Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors

Abstract

Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.

NTRK‐rearranged mesenchymal tumour in a 3‐year‐old female: a diagnostic quandary

“…They typically occur in children, adolescents and young adults, with rare reports in the third–fourth decade, and no gender predilection. These tumours may recur locally and have metastatic potential . Histologically, they are characterised by haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles, often in conjunction with myopericytic/HPC‐like vessels, infiltrative growth, mxyoid appearance or inflammatory myofibroblastic areas, fairly brisk mitoses (3–4 HPF, with some cases up to 10–15 per 10 HPF), and CD34/S100 positivity.…”

“…In such diagnostically challenging cases, screening with panTRK (or NTRK1/2) IHC may guide subsequent molecular testing for identification of TRK fusions. Correlation of the IHC results to TRK fusion detection has demonstrated high sensitivity and specificity in NTRK‐rearranged mesenchymal tumours, with positive and negative predictive values of 97 and 98%, respectively . NGS is a critical diagnostic adjunct in which a multiplex sequencing panel can detect TRK fusions as well as other potentially targetable molecular alterations.…”

“…These tumours may recur locally and have metastatic potential. 1,3,5,6 Histologically, they are characterised by haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles, often in conjunction with myopericytic/HPC-like vessels, infiltrative growth, mxyoid appearance or inflammatory myofibroblastic areas, fairly brisk mitoses (3-4 HPF, with some cases up to 10-15 per 10 HPF), and CD34/ S100 positivity. In addition to S100 positivity, the tumours often have areas with admixed mature adipose tissue; therefore, they were initially called lipofibromatosis-like neural tumours (LPF-NT).…”

“…Neurotrophic receptor tyrosine kinase genes, NTRK1 , NTRK2 and NTRK3 , encode the tropomyosin receptor kinases TRKA , TRKB and TRKC , respectively. Mesenchymal tumours, including low‐grade sarcomas harbouring NTRK gene fusions, are being increasingly described . We present a 3‐year‐old female with a diagnostically challenging skin and soft‐tissue tumour that clinically and immunohistochemically was a low‐grade spindle cell sarcoma mimicking dermatofibrosarcoma protuberans (DFSP).…”

“…Mesenchymal tumours, including low-grade sarcomas harbouring NTRK gene fusions, are being increasingly described. [1][2][3][4][5][6] We present a 3-year-old female with a diagnostically challenging skin and soft-tissue tumour that clinically and immunohistochemically was a low-grade spindle cell sarcoma mimicking dermatofibrosarcoma protuberans (DFSP). NTRK1 immunohistochemistry (IHC) and next-generation sequencing (NGS) confirmed the diagnosis of a NTRKrearranged mesenchymal tumour.…”