Ofori Kenneth, Pagan Carlos, Smithgall Marie C, Jadalla Asma Salah, Upadhyay Baskota Swikrity, Crapanzano John P, Hsiao Susan, Mansukhani Mahesh M
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York City, NY, United States.
Front Oncol. 2025 Aug 20;15:1601443. doi: 10.3389/fonc.2025.1601443. eCollection 2025.
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a recently described type of lung cancer, presenting as a bulky mass variably involving the mediastinum and the lung in patients with smoking history, and exhibits adverse prognosis. The essential diagnostic immunomorphologic features and typical genomic findings have been described. However, there is a continuing need to catalogue the spectrum of genomic changes underlying the disease, the heterogeneity of antigen expression in order to avoid diagnostic pitfalls, and any variability in patient outcomes. We sought to update the literature on the clinicopathologic and genomic characteristics of thoracic SMARCA4- dUT.
We searched for cases diagnosed in our institution, reviewed clinical data, performed comprehensive genomic analysis, and evaluated immunomorphologic features.
Four cases (three males and one female) were identified at a median age of 61.5 years (range, 49-72 years), all with smoking history. The series included a patient with limited disease treated with surgery and adjuvant chemotherapy, who remained disease-free over a year after diagnosis, underscoring the importance of lung cancer screening among smokers and the possibility of a subgroup of thoracic SMARCA4-dUT with less aggressive disease. In addition to the known immunophenotypic features of the disease, we identified the expression of FLI (in three out of three cases) and WT-1 (in one of three cases), which are endothelial and mesothelial markers, and are findings to be cognizant of to avoid misdiagnosis as angiosarcoma or mesothelioma, respectively. While the neuroendocrine markers synaptophysin and CD56 were variably expressed in some cases, the expression of INSM1 was absent in all cases. Genomic analysis demonstrated tobacco-related features, including a high median tumor mutation burden and variants. In this limited series, mutational signature analysis revealed evidence of SBS87 as the predominant single-base substitution COSMIC signature.
Our work expands the possible diagnostic antigen expression of thoracic SMARCA4-dUT, contributes to the emerging reports on patients with variant disease presentation, and highlights the need for large-scale genomic studies to determine additional mechanisms of the initiation of carcinogenesis.
胸段SMARCA4缺陷型未分化肿瘤（SMARCA4-dUT）是一种最近被描述的肺癌类型，在有吸烟史的患者中表现为体积较大的肿块，可不同程度地累及纵隔和肺，且预后不良。其基本的诊断性免疫形态学特征和典型的基因组学发现已被描述。然而，仍需要梳理该疾病潜在的基因组变化谱、抗原表达的异质性以避免诊断陷阱，以及患者预后的任何变异性。我们试图更新关于胸段SMARCA4-dUT临床病理和基因组特征的文献。
我们检索了在我们机构诊断的病例，回顾了临床数据，进行了全面的基因组分析，并评估了免疫形态学特征。
共鉴定出4例（3例男性和1例女性），中位年龄为61.5岁（范围49 - 72岁），均有吸烟史。该系列包括1例疾病局限的患者，接受了手术和辅助化疗，诊断后1年多无疾病复发，这强调了吸烟者肺癌筛查的重要性，以及存在胸段SMARCA4-dUT中疾病侵袭性较低的亚组的可能性。除了该疾病已知的免疫表型特征外，我们还鉴定出FLI（3例中的3例）和WT-1（3例中的1例）的表达，它们分别是内皮和间皮标志物，这是为避免分别误诊为血管肉瘤或间皮瘤而需要注意的发现。虽然神经内分泌标志物突触素和CD56在某些病例中表达不一，但所有病例均未检测到INSM1的表达。基因组分析显示出与烟草相关的特征，包括较高的肿瘤突变负荷中位数和多种变异。在这个有限的系列中，突变特征分析显示SBS87是主要的单碱基替换COSMIC特征。
我们的工作扩展了胸段SMARCA4-dUT可能的诊断性抗原表达，为关于疾病表现变异患者的新报道做出了贡献，并强调了进行大规模基因组研究以确定致癌起始的其他机制的必要性。
