NTRK-Rearranged soft tissue neoplasms: A review of evolving diagnostic entities and algorithmic detection methods

The spectrum of tumors with NTRK1/2/3 rearrangements has expanded with widespread use of next generation sequencing (NGS) technology. For many years it was known that a majority of infantile fibrosarcomas (IFS), and their counterpart in the kidney, cellular congenital mesoblastic nephroma, contain the recurrent ETV6-NTRK3 fusion. Sequencing RNA transcripts from IFS and their morphologically similar counterparts in older children and adults has shown rearrangements with other 5′ partners combined with NTRK1, NTRK2, and NTRK3 can also occur. For those tumors occurring outside of the infant age group, this has resulted in a proposed new diagnostic entity of “NTRK-rearranged spindle cell neoplasm.” The clinical behavior of NTRK rearranged soft tissue tumors varies, though most show localized disease with rare metastases. The pathology of NTRK rearranged tumors exists on a spectrum, with overlapping features of classic infantile fibrosarcoma, lipofibromatosis, and malignant peripheral nerve sheath tumor. In this tumor spectrum, clinical and pathologic predictive factors are largely still to be determined, with no clear association between histologic grade and severity of disease. Of critical importance is detection of the NTRK rearrangement in order to guide treatment in patients with unresectable and metastatic disease. While resection is the definitive treatment, these tumors do show response to targeted TRK kinase inhibitors. Multiple detection methods are available, including immunohistochemistry, FISH, and next generation sequencing, which each have their merits and potential pitfalls. We aim to review the clinical characteristics and histomorphology of mesenchymal tumors with NTRK rearrangements as well as discuss molecular detection methods and diagnostic algorithms specific for soft tissue tumors.