Infantile NTRK-associated Mesenchymal Tumors

Abstract

Pediatric fibroblastic/myofibroblastic lesions are a relatively common group of tumors with varying morphologies, for which the molecular mechanisms are becoming increasingly well characterized. Congenital infantile fibrosarcoma (CIFS), perhaps the most well studied of these lesions is characterized by a recurrent ETV6-NTRK3 gene fusion. However, a notable subset of locally aggressive congenital/infantile soft tissue lesions with similar morphologic features to CIFS, have not to-date, shown evidence of any canonical molecular aberration. We describe 6 patients with mesenchymal tumors composed of infiltrative fibroblastic/myofibroblastic tumor cells and showing a morphologic spectrum of features much analogous to that previously described in CIFS but without ETV6 fusion transcripts. These tumors lacked a uniform immunoprofile, but showed variable expression of CD34, S100, smooth muscle actin, and CD30. All patients first developed a mass in infancy (≤2 months of age). Using next-generation DNA sequencing, TMP3-NTRK1 fusions were identified in 4 cases, an LMNA-NTRK1 fusion in one case, and a variant EML4-NTRK3 fusion in one case. Similar to infantile fibrosarcoma, these tumors were locally aggressive (with local recurrences if incompletely excised) and rarely metastasized (lung metastases in one patient). Proper identification of these tumors including investigation for NTRK family gene rearrangements is essential for diagnostic accuracy, as well as for clinical management decisions. Given the morbidity associated with radical resection of large soft tissue tumors, children with unresectable, recurrent, and/or metastatic disease may benefit from treatment with NTRK targeted therapies.

PRRX‐NCOA1/2 rearrangement characterizes a distinctive fibroblastic neoplasm

“…The identification of disease‐defining molecular alterations is gradually enabling more refined subclassification of these tumors, and this can be exploited for diagnostic purposes. This is exemplified by reports of NTRK ‐rearranged fibroblastic tumors, EWSR1‐SMAD3 ‐rearanged fibroblastic tumor, and PRDM10 ‐rearranged soft tissue tumor…”

The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas

“…These fusions include the region encoding the tyrosine kinase domain of the TRK protein and result in constitutive kinase activity. TRK fusions have been described in a diverse range of pediatric malignancies, particularly infantile fibrosarcoma and other sarcomas …”

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.…”

“…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).…”