Updating the genomic and clinicopathologic features of thoracic SMARCA4-deficient undifferentiated tumor: a mini-series including a long-term survivor

Our plain-English summary of Updating the genomic and clinicopathologic features of thoracic SMARCA4-deficient undifferentiated tumor: a mini-series including a long-term survivor, by K. Ofori, C. Pagan, M.C. Smithgall, et al (Frontiers in Oncology, 2025).

The study

• Authors: K. Ofori, C. Pagan, M.C. Smithgall, A.S. Jadalla, S. Upadhyay Baskota, J.P. Crapanzano, S. Hsiao, M.M. Mansukhani
• Journal: Frontiers in Oncology
• Published: 2025;15:1601443
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: 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.

Methods: We searched for cases diagnosed in our institution, reviewed clinical data, performed comprehensive genomic analysis, and evaluated immunomorphologic features.

Results: 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 TP53 variants. In this limited series, mutational signature analysis revealed evidence of SBS87 as the predominant single-base substitution COSMIC signature.

Conclusion: 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.

Copyright © 2025 Ofori, Pagan, Smithgall, Jadalla, Upadhyay Baskota, Crapanzano, Hsiao and Mansukhani.

In plain English

This retrospective case series described four patients diagnosed with thoracic SMARCA4-deficient undifferentiated tumor, a recently described lung cancer, at Columbia University Irving Medical Center from January 2021 to January 2023. The study did not examine asbestos. All four patients had a smoking history. The authors reviewed records, tissue stains and tumor genetic tests. The two patients managed palliatively died; median overall survival was 4.1 months (95% confidence interval 1.1 months to not estimable). One patient, whose tumor was found on lung cancer screening, had surgery and chemotherapy and showed no relapse 411 days after diagnosis. Tumor cells stained for FLI1 in three of three tested cases and for WT-1 in one of three. The authors noted that WT-1 staining could cause confusion with malignant mesothelioma. Every tumor had a TP53 variant, and the median tumor mutation burden was 10 mutations per megabase. A mutational pattern called SBS87 appeared in all patients; tobacco-related patterns were not stably present. The authors concluded that the work expands the known staining features of this tumor. They named the small, single-institution sample as the main limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: retrospective single-institution case series (mini-series of four cases)
• Who was studied: Four patients (three men, one woman; median age 61.5 years, range 49 to 72) with thoracic SMARCA4-deficient undifferentiated tumor diagnosed at Columbia University Irving Medical Center, New York, January 2021 to January 2023
• Exposure: Smoking history in all four patients (median 14 packs per year, range 1 to 35). Asbestos exposure is not mentioned.
• Main results:
  • The median overall survival for the cohort was 4.1 months (95% CI 1.1 to not estimable) after a median follow-up of 183 days. The two patients managed palliatively died of disease.
  • Case 3, a 72-year-old man whose disease was detected on lung cancer screening, had a lobectomy and adjuvant chemotherapy and had no evidence of relapse 411 days after diagnosis.
  • FLI1 was positive in three of three tested cases.
  • WT-1, a marker also seen in mesothelioma, was expressed in one of three tested cases. The authors noted this could make it hard to tell the tumor apart from malignant mesothelioma.
  • INSM1, a neuroendocrine marker, was absent in three of three tested cases. CD56 was expressed in one of four cases.
  • The median tumor mutation burden was 10 mutations per megabase.
  • All four tumors carried a pathogenic TP53 variant.
  • The SBS87 mutational signature was stably present in all patients. The tobacco-related signatures SBS4 and SBS92 were not stably present in any patient.
  • All cases except case 3 (the disease-free patient) showed loss of CDKN2A/B.
• The authors' conclusion: The authors concluded that their work expands the possible diagnostic antigen expression of thoracic SMARCA4-dUT, contributes to reports of patients with variant disease presentation, and highlights the need for large-scale genomic studies.
• Limitations the authors state:
  • The small number of patients prevented definite identification of subgroups with statistically significant differences.
  • The study was from a single institution.
  • The targeted sequencing panel may not fully represent mutational processes, which could explain why smoking-related signatures were not dominant.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mediastinum, Prognosis, Chemotherapy, Low-Dose CT Screening, Wilms Tumor 1 (WT-1), Misdiagnosis, Mesothelioma.

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