Case Presentation – September 2026

SMARCA4-deficient Undifferentiated Lung Tumor

Written by: Jonathan Schlote, Student, Cleveland Clinic School of Health Professions Cytology Program, Cleveland, Ohio

Patient Age: 71-year-old female

Specimen Type: Lung FNA, Papanicolaou and Modified Romanowsky stained smears, ThinPrep® Non-Gyn slide, Cellient® cell block.

Patient History: The patient presented to the Emergency Department with shortness of breath. She is currently a smoker. A lung mass with mediastinal and hilar adenopathy was seen on imaging. She was admitted to the hospital and underwent bronchoscopy with staging.

Cytologic Diagnosis: SMARCA4-deficient undifferentiated tumor.

Biopsy / Pathologic Diagnosis: No biopsy was performed. IHC stains were performed on the Cellient cell block. The tumor is negative for multiple cytokeratins (AE1/3, CAM 5.2, CK7 and CK20), Claudin 4, TTF1, p40/p63, S100/ SOX10, and chromogranin/INSM1. SMARCA4 and SMARCA2 stains showed loss of staining in tumor cell nuclei. INI 1 was retained. Synaptophysin and GATA3 were focally positive, which is interpreted as non-specific. The final diagnosis is SMARCA4-deficient undifferentiated tumor.

Case provided by: Cleveland Clinic, Cleveland, Ohio.

SMARCA4-deficient Undifferentiated Lung Tumor

Etiology:

The SMARCA4 gene encodes the Brahma-related gene 1 protein (BRG1 protein) which is involved in modifying chromatin architecture, essential for the regulation of binding transcription factors to DNA.^1,2,3 Thus, it is essential in the regulation of gene expression and important for mammalian tissue development and differentiation.⁴

SMARCA4-deficient tumors get their name from a mutation resulting in the loss of expression of SMARCA4 and SMARCA2 and overexpression of SOX2.³ The resultant loss of protein expression is detectable by immunohistochemistry.^5,6 About 25% of cases exhibit a drastic diffuse reduction of staining, rather than a complete absence.⁷ SMARCA4 is considered a tumor suppressor gene, and mutation allows neoplastic tissue growth.^1,4,5

There are two types of SMARCA4-deficient tumors that occur in the lung, SMARCA4-deficient undifferentiated tumors, and SMARCA4-deficient non-small cell lung carcinomas (NSCLC).² There are morphologic differences between these two entities, discussed below, albeit subtle. They are mainly distinguished using immunohistochemical stains for epithelial markers, with SMARCA4-deficient non-small cell lung cancers expressing claudin 4 and cytokeratins while the undifferentiated tumors lack staining for these markers.²

There are several risk factors for SMARCA4-deficient tumors in the lung, but the most common, by far, is smoking. People with rhabdoid tumor predisposition syndrome 2, and Coffin-Siris syndrome are also predisposed to a SMARCA4 deficiency.⁴ While SMARCA4-deficient lung tumors can occur within a wide age range (28-90 years), they are typically found in middle-aged males.⁶

Clinical Features: 

SMARCA4-deficient undifferentiated lung tumors are aggressive malignancies with rapid progression, and they are almost always diagnosed at an advanced stage in which surgery is not a viable option.^7,8 They tend to present as large mediastinal masses, but may be found in the pleura or lung parenchyma.^3,6 Radiologically, they appear as ill-defined and heterogeneous tumors that compress and infiltrate surrounding tissue and organs.⁷ Symptoms are non-specific and include difficulty breathing, pleural effusion, chest pain, reflux, fatigue, and weight loss.¹

Treatment and Prognosis:

Chemotherapy, immunotherapy, radiotherapy, and localized surgical resection have been used in treatment.³ For patients beyond stage 1, SMARCA4-deficient tumors have a high chance of early recurrence after surgery. Immunotherapy is a valuable strategy to treat recurrence in early-stage patients.⁷ Treatments are often systemic, especially in later stage malignancies, and may include chemotherapy and immune-checkpoint inhibitors (ICI). Regardless of therapy, the prognosis is poor, and patients have a median survival of six to seven months after diagnosis. Survival is slightly better in patients with SMARCA4-deficient NSCLC.^3,7,8

Cytology:

SMARCA4 is expressed in the nucleus; SMARCA4-deficient neoplasms show a lack of staining in tumor cells, but expression is still visible in other cells and tissues like blood vessels and lymphocytes, which serve as an internal control.⁴ All SMARCA4-deficient malignant neoplasms share characteristic cytologic features, including poorly differentiated round large cell or rhabdoid cytomorphology.³ The relatively monomorphic appearance of the tumor cells is unusual, especially in contrast with the otherwise high-grade cytological characteristics. The tumor cells form disorganized, variably cohesive sheets with poorly defined cell borders and loosely connected nests of tumor cells.^1,3,8 They typically have vesicular chromatin with prominent, moderately sized nucleoli, abundant eosinophilic or clear cytoplasm, eccentric nuclei, and faint perinuclear hyaline inclusions. High mitotic activity and apoptosis are commonly present, while necrosis is prevalent and can be so extensive that viable cells are difficult to find.^3,5

Differential Diagnosis:

The largely undifferentiated appearance of SMARCA4-deficient undifferentiated lung tumors can make the diagnosis difficult. They share features of carcinomas and sarcomas. Thus, differential diagnoses are broad. Primary sarcomas involving the lung are extremely rare and SMARCA4 staining should be performed in any keratin negative case; SMARCA4-deficient tumors are more common than primary lung sarcomas.^2,5,9 A few of the most likely malignancies are SMARCA4-deficient NSCLC, conventional pulmonary NSCLC, and mesothelioma.^2,5

While there are many shared cytologic features between SMARCA4-deficient undifferentiated lung tumors and SMARCA4-deficient NSCLCs, there are some notable differences.² SMARCA4-deficient NSCLCs are poorly differentiated carcinomas with mostly cohesive groups of large cells with abundant pale cytoplasm, which is in contrast with the single‐cell, and less cohesive plasmacytoid cells with eccentric nuclei, rhabdoid cytomorphology, and necrosis, representative of SMARCA4-deficient undifferentiated tumors. Since both entities lack staining for SMARCA4, claudin-4, and/or keratins are used to differentiate them. Claudin‐4 and keratin stains are negative in SMARCA4-deficient undifferentiated lung tumors but are positive, often diffusely, in SMARCA4-deficient NSCLC.²

Based on the cytology and location of the tumor, conventional pulmonary NSCLC is among the most logical differentials. SMARCA4-deficient undifferentiated tumors of the lungs are also often related to smoking.^2,6 While the morphologic differences are not always distinct, there are some notable differences. NSCLC often shows evidence of specific differentiation; keratinization, gland formation, and cytoplasmic mucin which, by definition, are lacking in SMARCA4-deficient undifferentiated tumors.² There are significant differences in IHC staining. SMARCA4-deficient undifferentiated lung tumors do not express the usual lung‐associated markers. Specifically, they are negative for p40/p63 and TTF‐1.² And as the name indicates, SMARCA4 staining is negative or deficient in SMARCA4-deficient undifferentiated lung tumors and positive in conventional NSCLC.²

Mesothelioma is an important differential for poorly differentiated thoracic neoplasms with a lack of cohesion. SMARCA4-deficient tumors are often found in the pleural cavity, like mesotheliomas. However, SMARCA4 is very rarely absent in mesotheliomas (1% of cases) and SMARCA2 is always retained. So, loss of either of these markers can rule out mesothelioma in favor of a SMARCA4-deficient undifferentiated tumor.⁹ In addition, some IHC stains that would be positive in mesothelioma and negative in SMARCA4-deficient undifferentiated tumors are the mesothelial markers WT1, calretinin, D2‐40, HEG1.²

References:

1. Sauter JL, Graham RP, Larsen BT, et al. SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior. Mod Pathol, 30 (2017), pp. 1422-1432
2. Zalles N, Mukhopadhyay S, Satturwar S, et al. Fine‐needle aspiration and effusion cytology of thoracic SMARCA4–deficient undifferentiated tumor and SMARCA4‐deficient non–small cell lung carcinoma: A multi‐ institutional experience with 27 patients. Cancer Cytopathol. 2025;e22919. doi:10.1002/cncy.22919
3. Perret R, Chalabreysse L, Watson S, et al. SMARCA4-deficient Thoracic Sarcomas: Clinicopathologic Study of 30 Cases With an Emphasis on Their Nosology and Differential Diagnoses. Am J Surg Pathol. 2019;43(4):455-465. doi:10.1097/PAS.0000000000001188
4. Armstrong SM, Dickson BC. SMARCA4 / BRG1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainssmarca4brg1.html. Accessed February 19th, 2026
5. Russell-Goldman E, MacConaill L, Hanna J. Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm: first two cases with clinicopathologic and molecular comparison to eight visceral counterparts. Mod Pathol. 2022; 35(12): 1821-1828. doi:10.1038/s41379-022-01152-1
6. Cibas ES, Ducatman BS. Respiratory Tract and Mediastinum. In: Cytology : Diagnostic Principles and Clinical Correlates. Elsevier; 2020:94.
7. Luo J, Ding B, Campisi A, Chen T, Teng H, Ji C. Molecular, clinicopathological characteristics and surgical results of resectable SMARCA4-deficient thoracic tumors. J Cancer Res Clin Oncol. 2023;149(8):4455-4463. doi:10.1007/s00432-022-04359-6.
8. Kezlarian B, Montecalvo J, Bodd FM, Chang JC, Riedel E, White C, . . . Sauter J L. (2023). Diagnosis of thoracic SMARCA4-deficient undifferentiated tumor in cytology. Cancer Cytopathology, 131(8), 526-534. Retrieved from https://rave.ohiolink.edu/ejournals/article/390390237
9. Early CA, Wangsiricharoen S, Jones RM, VandenBussche CJ. Review of SMARCA4 (BRG1)-deficient carcinomas following a malignant pleural effusion specimen confounded by reduced claudin-4 expression. J Am Soc Cytopathol. 2021;10(2):197-207. doi:10.1016/j.jasc.2020.08.002