitz Chemnitz Germany

Department of Pediatrics Institute of Child Health Kolkata India

Department of Pediatrics University Medical Center Hamburg Eppendorf Hamburg Germany

Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center Cincinnati OH

Division of Pathology Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine Cincinnati OH

French Reference Center for Histiocytosis Department of Pediatric Hematology and Oncology Trousseau Hospital Assistance Publique Hôpitaux de Paris Sorbonne Université Paris France

Paris Saclay University Versailles SQY University EA4340 BECCOH Assistance Publique Hôpitaux de Paris Ambroise Paré Hospital Smart Imaging Service de Pathologie Boulogne France

Sophia Children's Hospital Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

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

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