Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities.

BIOXSYS s r o Na Kopecku 15 Usti nad Labem Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University Prague and Faculty Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University Prague and Faculty Hospital Motol Prague Czech Republic

Department of Radiology 2nd Faculty of Medicine Charles University Prague and Faculty Hospital Motol Prague Czech Republic

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Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PHB. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. 1998;58(22):5046-5048.

Rubin BP, Chen C-J, Morgan TW, et al. Congenital mesoblastic nephroma t(12;15) is associated withETV6-NTRK3 gene fusion. Am J Pathol. 1998;153:1451-1458. https://doi.org/10.1016/s0002-9440(10)65732-x

Church AJ, Calicchio ML, Nardi V, et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Mod Pathol. 2018;31(3):463-473. https://doi.org/10.1038/modpathol.2017.127

Bayindir P, Guillerman RP, Hicks MJ, Chintagumpala MM. Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy. Pediatr Radiol. 2009;39(10):1066-1074. https://doi.org/10.1007/s00247-009-1348-9

Wegert J, Vokuhl C, Collord G, et al. Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants. Nat Commun. 2018;9(1):2378. https://doi.org/10.1038/s41467-018-04650-6

Argani P, Fritsch M, Kadkol SHS, Schuster A, Beckwith JB, Perlman EJ. Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors. Mod Pathol. 2000;13(1):29-36. https://doi.org/10.1038/modpathol.3880006

Kao YC, Fletcher CDM, Alaggio R, et al. Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma. Am J Surg Pathol. 2018;42(1):28-38. https://doi.org/10.1097/PAS.0000000000000938

Davis JL, Lockwood CM, Stohr B, et al. Expanding the spectrum of pediatric NTRK -rearranged mesenchymal tumors. Am J Surg Pathol. 2019;43:435-445. https://doi.org/10.1097/PAS.0000000000001203

Davis JL, Lockwood CM, Albert CM, Tsuchiya K, Hawkins DS, Rudzinski ER. Infantile NTRK-associated mesenchymal tumors. Pediatr Dev Pathol. 2018;21(1):68-78. https://doi.org/10.1177/1093526617712639

Kang J, Park JW, Won JK, et al. Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors. Diagn Pathol. 2020;15:114. https://doi.org/10.1186/s13000-020-01031-w

Tannenbaum-Dvir S, Glade Bender JL, Church AJ, et al. Characterization of a novel fusion gene EML4 - NTRK3 in a case of recurrent congenital fibrosarcoma. Mol Case Stud. 2015;1(1):a000471. https://doi.org/10.1101/mcs.a000471

Hughes CE, Correa H, Benedetti DJ, Smith B, Sumegi J, Bridge J. Second report of PDE10A-BRAF fusion in pediatric spindle cell sarcoma with infantile fibrosarcoma-like morphology suggesting PDE10A-BRAF fusion is a recurrent event. Pediatr Dev Pathol. 2021. https://doi.org/10.1177/10935266211012186. [Epub ahead of print]

Penning AJ, Al-Ibraheemi A, Michal M, et al. Novel BRAF gene fusions and activating point mutations in spindle cell sarcomas with histologic overlap with infantile fibrosarcoma. Mod Pathol. 2021;34:1530-1540. https://doi.org/10.1038/s41379-021-00806-w

Zhao M, Yin M, Kuick CH, et al. Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6-NTRK3 fusion, and the rare KLHL7-BRAF fusion. Histopathology. 2020;77(4):611-621. https://doi.org/10.1111/HIS.14194

Antonescu CR, Dickson BC, Swanson D, et al. Spindle cell tumors with RET gene fusions exhibit a morphologic Spectrum akin to tumors with NTRK gene fusions. Am J Surg Pathol. 2019;43(10):1384-1391. https://doi.org/10.1097/PAS.0000000000001297

Flucke U, van Noesel MM, Wijnen M, et al. TFG-MET fusion in an infantile spindle cell sarcoma with neural features. Genes Chromosomes Cancer. 2017;56:663-667. https://doi.org/10.1002/gcc.22470

Coffin CM, Beadling C, Neff T, Corless CL, Davis JL. Infantile fibrosarcoma with a novel RAF1 rearrangement: the contemporary challenge of reconciling classic morphology with novel molecular genetics. Hum Pathol Case Rep. 2020;22:200434. https://doi.org/10.1016/j.ehpc.2020.200434

Gupta A, Belsky JA, Schieffer KM, et al. Infantile fibrosarcoma-like tumor driven by novel RBPMS-MET fusion consolidated with cabozantinib. Cold Spring Harb Mol Case Stud. 2020;6:a005645. https://doi.org/10.1101/MCS.A005645

IARC. WHO Classification of Soft Tissue and Bone Tumours. 2020.

Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469-474. https://doi.org/10.1038/nature26000

Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-566. https://doi.org/10.1038/nature05945

Jiang Q, Tong HX, Hou YY, et al. Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma. Orphanet J Rare Dis. 2017;12(1):97. https://doi.org/10.1186/s13023-017-0647-8

Lee JC, Li CF, Huang HY, et al. ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol. 2017;241(3):316-323. https://doi.org/10.1002/path.4836

Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46:1773-1780. https://doi.org/10.1016/j.ejca.2010.04.002

Sokai A, Enaka M, Sokai R, et al. Pulmonary inflammatory myofibroblastic tumor harboring EML4-ALK fusion gene. Jpn J Clin Oncol. 2014;44:93-96. https://doi.org/10.1093/jjco/hyt173

The significance of the fusion partner gene genomic neighborhood analysis in translocation-defined tumors