Year: 2025
Type: article
Study design: Observational Study
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.
Source: Blood Advances
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
Institutions: Université Paris-Saclay, Assistance Publique – Hôpitaux de Paris, Hôpital Ambroise-Paré, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie, Hôpital Necker-Enfants Malades, Leiden University Medical Center, Cincinnati Children's Hospital Medical Center, University of Cincinnati, University Medical Center Hamburg-Eppendorf, Klinikum Chemnitz, Charles University, University Hospital in Motol, Erasmus MC, Erasmus MC - Sophia Children’s Hospital, University Medical Center Utrecht, Duke Medical Center, University of Pittsburgh, UPMC Health System, University of Pittsburgh Medical Center, Children's Hospital of Philadelphia, Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux, Heinrich Heine University Düsseldorf, Inserm, Sorbonne Université, Hôpital Armand-Trousseau, Centre de Recherche Saint-Antoine, Memorial Sloan Kettering Cancer Center, Rutgers Cancer Institute, Institute of Child Health, Pitié-Salpêtrière Hospital, Centre d'Immunologie et des Maladies Infectieuses, Children's Hospital of Pittsburgh
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Award: Cancer Center Support Grant
OpenAlex ID: W4410025924