Infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) commonly harbors the classic ETV6-NTRK3 translocation. However, there are recent reports of mesenchymal tumors with IFS-like morphology harboring fusions of other receptor tyrosine kinases or downstream effectors, including NTRK1/2/3, MET, RET, and RAF1 fusions as well as one prior series with BRAF fusions. Discovery of these additional molecular drivers contributes to a more integrated diagnostic approach and presents important targets for therapy. Here we report the clinicopathologic and molecular features of 14 BRAF-altered tumors, of which 5 had BRAF point mutations and 10 harbored one or more BRAF fusions. Of the BRAF fusion-positive tumors, one harbored two BRAF fusions (FOXN3-BRAF, TRIP11-BRAF) and another harbored three unique alternative splice variants of EPB41L2-BRAF. Tumors occurred in ten males and four females, aged from birth to 32 years (median 6 months). Twelve were soft tissue based; two were visceral including one located in the kidney (cCMN). All neoplasms demonstrated ovoid to short spindle cells most frequently arranged haphazardly or in intersecting fascicles, often with collagenized stroma and a chronic inflammatory infiltrate. No specific immunophenotype was observed; expression of CD34, S100, and SMA was variable. To date, this is the largest cohort of BRAF-altered spindle cell neoplasms with IFS-like morphology, including not only seven novel BRAF fusion partners but also the first description of oncogenic BRAF point mutations in these tumors.

Department of Laboratories Seattle Children's Hospital Seattle WA USA

Department of Laboratory Medicine and Pathology Mayo Clinic Scottsdale AZ USA

Department of Laboratory Medicine and Pathology School of Medicine University of Washington Seattle WA USA

Department of Pathology Bioptical Laboratory Ltd Plzen Czech Republic

Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA USA

Department of Pathology Cleveland Clinic Cleveland OH USA

Department of Pathology Faculty of Medicine Comenius University Jessenius Medical Faculty Bratislava Czech Republic

Department of Pathology Oregon Health and Science University Portland OR USA

Department of Pathology University of California San Francisco San Francisco CA USA

Department Pathology Faculty of Medicine Charles University Plzen Czech Republic

Knight Cancer Institute Oregon Health and Science University Portland OR USA

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Mod Pathol. 2022 Jul;35(7):989-992. doi: 10.1038/s41379-021-00852-4. PubMed

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S100 and CD34 positive spindle cell tumors of the uterine cervix with EGFR mutation: a hitherto unrecognized neoplasm phenotypically and epigenetically overlapping with "NTRK-rearranged spindle cell neoplasms" of the uterus