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NTRK-Rearranged soft tissue neoplasms: A review of evolving diagnostic entities and algorithmic detection methods
Lea F Surrey1, Jessica L Davis2
1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
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.
Insights
Tumors with NTRK gene rearrangements, including infantile fibrosarcoma, are increasingly identified by next-generation sequencing (NGS). These NTRK-rearranged spindle cell neoplasms show varied behavior and pathology, necessitating accurate detection for targeted therapy.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- NTRK gene rearrangements (NTRK1/2/3) are found in a spectrum of tumors, notably infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma.
- Next-generation sequencing (NGS) has expanded the identification of NTRK rearrangements beyond infantile cases, leading to the concept of 'NTRK-rearranged spindle cell neoplasm'.
- These tumors present a diagnostic challenge due to overlapping histopathologic features with other mesenchymal neoplasms.
Purpose of the Study:
- To review the clinical characteristics and histomorphology of mesenchymal tumors harboring NTRK rearrangements.
- To discuss various molecular detection methods for NTRK rearrangements, including their advantages and limitations.
- To propose diagnostic algorithms for identifying these rare but targetable tumors in soft tissue.
Main Methods:
- Review of existing literature on NTRK-rearranged soft tissue tumors.
- Analysis of clinical and pathological data from reported cases.
- Discussion of molecular diagnostic techniques: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS).
Main Results:
- NTRK rearrangements are identified in a diverse group of soft tissue tumors, extending beyond infantile fibrosarcoma.
- Clinical behavior varies, with most cases showing localized disease, but predictive factors remain to be fully determined.
- Histopathology shows overlap with infantile fibrosarcoma, lipofibromatosis, and malignant peripheral nerve sheath tumors.
Conclusions:
- Accurate detection of NTRK rearrangements is crucial for guiding treatment, especially in unresectable or metastatic disease.
- NTRK-rearranged tumors show sensitivity to TRK kinase inhibitors, offering a targeted therapeutic option.
- A combination of histomorphology and molecular testing is essential for diagnosis and patient management.
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