NTRK1-rearranged histiocytosis: clinicopathologic and molecular features

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.

Graphical abstract

Figure 1.

Skin involvement by NTRK1-rearranged histiocytosis. (A) Single lesion on the eyelid of a 2-year-old girl (AP13). (B-C) Skin lesions of a 70-year-old female (AP11). (D-E) Multiple skin lesions of a female newborn (AP27). (F) Multiple skin nodules of a male newborn (AP24).

Figure 2.

Extracutaneous or systemic involvement by NTRK1-rearranged histiocytosis. (A) Liver involvement in a female newborn (AP27). (B-C) Kidney and bone involvement in a male newborn (PK1). (D-E) Large nodule obstructing the right main bronchus in a male infant (AP32). (F-G) Histology of liver and bronchia involvement (hematoxylin and eosin, original magnification ×20).

Figure 3.

Histology and immunophenotype of NTRK1-rearranged histiocytosis. Low magnification photomicrographs of 2 exemplary skin lesions with either a well-limited pushing nodule in the dermis (A; AP30) or a more infiltrative lesion with finger-like borders (B; AP16). Histiocytes were medium sized with eosinophilic cytoplasm in early type lesions (C; AP11), whereas mature lesions contained larger mononucleated cells with a foamy cytoplasm (D; AP30) and multinucleated Touton giant cells (E; AP17). Some multinucleated cells demonstrated emperipolesis (arrow). Case AP25 was early type in the upper part and mature in the deep dermis (F). (A-F) Hematoxylin and eosin staining. Immunohistochemistry with pan-TRK (G-K) showing strong expression of multinucleated cells (G; AP19) and mononucleated spindle cells (H; AP31) and milder expression in an early type lesion (I; AP32). Positive cells were detectable within the epidermis in a few cases (J; AP12). In this early type lesion, only a fraction of the mononucleated histiocytes expressed pan-TRK (K; AP09). Cells were positive with histiocyte markers, such as PU.1 (L; AP10), and some also expressed S100 (M; AP24). Frequent positivity for cyclin D1 (N; AP30) and phosphorylated extracellular signal-regulated kinase (phophoERK) (O; AP32) confirmed the activation of the MAPK pathway in these neoplasms with NRTK1 fusions.

Figure 4.

NTRK1 rearrangements. (A) Frequencies of fusion partner genes. (B) Illustration of the most frequent fusion. (C) Localizations of the fusion breakpoints at the NTRK1 locus.