Intestinal SMARCA4-deficient undifferentiated carcinoma: a case series and systematic review of the literature

BACKGROUND: Intestinal SMARCA4-deficient undifferentiated carcinoma (SMARCA4-DUC) is a rare and highly aggressive malignancy. Its clinicopathological features remain poorly defined. No standardized treatment has been established. METHODS: We report two new cases and review 18 previously published cases, providing a descriptive summary of clinicopathological, molecular, and therapeutic features. RESULTS: The aggregated 20 cases included 80% males, with a mean age of 56 years. The tumors exhibited diffuse sheet-like growth of epithelioid cells, with rhabdoid morphology observed in 81.25% (13/16) of cases. Necrosis and mitotic activity were frequent. Immunohistochemistry confirmed SMARCA4 loss and variable CK/CK7 expression, while CDX-2 and CK20 were consistently negative. Ki-67 was uniformly high. Although molecular profiling data in this study were limited, TP53 mutations were identified in all three cases with available NGS data. Distant metastasis was present in 41.2% of patients at initial diagnosis. The median overall survival was 11 months (range 1.5-29 months). Chemotherapy responses were poor, but responses to immune checkpoint inhibitors were heterogeneous: two patients achieved sustained complete remission (> 18 months) on pembrolizumab, while three others experienced no benefit. CONCLUSIONS: Intestinal SMARCA4-deficient carcinoma is a rare high-grade malignancy with a poor prognosis and currently no standard treatment regimen. In this small aggregated series, two patients achieved durable complete responses to pembrolizumab monotherapy, suggesting that a subset of these tumors may benefit from immune checkpoint inhibitors. However, given the inconsistent responses observed, these preliminary findings require validation in future multicenter, large-scale prospective studies.