SMARCA4-Mutated Malignancies: Cytologic Diagnostic Challenges and Clinicopathologic Correlates

Background: SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) have been included in the latest WHO classification of tumors. This study examined the cytomorphology and clinical management of malignant neoplasms harboring SMARCA4 mutations.Methods: Fine-needle aspiration biopsy (FNAB) and core needle biopsy (CNB) touch preparation were evaluated. Next-generation sequencing (NGS) and clinical data were analyzed.Results: Twenty-seven cytology cases with SMARCA4 mutations were identified, 12 primary and 15 metastatic, involving lung (11), lymph nodes (8), liver (2), chest wall (2), body fluid (1 pleural, 1 peritoneal), peritoneum (1), and gallbladder (1). Lung origin was confirmed in 21 cases: 17 adenocarcinomas, 1 squamous cell carcinoma, 1 mucoepidermoid carcinoma, 1 small cell carcinoma, and 1 undifferentiated carcinoma. Overall, metastasis was present in 24 (89%) patients. Predominant architectures included nested, single-cell, tubular/acinar, and 3D clusters. Cells were most commonly round and columnar, with medium cytoplasm mostly showing, vacuoles and granular features. Nuclear grade 2-3 was seen in 93% of cases, with prominent nucleoli and coarse chromatin. SAMRCA4 aberrations included mutations (26) and loss (1). Driver mutations included KRAS (9) and EGFR (2). Other recurrent mutations included TP53 (19), CDKN2A (6), STK11 (6), and ARID1A (5). Treatment included chemotherapy (74%), radiotherapy (41%), surgical resection (19%). Mean follow-up was 14 months, with 59% 1-year overall survival. Twenty-two (81%) patients were current or previous smokers.Conclusion: SMARCA4-mutated malignancies show diverse differentiation and lack consistent cytomorphologic features. Majority of cases were differentiated malignancies and only three cases (11%) were undifferentiated, suggesting SMARCA4 mutations are not exclusive drivers of undifferentiated malignancy.