Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Bioptical Laboratory Ltd Pilsen Czech Republic

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Pathology Hacettepe University Ankara Turkey

Department of Pathology Na Bulovce Hospital Prague Czech Republic

Department of Pathology Regional Hospital Karlovy Vary Karlovy Vary Czech Republic

Department of Pathology Regional Hospital Příbram Příbram Czech Republic

Department of Pathology Sestre Milosrdnice University Hospital Center Zagreb Croatia

Department of Pathology University of Kansas Kansas City KS USA

Department of Pediatric Hematology and Oncology National Institute of Children's Diseases and Medical Faculty Comenius University Bratislava Slovakia

Department of Pediatrics and Medical Genetics Oncohematology Unit Medical University Plovdiv University Hospital Sveti Georgi Plovdiv Bulgaria

Institute of Pathological Anatomy Jessenius Faculty of Medicine in Martin Comenius University Martin Slovakia

Medical Laboratory CSD Health Care Ltd Kyiv Ukraine

Robert J Tomsich Pathology and Laboratory Medicine Institute Cleveland Clinic Cleveland OH USA

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