NTRK-fusion cutaneous sarcoma

Spectrum of NTRK-fusion soft-tissue / cutaneous tumours

• NTRK-rearranged spindle-cell neoplasm (WHO 2020 emerging entity) — adolescents and young adults; superficial / deep soft tissue; spindled morphology; CD34, S100 positive; pan-Trk positive.
• Infantile fibrosarcoma — neonates and infants; ETV6-NTRK3 fusion; congenital large soft-tissue mass; chemosensitive but TRK-inhibitor responsive.
• Lipofibromatosis-like neural tumour (LPF-NT) — childhood; superficial / deep soft tissue; lipofibromatosis-like architecture; NTRK1 fusions; pan-Trk and S100 positive.
• Inflammatory myofibroblastic tumour — most are ALK-rearranged but a small subset harbours NTRK fusions.
• NTRK fusions also occur in some cases of GIST, malignant peripheral nerve sheath tumour, secretory carcinoma and other tumours — small subsets but therapeutically actionable.

Clinical features

• Slow-growing dermal / subcutaneous mass, often in young to middle-aged adult.
• Trunk and limbs; can occur in head/neck.
• Wide morphological and clinical spectrum — from indolent to locally aggressive to overtly malignant.
• Often misdiagnosed as benign soft-tissue tumour, fibromatosis or inflammatory myofibroblastic tumour before molecular testing.

Diagnostic workflow

• Pan-Trk immunohistochemistry — sensitive screen; positivity strongly suggests an NTRK fusion.
• Confirmation by:
  • RNA-based next-generation sequencing — gold standard; identifies the fusion partner.
  • FISH for NTRK1/2/3 break-apart probes — alternative.
• NTRK testing should be considered in any morphologically unusual cutaneous spindle-cell tumour, particularly if other diagnostic markers are negative or the clinical context suggests a possible response to targeted therapy.
• Discuss with sarcoma MDT and consider tissue submission to the National NTRK Testing Service (UK Genomic Medicine Service Alliance pathway) for advanced disease.

Management

• Localised resectable disease: wide local excision per soft-tissue sarcoma principles (clear margins, fascia included, sarcoma MDT input).
• Adjuvant radiotherapy for incomplete margins or high-risk disease.
• Locally advanced / unresectable / metastatic disease:
  • Larotrectinib (Vitrakvi) — selective TRK inhibitor; NICE TA630 (2020) recommends use within the Cancer Drugs Fund / managed-access criteria rather than as routine commissioning; response rate ~75%, durable. Confirm current NICE / NHS England status because managed-access review outcomes may change.
  • Entrectinib (Rozlytrek) — multikinase TRK / ROS1 / ALK inhibitor (BBB-penetrant); was Cancer Drugs Fund-only under NICE TA644 (2020) and is not recommended for routine NHS use following NICE TA1118 (terminated appraisal, 2026); patients already established on it may continue until they and their NHS healthcare professional consider it appropriate to stop.
  • Resistance can develop via secondary NTRK kinase-domain mutations — second-generation TRK inhibitors (selitrectinib, repotrectinib) under investigation.
• Conventional sarcoma chemotherapy is less effective than targeted therapy and is reserved for TRK-inhibitor-resistant disease.
• Counsel about adverse effects: dizziness, fatigue, oedema, weight gain, transaminitis, withdrawal pain on stopping.

Prognosis

Highly variable depending on the specific entity. Localised NTRK-rearranged spindle-cell neoplasms have a substantial recurrence and metastatic risk if not widely excised; with TRK inhibitors, even metastatic disease can achieve prolonged disease control (median progression-free survival 28+ months in some series). Long-term surveillance is essential, and TRK-inhibitor resistance monitoring with repeat biopsy / circulating tumour DNA may guide salvage therapy.