Infantile fibrosarcoma–like tumor driven by novel RBPMS-MET fusion consolidated with cabozantinib

Abstract

Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. ETV6-NTRK3 fusions account for ∼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity. This patient presented at birth with a right facial mass, enlarging at 1 mo to 4.9 × 4.5 × 6.3 cm. Biopsy demonstrated hypercellular fascicles of spindle cells with patchy positivity for smooth muscle actin (SMA) and negativity for S100, desmin, myogenin, and MyoD1. Targeted RNA sequencing identified a novel RBPMS-MET fusion with confirmed absence of ETV6-NTRK3, and the patient was diagnosed with an IFS-like tumor. A positron emission tomography (PET) scan was negative for metastatic disease. VAC was given for a duration of 10 mo. Resection at 13 mo of age demonstrated positive margins. Cabozantinib, a MET-targeting TKI, was initiated. The patient tolerated cabozantinib well and has no evidence of disease at 24 mo of age. We describe a novel RBPMS-MET driver fusion in association with a locally aggressive IFS-like tumor. MET functions as an oncogene and, when associated with the RNA binding protein RBPMS, forms an in-frame fusion product that retains the MET kinase domain. This fusion is associated with aberrant cell signaling pathway expression and subsequent malignancy. We describe treatment with cabozantinib in a patient with an IFS-like neoplasm.

Mesenchymal neoplasms with NTRK and other kinase gene alterations

“…LPFNT and this spectrum of tumours resembling peripheral nerve sheath tumours frequently harbour NTRK1 or NTRK3 fusions, with RET, MET, ALK, ABL1, ROS1, RAF1, BRAF and NTRK2 fusions occurring less frequently. 15,20,21,49,51,54,62,[67][68][69][70] NTRK3, RAF1 and BRAF fusions are more commonly described in higher grade fibrosarcoma-like tumours in adults and children. 19,53,54,62 Similar to IFS, tumours with NTRK rearrangements show immunohistochemical staining for panTRK (cytoplasmic in NTRK1/2 rearrangement, nuclear in NTRK3 rearrangements), but this will be negative in the setting of alternative gene alterations (Figure 2).…”

“…28,[44][45][46] Within the last 5-10 years, with the increasing availability of clinical next-generation sequencing tests, a growing number of alterative fusions and activating mutations involving other receptor or cytoplasmic kinases have been described in IFS. First recognised were other alterations in the NTRK gene family, including fusions in NTRK1, NTRK2 and alternative NTKR3 fusions, 12,30,47,48 followed by descriptions of fusions in other kinases involved in mitogen-activated protein kinase (MAP) kinase pathway signalling, including MET, RET, ALK, ABL1, BRAF and RAF1 (cRAF), [15][16][17][49][50][51][52][53] each with a variety of gene partners. Less frequently, IFS may harbour point mutations or insertions in BRAF.…”

An unusual fusion gene EML4‐ALK in a patient with congenital mesoblastic nephroma

“…BRAF alterations, RET fusions, and NTKR1/2 were previously described in both entities-IFS and CMN, 3,5,[7][8][9][10][11][12][13][14][15] whether RAF1 fusions and MET fusions particularly in IFS. [16][17][18] In this study, we report EML4-ALK gene fusion in a case of a congenital renal tumor resembling CMN in a newborn boy.…”

“…Among mesenchymal tumors, various means of oncogenic signaling through the MAP kinase (e.g., rearrangement of NTRK, RET, BRAF, MET, and RAF1) have been demonstrated in IFS and CMN. [1][2][3][5][6][7][11][12][13][14][15][16][17][18] In addition, in rare cases of CMNs, an oncogenic variant of BRAF (internal BRAF deletion) 5 or activating point mutation of BRAF 13 has been detected.…”

“…The spectrum of so‐called “infantile fibrosarcoma and mesoblastic nephroma” has expanded to include tumors with NTRK , MET, RAF1 , RET gene fusions, and BRAF fusions and point mutations. BRAF alterations, RET fusions, and NTKR1/2 were previously described in both entities—IFS and CMN, 3,5,7‐15 whether RAF1 fusions and MET fusions particularly in IFS 16‐18 …”