Expanding the spectrum of AFF2 undifferentiated sarcoma associated to endometriosis: A novel ZDHHC9::AFF2 fusion sarcoma with high-grade features and poor prognosis

The AFF2 gene encodes a protein involved in transcriptional regulation and chromatin remodeling. While primarily associated with Fragile X syndrome, AFF2 fusions have recently been identified in certain malignancies, mostly sinonasal squamous cell carcinoma. Recently it has been implicated in an intra-abdominal sarcoma linked to endometriosis. We present the case of a 71-year-old woman with a 19 cm ovarian mass arising in cystic endometriosis. Histological examination revealed high-grade undifferentiated sarcoma with spindle to epithelioid morphology, high nuclear atypia, a high mitotic index, and extensive necrosis. Immunohistochemistry demonstrated positivity for Vimentin, ER, PR, CD10, focal WT1, Desmin, and NTRK, with aberrant p53 expression in 75% of tumor cells. RNA sequencing identified a novel ZDHHC9::AFF2 fusion. The patient underwent chemotherapy with epirubicin and ifosfamide but experienced recurrence with lymph node and peritoneal involvement and succumbed to the disease after 9 months. In conclusion, this case expands the morphological spectrum of AFF2-related sarcomas, providing further evidence of their pathological heterogeneity. Moreover, it identifies a novel fusion, which may have implications for tumor classification and diagnostic refinement. The morphological findings also suggest a possible association with poor clinical outcomes.