Congenital Mesoblastic Nephroma Is Characterized by Kinase Mutations Including EGFR Internal Tandem Duplications, ETV6-NTRK3 Fusion, and Rare KLHL7-BRAF Fusion

Aims Congenital mesoblastic nephroma (CMN) is histologically classified into classical, cellular, and mixed subtypes. The aims of this study are to characterize the clinical, pathological and molecular features of a series of CMN, and to determine the utility of pan-Trk and EGFR immunohistochemistry as surrogate markers for NTRK gene fusions and EGFR internal tandem duplications (ITD). Methods and results 22 archival CMN cases (12 classical, 5 cellular, and 5 mixed) were tested for the ETV6-NTRK3 fusion and EGFR ITD transcripts using reverse transcriptase PCR, and next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®). All 12 classical CMN had EGFR ITD. Of the 5 cellular CMN, 4 had ETV6-NTRK3 gene fusion and one had a KLHL7-BRAF fusion. Of the 5 mixed CMN, 4 had EGFR ITD, and one had ETV6-NTRK3 gene fusion. Pan-Trk immunoreactivity was 100% sensitive and 94.1% specific for the presence of the NTRK gene rearrangement. However, EGFR staining was only 62.5% sensitive and 33.3% specific for EGFR ITD. Conclusions EGFR ITD is a consistent genetic event in classical CMN. A majority of cellular CMN have the ETV6-NTRK3 gene fusion. Rare cellular CMN may harbour non-canonical mutations such as the KLHL7-BRAF fusion found in one case. Mixed CMN may have either EGFR ITD or ETV6-NTRK3 gene fusion. Pan-Trk immunohistochemistry is a sensitive albeit not perfectly specific marker for the NTRK rearrangement. EGFR immunohistochemistry is not helpful as a marker of EGFR ITD.