TY - JOUR
T1 - NTRK1-rearranged histiocytosis
T2 - clinicopathologic and molecular features
AU - Fragneau, Rivers
AU - Fraitag, Sylvie
AU - Kemps, Paul G.
AU - Hélias-Rodzewicz, Zofia
AU - Roy, Somak
AU - Bonsang, Benjamin
AU - Bartlett, Allison L.
AU - Dhar, Subhra
AU - Jankofsky, Martin
AU - Zlocha, Jozef
AU - Svojgr, Karel
AU - Krsková, Lenka
AU - de Vries, Andrica C.H.
AU - Verdijk, Robert M.
AU - van Laar, Jan A.M.
AU - Leguit, Roos J.
AU - Drabent, Philippe
AU - Carlsen, Eric D.
AU - Ho, Jonhan
AU - Karunamurthy, Arivarasan D.
AU - Santi, Mariarita
AU - Jullié, Marie Laure
AU - Babor, Florian
AU - Lorsbach, Robert
AU - van Halteren, Astrid G.S.
AU - Héritier, Sébastien
AU - Diamond, Eli L.
AU - Durham, Benjamin H.
AU - Kumar, Ashish R.
AU - Bhattacharya, Arunaloke
AU - Haroche, Julien
AU - Donadieu, Jean
AU - Borkhardt, Arndt
AU - Picarsic, Jennifer L.
AU - Emile, Jean François
N1 - Publisher Copyright:
© 2025 American Society of Hematology. Published by Elsevier Inc.
PY - 2025/7/22
Y1 - 2025/7/22
N2 - 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.
AB - 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.
KW - • NTRK1-rearranged histiocytosis often presents as 1 or multiple cutaneous xanthogranulomas but may rarely involve extracutaneous tissues
KW - • Targeted therapy with the TRK inhibitor larotrectinib is highly effective in patients with severe extracutaneous disease
KW - Receptor, trkA/genetics
KW - Humans
KW - Middle Aged
KW - Child, Preschool
KW - Infant
KW - Male
KW - Young Adult
KW - Gene Rearrangement
KW - Adolescent
KW - Adult
KW - Female
KW - Histiocytosis/genetics
KW - Aged
KW - Child
KW - Infant, Newborn
UR - https://www.scopus.com/pages/publications/105011531421
UR - https://www.mendeley.com/catalogue/15d74aea-020d-3e71-abaf-284f2b28320d/
U2 - 10.1182/bloodadvances.2025016167
DO - 10.1182/bloodadvances.2025016167
M3 - Article
C2 - 40315374
AN - SCOPUS:105011531421
SN - 2473-9529
VL - 9
SP - 3617
EP - 3628
JO - Blood advances
JF - Blood advances
IS - 14
ER -