SMARCA4 gene, located on chromosome 19q13, encodes the BRG1 protein, which serves as the catalytic subunit of the SWI/SNF chromatin remodeling complex and participates in regulating chromatin structure remodeling processes [1]. The SWI/SNF complex is a multi-protein assembly composed of several subunits and is widely involved in fundamental cellular processes, including gene expression, cell proliferation, differentiation, and DNA repair [2]. Deletions or mutations of SMARCA4/BRG1 have been shown to be associated with the development of various cancers and sarcomas, including those in the nasal cavity [3], thoracic region [4], ovary [5], uterus [6], and gastrointestinal tract [7]. Particularly, SMARCA4-deficient undifferentiated tumors are common in the chest and are typically highly malignant, prone to distant metastasis. These tumors are characterized by undifferentiated cell morphology, with some tumor cells displaying rhabdomyoid features, and these types of tumors generally have a poor prognosis [8]. Further research into the molecular mechanisms underlying SMARCA4 deficiency is crucial for improving diagnostic and therapeutic strategies for patients with these aggressive malignancies.

Among these, SMARCA4-deficient NSCLC has recently garnered attention as a rare primary malignant lung tumor in humans. It was included as a new tumor type in the fifth edition of the World Health Organization (WHO) classification of thoracic tumors in 2021. This tumor exhibits atypical pathological features of NSCLC, high invasiveness, and resistance to treatment [9]. Morphologically, it presents as high-grade malignancy, ranging from typical adenocarcinoma to poorly differentiated carcinoma, even showing rhabdomyoid features. As a result, the tumor exhibits high pathological heterogeneity, complex morphology, and lacks distinct signature features. Clinically, SMARCA4-deficient NSCLC often presents with non-specific early symptoms such as dyspnea, chest pain, cough, hemoptysis, and superior vena cava syndrome. Due to its highly aggressive nature, many patients present with local or distant metastases at the time of diagnosis, with common metastatic sites including bones, liver, and brain [[10], [11], [12]]. In light of its rapid progression and tendency to present with advanced-stage disease, SMARCA4-deficient NSCLC poses significant diagnostic and therapeutic challenges. Early detection is crucial to improving patient outcomes, but given the lack of distinctive early symptoms, there is a pressing need for the development of more effective screening methods and therapeutic strategies tailored to this aggressive form of lung cancer. Furthermore, SMARCA4-deficient NSCLC is often associated with the inactivation of the TP53 gene, further enhancing its malignant characteristics at the molecular level. The loss or mutation of SMARCA4 disrupts chromatin remodeling, increasing tumor malignancy and metastatic potential [13].

SMARCA4 mutations are considered hallmark genetic alterations in these types of tumors. Studies have shown that SMARCA4 mutations are often coexistent with common driver mutations in smoking-related NSCLC, such as KRAS and STK11, but are mutually exclusive with common targetable mutations in NSCLC, such as EGFR, ALK, and ROS1. Patients with multiple coexisting mutations generally have a poorer prognosis [14,15]. Clinical data indicate that approximately 83 % of patients with SMARCA4-deficient NSCLC are diagnosed at stage IV of the TNM classification, with a median progression-free survival (PFS) of only 30 days. Although platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) provides some therapeutic benefit for these patients, their long-term efficacy remains unclear [16,17].

Therefore, in-depth research on the clinicopathological features of SMARCA4-deficient NSCLC and the development of effective survival prediction models are of great significance for precision treatment and prognosis evaluation. This article aims to retrospectively analyze the clinical data of patients with SMARCA4-deficient NSCLC and SMARCA4-intact NSCLC, explore their morphological and immunohistochemical characteristics, and provide references for pathologic diagnosis of suspicious SMARCA4 expression loss in NSCLC cases. Additionally, we will preliminarily investigate the molecular alterations in SMARCA4-mutant lung adenocarcinoma and their relationship with immunohistochemical markers, and further assess the potential impact of these molecular features on patient prognosis.