Thoracic SMARCA4-deficient sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas

Abstract Background Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described, and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare to those of non-sarcomatoid SMARCA4-deficient non-small cell lung carcinomas (SD-NSCC). Methods We identified 22 thoracic SMARCA4-deficient sarcomatoid tumors (SD-STs) with round cell/rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical and genomic characteristics using 341-468 gene next-generation sequencing and other molecular platforms. Results The relationship of SD-STs with NSCC was supported by 1) the presence of NSCC components juxtaposed with sarcomatoid areas in 5 cases, 2) focal expression of NSCC lineage markers TTF1 or p40 in 4 additional cases, 3) smoking history in all but one patient (mean 51 pack-years), accompanied by genomic smoking signature, and 4) high tumor-mutation burden (mean 14.2 mutations/Mb) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-STs exhibited significantly larger primary tumor size (p Conclusion SD-STs represent primarily smoking-associated undifferentiated/dedifferentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.