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Updated: Aug 9, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
SMARCA4-altered malignancies: Cytologic diagnostic challenges and clinicopathologic correlation
Behtash G Nezami1, Qiuying Shi2, Xiaoqi Lin1
1Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
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.
Insights
SMARCA4-altered malignancies present diverse features, often linked to poor prognosis. While associated with undifferentiated tumors, SMARCA4 alterations are not exclusive drivers, indicating complex oncogenesis.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are newly classified by WHO.
- This study investigates SMARCA4-altered malignancies' cytomorphology, management, molecular profile, and prognosis.
Purpose of the Study:
- To characterize SMARCA4-altered malignancies.
- To analyze their cytomorphologic, molecular, and clinical features.
- To assess the prognostic impact of SMARCA4 alterations.
Main Methods:
- Review of biopsied cytologic slides.
- Next-generation sequencing (NGS) for molecular analysis.
- Analysis of clinical data and patient outcomes.
Main Results:
- 34 cases with SMARCA4 alterations identified, primarily from lung, lymph nodes, and liver.
- Commonly adenocarcinoma (70%), with varied cytomorphology and high nuclear grade (93%).
- Frequent co-mutations in TP53 (62%), KRAS (35%), STK11 (15%); prognosis affected by allelic status and DDR pathway mutations.
Conclusions:
- SMARCA4-altered malignancies exhibit diverse differentiation and lack specific cytomorphologic markers.
- While associated with poor prognosis, SMARCA4 alterations are not solely responsible for undifferentiated tumor formation.
- Most cases were differentiated, with only 12% being undifferentiated.
