Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6–NTRK3 fusion, and the rare KLHL7–BRAF fusion

Abstract

Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6-NTRK3 fusion, and the rare KLHL7-BRAF fusion Aims: Congenital mesoblastic nephroma (CMN) is histologically classified into classic, cellular and mixed subtypes. The aims of this study were to characterise the clinical, pathological and molecular features of a series of CMNs, and to determine the utility of pan-Trk and epidermal growth factor receptor (EGFR) immunohistochemistry as surrogate markers for NTRK gene fusions and EGFR internal tandem duplications (ITDs). Methods and results: Twenty-two archival CMN cases (12 classic, five cellular, and five mixed) were tested for the ETV6-NTRK3 fusion and EGFR ITD transcripts by the use of reverse transcriptase polymerase chain reaction (PCR), and next-generation sequencing-based anchored multiplex PCR. All 12 classic CMNs had EGFR ITD. Of the five cellular CMNs, four had the ETV6-NTRK3 fusion and one had the KLHL7-BRAF fusion. Of the five mixed CMNs, four had EGFR ITD, and one had the ETV6-NTRK3 fusion. Pan-Trk immunoreactivity was 100% sensitive and 94.1% specific for the presence of NTRK 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 classic CMN. A majority of cellular CMNs have the ETV6-NTRK3 fusion. Rare cellular CMNs may harbour non-canonical mutations such as the KLHL7-BRAF fusion, which was found in one case. Mixed CMNs may have either EGFR ITD or the ETV6-NTRK3 fusion. Pan-Trk immunohistochemistry is a sensitive, albeit not perfectly specific, marker for NTRK rearrangement. EGFR immunohistochemistry is not helpful as a marker of EGFR ITD.

EGFR internal tandem duplications in fusion‐negative congenital and neonatal spindle cell tumors

“…This EGFR ITD results in an adjacent repeat of the tyrosine kinase domain and is thus alternately termed an EGFR kinase domain duplication. Subsequent reports have identified the same EGFR ITD in 21 additional cases of classic and mixed CMN 15,16 and recently in four cases of IFS of the extremities 17 . In children, EGFR ITD thus far appears to be most commonly seen in congenital tumors of the kidney, most typically in CMN with classic or mixed histologic types.…”

ALK rearrangements in infantile fibrosarcoma‐like spindle cell tumours of soft tissue and kidney

“…7 Mixed CMN have similar alterations to cellular CMN with the addition of EGFR internal tandem duplications, and classic CMN is associated primarily with EGFR internal tandem duplications. 9,41 Additionally, three recent adult cases of 'NTRK-rearranged' spindle cell neoplasms and one paediatric case of cCMN with ALK fusions have been reported in the literature. [33][34][35][36] This series, with identification of ALK fusions in both IFS and cCMN, further highlights the biological relationship of these tumours.…”

Paediatric BCOR‐associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15

“…ITDs were first identified affecting the FLT3 gene in patients with acute myeloid leukaemia [28]. ITD involving EGFR has been reported in a case of CCSK [29] and is also a consistent finding in the classic type of congenital mesoblastic nephroma [30], another rare type of paediatric renal tumour.…”