Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors

Abstract

The family of pediatric fibroblastic and myofibroblastic proliferations encompasses a wide spectrum of pathologic entities with overlapping morphologies and ill-defined genetic abnormalities. Among the superficial lesions, lipofibromatosis (LPF), composed of an admixture of adipose tissue and fibroblastic elements, in the past has been variously classified as infantile fibromatosis or fibrous hamartoma of infancy. In this regard, we have recently encountered a group of superficial soft tissue tumors occurring in children and young adults, with a notably infiltrative growth pattern reminiscent of LPF, variable cytologic atypia and a distinct immunoprofile of S100 protein and CD34 reactivity, suggestive of neural differentiation. SOX10 and melanocytic markers were negative in all cases tested. In contrast, a control group of classic LPF displayed bland, monomorphic histology and lacked S100 protein immunoreactivity. In order to define the pathogenetic abnormalities in these seemingly distinctive groups, we performed RNA sequencing for fusion gene discovery in 2 cases each, followed by screening for any novel alterations identified in a larger cohort representing both entities. The 2 index LPF-like neural tumors (LPF-NT) showed TPR-NTRK1 and TPM3-NTRK1 gene fusions, which were further validated by FISH and RT-PCR. Subsequent FISH screening of 14 LPF-NT identified recurrent NTRK1 gene rearrangements in 10 (71%) cases. Of the NTRK1 negative LPF-NT cases, one case each showed ROS1 and ALK gene rearrangements. In contrast none of the 25 classic LPF showed NTRK1 gene rearrangements, although regional abnormalities were noted in the 1q21–22 region by FISH in a majority of cases. Furthermore, NTRK1 immunostaining was positive only in NTRK1-rearranged S100 positive LPF-NT, but negative in classic LPF. These results suggest that NTRK1 oncogenic activation through gene fusion defines a novel and distinct subset of soft tissue tumors resembling LPF, but displaying cytologic atypia and a neural immunophenotype, provisionally named LPF-like neural tumors.

TFG‐MET fusion in an infantile spindle cell sarcoma with neural features

“…7, 8 One additional tumor considered in the differential diagnosis was the recently described S100-positive lipofibromatosis-like neural tumor, which can occur in young children, including infants. 5 Similar to our case, these lesions may show areas of increased cellularity, scattered mitotic activity, and an infiltrative growth within adjacent adipose tissue. However, they also show CD34 and NTRK1 reactivity and NTRK1 gene rearrangements.…”

“…Lastly, the most recent example is the lipofibromatosis-like neural tumor with recurrent NTRK1 -related fusions, in which the neural phenotype was defined based on its consistent S100 protein reactivity, but similarly lacking SOX10 positivity. 5 The significance of S100 positivity alone remains elusive and additional studies are required to establish if this finding is indeed related to neuroectodermal differentiation. Furthermore, these examples illustrate that immunohistochemical results taken out of context might be misleading in the setting of fusion-positive mesenchymal tumors, where there is often no good correlation between immunoprofile and line of differentiation.…”

“…RNA extracted from fresh frozen tissue was subjected to whole transcriptome paired-end RNA sequencing using Illumina platform, as previously described. 5 The data was then analyzed with FusionSeq computational method, which identified a TFG-MET fusion candidate (Fig. 3).…”

Recurrent SRF-RELA Fusions Define a Novel Subset of Cellular Myofibroma/Myopericytoma

“…Their cases showed consistently high mitotic activity, ranging from 12–17 MF/ 10 HPFs. It remains unclear if these NTRK1 -rearraranged atypical/malignant myofibroblastic tumors have any relationship to our cohort of cellular myofibroblastic lesions, since all 20 cases of myofibromas/myopericytomas, spanning classic, cellular and malignant examples, from our files lacked NTRK1 genetic abnormalities 16 . We believe that the cases described recently by Linos and colleagues 17 , as ‘myofibroma with atypical features’, based on increased cellularity, infiltrative borders and increased mitotic activity (but not increased pleomorphism), resemble closely our cohort and may represent SRF -positive cellular variants of myofibroma or myoepricytoma as described here.…”

Role of Next-Generation Sequencing as a Diagnostic Tool for the Evaluation of Bone and Soft-Tissue Tumors

“…No staining with antibodies against desmin, GFAP, STAT6, HMB45, Melan-A, and SOX10 was reported. Agaram et al [80] reported a TPR-NTRK1 or TPM3-NTRK1 gene fusion in 71% of cases. Furthermore, the performed NTRK1 immunostaining was positive only in NTRK1-rearranged S100-positive LPF-NT but negative in classic LPF.…”