Case Report: SMARCA4-deficient uterine sarcoma with exceptional response to immune checkpoint inhibitor therapy

SMARCA4-deficient uterine sarcoma (SDUS) is a rare and aggressive undifferentiated uterine mesenchymal malignancy characterized by inactivation of SMARCA4 gene leading to loss of nuclear SMARCA4/BRG1 immunohistochemical staining. Fewer than 40 cases have been reported worldwide since its first description in 2018, and the disease carries a median overall survival of only 7-9 months. SMARCA4 loss is observed across a spectrum of aggressive neoplasms, including smallcell carcinoma of the ovary, hypercalcemic type (SCCOHT), SMARCA4-deficient thoracic sarcoma, and SMARCA4-deficient nonsmallcell lung cancer, suggesting shared therapeutic vulnerabilities.

A 48-year-old woman presented with irregular vaginal bleeding for two years. Physical examination and magnetic resonance imaging (MRI) revealed a large pelvic mass centered in the uterus. The patient underwent total abdominal hysterectomy with bilateral salpingectomy, and pathological examination confirmed SDUS (stage IB, FIGO 2018). Genetic testing identified a somatic SMARCA4 splice-site variant (c.3951 + 2T>G). The tumor was TMB-low (0.06 Mut/Mb), PD-L1-negative (<1% by 22C3 pharmDx), microsatellite stable (MSS), and HLA-class-I heterozygous. Despite these conventional immunotherapy-unfavorable markers, adjuvant Gemcitabine-Docetaxel chemotherapy combined with pembrolizumab yielded a progression-free survival (PFS) of 23 months as of the last follow-up, far exceeding the previously reported median survival of SDUS.

This case demonstrates that immune checkpoint inhibitors (ICI) may provide meaningful therapeutic benefit in selected patients with SDUS, including those lacking conventional predictive biomarkers (TMB-high, PD-L1 positivity, or MSI-H). While the observed 23-month PFS supports the hypothesis that SMARCA4 deficiency merits further investigation as a candidate molecular correlate of ICI responsiveness, definitive validation requires larger cohorts and ideally prospective, biomarker-driven studies. Definitive diagnosis relies on morphologic evaluation, loss of BRG1 protein expression by immunohistochemistry with retained INI-1, and detection of SMARCA4 gene alterations through genetic testing.