SMARCA4-altered malignancies: Cytologic diagnostic challenges and clinicopathologic correlation.

BACKGROUND: SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) have been included in the latest WHO classification of tumors. This study examined the cytomorphology, management, molecular features and prognosis of malignancies harboring SMARCA4 alterations. METHODS: Biopsied cytologic slides were reviewed. Next-generation sequencing (NGS) and clinical data were analyzed. RESULTS: Thirty-four cases with SMARCA4 alterations were identified, including 13 primary and 21 metastatic tumors, sampled primarily from lung (35%), lymph nodes (26%) and liver (15%). Tumor origins were predominantly the lung (61%) and gallbladder (9%). The most common tumor type was adenocarcinoma (70%). 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. SMARCA4 alteration included mutations (32) and loss (2). These tumors are characterized by a high co-mutation burden, including TP53 (62%), KRAS (35%), and STK11 (15%). Prognosis is further modulated by allelic status (biallelic vs. monoallelic vs. subclonal), and mutations in DDR pathway (24%). Most tumors presented as stage IV. 26% received surgical resection. Overall, 74% underwent chemotherapy and 29% radiotherapy. Mean follow-up was 17 months, with 2-year OS of 49.1%. Twenty-three (68%) patients were current or former smokers. CONCLUSION: SMARCA4-altered malignancies show diverse differentiation and lack consistent cytomorphologic features. Majority of cases were differentiated malignancies and only four cases (12%) were undifferentiated, suggesting SMARCA4 alterations were associated with poor prognosis but were not exclusive drivers of undifferentiated malignancy.