With the increasing use of innovative next generation sequencing (NGS) platforms in routine diagnostic and research settings, the genetic landscape of uterine sarcomas has been dynamically evolving during the last two decades. Notably, the majority of recently recognized genotypes in uterine sarcomas represent gene fusions, while recurrent oncogene mutations of diagnostic and/ or therapeutic value have been rare. Recently, a distinctive aggressive uterine sarcoma expressing S100 and SOX10, but otherwise lacking diagnostic morphological, immunophenotypic and molecular features of other uterine malignancies has been presented in a scientific abstract form (USCAP, 2023), but detailed description and delineation of the entity is still missing. We herein describe two high-grade unclassified uterine sarcomas characterized by spindle to round cell morphology and diffuse expression of S100 and SOX10, originating in the uterine body and cervix of 53- and 45-year-old women and carrying an ERBB3 (p.Glu928Gly) and an ERBB2 (p.Val777Leu) mutation, respectively. Both tumors harbored in addition genomic HER2 amplification, ATRX mutation and CDKN2A deletion. Methylation studies revealed a methylome most similar to MPNST-like tumors, but distinct from melanoma, MPNST, clear cell sarcoma, and endometrial stromal sarcoma. Case 1 died of progressive peritoneal metastases after multiple trials of chemotherapy 47 months after diagnosis. Case 2 is a recent case who presented with a cervical mass, which was biopsied. This study defines a novel heretofore unrecognized aggressive uterine sarcoma with unique phenotypic and genotypic features. Given the potential value of targeting HER2, recognizing this tumor type is mandatory for appropriate therapeutic strategies and for better future delineation of the entity.

• Keywords
• EGFR, Molecular profiling; nerve sheath tumor, Targeted therapy, Tyrosine kinase fusions, Undifferentiated uterine sarcoma,
• MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Uterine Neoplasms * genetics   pathology   MeSH
• S100 Proteins genetics   metabolism   MeSH
• Receptor, ErbB-2 * genetics   MeSH
• Receptor, ErbB-3 * genetics   MeSH
• Sarcoma * genetics   pathology   MeSH
• Neoplasm Grading MeSH
• SOXE Transcription Factors * genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• ERBB2 protein, human MeSH Browser
• ERBB3 protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• S100 Proteins MeSH
• Receptor, ErbB-2 * MeSH
• Receptor, ErbB-3 * MeSH
• SOX10 protein, human MeSH Browser
• SOXE Transcription Factors * MeSH