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

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

Authors:	Rekhtman, N.; Montecalvo, J.; Chang, J. C.; Alex, D.; Ptashkin, R. N.; Ai, N.; Sauter, J. L.; Kezlarian, B.; Jungbluth, A.; Desmeules, P.; Beras, A.; Bishop, J. A.; Plodkowski, A. J.; Gounder, M. M.; Schoenfeld, A. J.; Namakydoust, A.; Li, B. T.; Rudin, C. M.; Riely, G. J.; Jones, D. R.; Ladanyi, M.; Travis, W. D.
Article Title:	SMARCA4-deficient thoracic sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas
Abstract:	Introduction: 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 with those of nonsarcomatoid SMARCA4-deficient non–small cell lung carcinomas (SD-NSCC). Methods: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or 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-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30–50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers. Conclusions: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated 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. © 2019 International Association for the Study of Lung Cancer
Keywords:	immunohistochemistry; adult; cancer survival; clinical article; controlled study; human tissue; protein expression; aged; middle aged; genetic trait; human cell; pathogenesis; molecular genetics; disease association; tumor volume; smoking; pathology; lung; sarcomatoid carcinoma; aging; sarcomatoid; anaplastic carcinoma; rhabdoid tumor; histogenesis; non small cell lung cancer; protein p40; small cell sarcoma; thoracic; brg1 protein; rhabdoid; brg1; high throughput sequencing; human; male; female; priority journal; article; claudin 4; smarca4; homeobox protein nkx 2.1; thoracic sarcomatoid tumor
Journal Title:	Journal of Thoracic Oncology
Volume:	15
Issue:	2
ISSN:	1556-0864
Publisher:	Elsevier Inc.
Date Published:	2020-02-01
Start Page:	231
End Page:	247
Language:	English
DOI:	10.1016/j.jtho.2019.10.023
PUBMED:	31751681
PROVIDER:	scopus
PMCID:	PMC7556987
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077354691&doi=10.1016%2fj.jtho.2019.10.023&partnerID=40&md5=36d3b3c4395842a223ea4e63fda63af4
Notes:	Article -- Export Date: 2 March 2020 -- Source: Scopus