Abstract

Neurotrophic tyrosine receptor kinase (NTRK) is a gene family encoding for Tropomyosin receptor kinases (Trks) which mediate neurotrophin-induced MAPK activation. NTRK rearrangement is the provisional classifying unifier of a histologically diverse subset of spindle cell neoplasms which present in the superficial or deep dermis or subcutis.   We report four spindle cell neoplasms with NTRK rearrangement and varied presentation, histopathology, and NTRK fusions. Patients ranged from 1-86 years in age; two male and two female. Tumors presented in subcutaneous soft tissue in two cases and superficial dermis in two others. Histopathologic findings ranged from spindle cell morphology with whorled architecture mimicking dermatofibrosarcoma protuberans (DFSP) to aggressive, lipofibromatosis-like growth. The tumors showed none to patchy positive immunostaining for S100, and patchy to diffuse staining for CD34, without staining for Sox-10, myogenic or vascular markers. Pan-TRK immunohistochemistry was positive in all 4 cases. The tumors harbored EML4::NTRK3, LMNA::NTRK1, PPFIBP1::NTRK3, and HMBOX1::NTRK3 fusions.  While these NTRK fusion partners were distinct, three represented genes encoding cytoskeletal/scaffolding proteins, compatible with prior hypotheses suggesting that aberrant Trk activation can occur through fusion partner mediated dimerization. The remaining partner, HMBOX1, has direct DNA binding activity but is without a clearly defined mechanism in neoplasia.   Awareness of features of NTRK-rearranged spindle cell neoplasms is essential for diagnostic consideration and initiating appropriate molecular pathology workup. There may be significant histopathologic overlap between NTRK-rearranged spindle cell neoplasms and other spindle cell tumors including DFSP. Pan-TRK immunohistochemistry can be a resource-effective screening tool for NTRK fusion.