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

Authors

Behtash G Nezami, Qiuying Shi, Xiaoqi Lin

Published in

Human pathology. Pages 106229. Aug 04, 2026. Epub Aug 04, 2026.

Abstract

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.
Biopsied cytologic slides were reviewed. Next-generation sequencing (NGS) and clinical data were analyzed.
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.
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.

PMID:
42551596
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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