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Therapeutic misalignment averted by clonal evolutionary evidence: molecular confirmation of hepatic metastasis in SMARCA4-deficient non-small cell lung cancer initially misdiagnosed as resectable cholangiocarcinoma

Year: 2026

Type: article

Abstract: Objectives SMARCA4 -deficient non-small cell lung cancer ( SMARCA4 -dNSCLC) exhibits significant histomorphological diversity and intertumoral heterogeneity. Immunophenotypically, it often lacks lineage-specific markers, making diagnosis challenging, especially in cases of hepatic metastasis. Currently, no reliable method exists to distinguish these metastases from primary hepatic malignancies based on conventional pathology. Therefore, molecular profiling of somatic alterations combined with clonal evolutionary analysis is critical for accurate diagnosis. Methods Histomorphological and immunophenotypic differences between pulmonary and hepatic lesions were assessed via hematoxylin and eosin staining and immunohistochemistry. Somatic mutational profiles were analyzed using next-generation sequencing, followed by clonal evolutionary analysis to confirm primary lung malignancy and hepatic metastasis. Results This study presents a case of SMARCA4 -dNSCLC exhibiting notable histomorphological and immunophenotypic divergence between the primary lung tumor and its hepatic metastasis. This heterogeneity led to a misdiagnosis of primary intrahepatic cholangiocarcinoma at another hospital. Molecular analysis showed that both lung and liver tumors harbored consistent SMARCA4 and TP53 mutations. Clonal evolutionary analysis revealed that both major and subclones were more prevalent in the lung tumor than in the liver metastasis. The evolutionary tree topology strongly suggested a unidirectional trajectory from the primary lung tumor to liver metastasis. Conclusion This study provides the first genomic evidence of shared and divergent somatic mutations in SMARCA4 -dNSCLC and its hepatic metastasis. Clonal evolutionary analysis confirmed the diagnosis of SMARCA4 -dNSCLC with hepatic metastasis, resolving diagnostic challenges and supporting precision therapy.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1743908

Authors: Ruirui Fan, Yanyan Zhan, Junrong Yan, Jie Gao

Institution: Peking Union Medical College Hospital

Language: English

Topic: Chromatin Remodeling and Cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801