Case Report: Recurrent malignant phyllodes tumor with malignant peripheral nerve sheath tumor-like differentiation...

Malignant phyllodes tumor (MPT) is a rare breast neoplasm with high recurrence rates and potential for heterologous sarcomatous differentiation. Malignant peripheral nerve sheath tumor (MPNST)-like differentiation in MPT is exceptionally rare and presents considerable diagnostic and therapeutic challenges. We report a case of a 24-year-old female with recurrent MPT exhibiting MPNST-like differentiation and integrated immunophenotypic and genomic characterization. The patient initially presented in November 2023 with a 3.8 cm right breast MPT treated by wide local excision. Five months later, ultrasound revealed local recurrence (5.8 cm), prompting right mastectomy in April 2024. Sixteen months after mastectomy, a 1 cm right chest wall nodule was identified and completely excised. Pathological examination revealed a high-grade spindle cell malignant neoplasm with MPNST-like morphology, brisk mitotic activity (>10 mitoses/10 HPF), and a Ki-67 index of 80-90%. Immunohistochemistry demonstrated focal S100 positivity, partial SOX10 expression, complete loss of H3K27me3, and absent RB1 protein expression, with cytoplasmic β-catenin positivity supporting phyllodes stromal lineage. A structured differential diagnosis excluded metaplastic spindle cell carcinoma, monophasic synovial sarcoma, fibromatosis/desmoid-type fibromatosis, myofibroblastic sarcoma, undifferentiated pleomorphic sarcoma, and primary de novo MPNST. Paired tumor-normal whole-exome sequencing of the recurrent lesion identified a TP53 truncating mutation (p.R342*) and an RB1 frameshift mutation (p.S127Vfs*9), the latter concordant with RB1 protein loss by immunohistochemistry. The tumor was microsatellite stable and tumor mutational burden-low, with no reportable copy-number alterations, gene rearrangements or fusions, clinically significant germline variants, or reportable SUZ12/EED alterations. These findings support molecular characterization of the recurrent lesion but do not establish clonal continuity with prior tumors or a definitive PRC2-driven mechanism. This case highlights the diagnostic value of integrating serial morphology, immunohistochemistry, and genomic profiling in recurrent MPT with rare MPNST-like differentiation. The combined findings of H3K27me3 and RB1 immunophenotypic loss, TP53 truncation, and RB1 frameshift mutation raise the possibility that chromatin-associated and cell-cycle alterations may contribute to neural crest-like heterologous differentiation, although this hypothesis requires further validation.