Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Mod Pathol. 2018 Mar;31(3):463-473. doi: 10.1038/modpathol.2017.127. Epub 2017 Nov 3.


Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms / genetics
  • Carcinoma / genetics
  • Cell Cycle Proteins / genetics*
  • Child, Preschool
  • Discoidin Domain Receptor 2 / genetics*
  • Female
  • Fibrosarcoma / diagnosis*
  • Fibrosarcoma / genetics
  • Genetic Testing
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Infant, Newborn
  • Kidney Neoplasms / congenital
  • Kidney Neoplasms / diagnosis*
  • Kidney Neoplasms / genetics
  • Male
  • Microtubule-Associated Proteins / genetics*
  • Middle Aged
  • Neoplasm Recurrence, Local / genetics*
  • Nephroma, Mesoblastic / congenital
  • Nephroma, Mesoblastic / diagnosis*
  • Nephroma, Mesoblastic / genetics
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogene Proteins c-ets / genetics
  • Repressor Proteins / genetics
  • Sequence Analysis, RNA
  • Serine Endopeptidases / genetics*


  • Cell Cycle Proteins
  • ETS translocation variant 6 protein
  • Microtubule-Associated Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • DDR2 protein, human
  • Discoidin Domain Receptor 2
  • EML4 protein, human
  • Serine Endopeptidases

Supplementary concepts

  • Secretory breast carcinoma