SMARCA4-Deficient Undifferentiated Carcinoma: A Report of 2 Cases.

Abstract

BACKGROUND SMARCA4-deficient undifferentiated carcinoma (SMARCA4-DUC) is a rare and aggressive malignancy caused by inactivation of the SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 4) gene, a critical component of the SWI/SNF chromatin-remodeling complex. Initially identified in thoracic tumors, it is increasingly recognized in extrathoracic sites, including the gastrointestinal tract. These tumors often mimic other malignancies, such as poorly differentiated adenocarcinomas, malignant melanoma, hematolymphoid malignancies, or sarcomas, complicating diagnosis. Histologically, SMARCA4-DUC shows expression loss of BRG1 (the protein encoded by SMARCA4) on immunohistochemistry (IHC). SMARCA4-DUC exhibits rapid progression, local invasion, and poor prognosis due to its undifferentiated morphology and high proliferative capacity. CASE REPORT Case 1 was a 71-year-old woman with a 13.6-cm gastric tumor involving GE junction, with direct invasion to pancreas and transverse mesocolon. Initial impression suggested gastrointestinal stromal tumor (GIST) of stomach or sarcoma. Endoscopic biopsy followed by targeted next-generation sequencing revealed a pathogenic SMARCA4 mutation. After confirming SMARCA4-DUC, she underwent extensive open surgery followed by postoperative adjuvant paclitaxel-carboplatin chemotherapy. She developed recurrence and was transferred to hospice care. Case 2 was an 80-year-old man with a 9.0-cm gastric tumor at cardia, directly invading the pancreas. Endoscopic biopsy revealed poorly differentiated tubular adenocarcinoma. Following laparoscopic gastrectomy, the specimen showed a predominantly undifferentiated malignant tumor with focal adenocarcinoma components. IHC demonstrated loss of BRG1 expression in the undifferentiated tumor component, confirming SMARCA4-DUC. He completed several cycles of adjuvant XELOX, without recurrence. CONCLUSIONS These 2 cases of SMARCA4-DUC of the stomach underscore the importance of molecular diagnostics and multidisciplinary management to avoid delayed diagnosis and to establish appropriate therapeutic strategies.