Updating the Genomic and Clinicopathologic Features of Thoracic SMARCA4 Deficient Undifferentiated Tumor: A Mini-series Including a Long-term Survivor

Kenneth Ofori^1*Carlos Pagan²Marie C Smithgall²Asma Salah Jadalla¹Swikrity Upadhyay Baskota³John P Crapanzano²Susan Hsiao²Mahesh Mansukhani^2*

• ¹Department of Pathology and Laboratory Medicine, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
• ²Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York City, New York, United States
• ³Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, California, United States

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 lung, in patients with smoking history, and exhibits adverse prognosis. The essential diagnostic immuno-morphologic features and typical genomic findings have been described. However, there is continuing need to catalogue the spectrum of genomic changes underlying the disease, 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 immuno-morphologic features. Four cases (3M, 1F) were identified at median age of 61.5 years (range:49-72), 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 known immunophenotypic features of the disease, we identified expression of FLI (3/3 cases) and WT-1 (1/3 cases), endothelial and mesothelial markers: 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, expression of INSM1 was absent in all cases. Genomic analysis demonstrated tobacco-related features including high median tumor mutation burden and TP53 variants. Mutational signature analysis revealed evidence of the non-tobacco related SBS87 as the predominant single base substitution COSMIC signature. Our work expands the possible diagnostic antigen expression of thoracic SMARCA4-dUT, contributes to emerging reports of patients with variant disease presentation, and highlights need for large-scale genomic studies to determine additional mechanisms of initiation carcinogenesis.