Evaluation of pan-TRK immunostaining in malignant peripheral nerve sheath tumours: does its positivity indicate NTRK rearrangements or neural differentiation?

Aims Histological features of conventional malignant peripheral nerve sheath tumour (C-MPNST) resemble those of neurotrophic tropomyosin or tyrosine receptor kinase gene ( NTRK )-rearranged spindle cell neoplasm, a new entity of soft-tissue tumour. Pan-TRK immunohistochemistry has recently become popular for detecting NTRK rearrangements cost-effectively, but its positivity can also reflect neural differentiation. We investigated what pan-TRK positivity truly indicates in a large case series of neurogenic tumours. Methods Pan-TRK, S100, SOX10 and histone 3 lysine 27 trimethylation (H3K27me3) immunohistochemical analyses were performed on 99 C-MPNSTs, 17 malignant triton tumours, 8 epithelioid MPNSTs (E-MPNSTs), 2 atypical neurofibromatous neoplasms with uncertain biologic potential (ANNUBPs) and 1 glandular MPNST. For pan-TRK-positive cases, NTRK rearrangements were examined by molecular methods. Results 15 cases (11 C-MPNSTs, 3 E-MPNSTs and 1 ANNUBP) were positive for pan-TRK. Clinically, the positivity rates were significantly higher in older patients (≥50 years, 21.3% vs <50 years, 3.0%; p=0.0014) and sporadic cases (17.6% vs 5.1%; p=0.0287). In histological analyses, the positivity rate was significantly higher in E-MPNSTs than in C-MPNSTs (37.5% vs 11.1%; p=0.0333). Immunohistochemically, the expression of both S100 and SOX10 was significantly correlated with pan-TRK positivity (p=0.0310 and 0.0145, respectively). Although DNA-based sequencing was successfully performed for 11 cases, no evident NTRK rearrangements were detected. Conclusions This study suggests that pan-TRK immunostaining may be useful for confirming neural differentiation in MPNST. However, whether its positivity reflects NTRK rearrangements or neural differentiation must be carefully assessed in combination with various immunohistochemical and molecular tests.