Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib

Abstract

Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life. The presence of ETV6 and NTRK3 gene rearrangement is characteristic of IFS, which can be detected on routine fluorescence in situ hybridization (FISH) testing. Patients with IFS typically respond well to surgical resection and chemotherapy and have an overall survival of ∼90%. In this report, we outline the use of integrative clinical sequencing (ICS) including RNA-seq in a patient with refractory, metastatic IFS to reveal an unusual fusion (LMNA-NTRK1), not detected by routine FISH testing, which was treated with oral crizotinib and resulted in a complete and durable long-term response. This study highlights the utility of ICS in identifying cryptic gene fusions, especially in refractory malignancies, and demonstrates how such information can be used to select targeted therapies in patients with actionable molecular alterations.

Keywords: desmoid tumors.

Figure 1.

(A) Bland low-grade spindle cell proliferation infiltrating fat, 40×. (B) Tumor cells are round to ovoid with no significant atypia or mitotic figures. Focal myxoid areas present (arrows). (C) There is a spindle cell proliferation arranged in fascicles and sheets with some hemangiopericytoma-like vascular channels. (D) Lung with metastatic high-grade sarcoma.

Figure 2.

Initial recurrence before crizotinib therapy: (A) a 0.63-mm slice thickness spiral axial image of the chest with intravenous iodinated contrast demonstrates a well-defined 8-mm right middle lobe lung nodule consistent with metastatic disease (arrow); and (B) an 8-mm maximum intensity projection (MIP) image with clear delineation of a 4.5-mm right lower lobe pulmonary metastasis in relationship to the pulmonary vasculature (arrow). Two months after initiation of crizotinib therapy: (C) a 0.63-mm spiral axial image with reduction in the size of the right middle lobe nodule (5.3 mm, arrow); and (D) a thin section axial image with decrease in size of the right lower lobe nodule, now 2.4 mm (arrow). Twenty-one months after initiation of crizotinib therapy: (E) residual linear scarring is noted in the region of the original right middle lobe metastasis; and (F) no clear residual nodule seen in the right lower lobe. Follow-up CT imaging (G, thin slice axial image; H, MIP image) demonstrates complete resolution of the nodules ∼12 mo after cessation of crizotinib therapy and ∼43 mo since its introduction.

Figure 3.

The LMNA–NTRK1 fusion protein encodes a coiled-coil dimerization domain of LMNA (exon 2, NM_170707) fused to the tyrosine kinase domain of NTRK1 (exon 10, NM_001012331).