ABSTRACT Uterine sarcomas are rare and aggressive mesenchymal malignancies that account for a small proportion of uterine cancers but contribute disproportionately to disease-related mortality. SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) is very rare, with <30 cases reported in the literature. They are highly aggressive, often seen in young to middle-aged women, with rapid recurrence and poor outcomes. Loss of function of SMARCA4 disrupts epigenetic regulation, impairs cellular differentiation and drives tumour dedifferentiation, thereby conferring an aggressive clinical phenotype and potential resistance to conventional therapies. We report the case of a 45-year-old woman presenting with abnormal uterine bleeding who was diagnosed with SDUS following robotic hysterectomy with bilateral salpingo-ophorectomy and pelvic lymphadenectomy. Histopathology revealed a high-grade spindle cell neoplasm with diffuse CD10, smooth muscle actin and Cyclin D1 positivity, aberrant p53 null pattern and elevated Ki 67 (20%–25%). Comprehensive genomic profiling (CGP) demonstrated a mutation in the SMARCA4 gene leading to loss of function, confirming a SMARCA4-deficient sarcoma. This case highlights the pivotal role of CGP in the accurate classification and risk stratification of high-grade uterine sarcomas. Identification of SMARCA4 mutation established the diagnosis of a rare, molecularly defined subset of high-grade endometrial stromal sarcoma associated with aggressive biological behaviour and adverse prognosis, which may exhibit sensitivity to emerging targeted and epigenetic therapies, including EZH2 inhibition and novel immunotherapeutic strategies. Our findings support that the routine integration of molecular profiling can refine prognostication and enable precision-guided therapeutic decisions.
Patel et al. (Thu,) studied this question.