Thursday, March 31, 2016

Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria

Brandon R. Driver MDBryce P. Portier MDDina R. Mody MDMichael Deavers MDEric H. Bernicker MDMin P. Kim ,MDBin S. Teh MDJose F. Santacruz MDLisa Kopas MDReginald F. Munden MDPhilip T. Cagle MD
From the Departments of Pathology and Genomic Medicine (Drs Driver, Portier, Mody, Deavers, and Cagle); Medicine, Thoracic Medical Oncology (Dr Bernicker); Thoracic Surgery (Dr Kim); Radiation Oncology (Dr Teh); Interventional Pulmonology, Critical Care, and Pulmonary Medicine (Drs Santacruz and Kopas); Radiology (Dr Munden), Houston Methodist Hospital, Houston; and Weill Cornell Medical College, New York, New York.
Reprints: Brandon R. Driver, MD, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin St, Houston, TX 77030 (email: ).
The authors have no relevant financial interest in the products or companies described in this article.
Context.—The classification of pulmonary large cell carcinoma has undergone a major revision with the recent World Health Organization (WHO) 2015 Classification. Many large cell carcinomas are now reassigned to either adenocarcinoma with solid pattern or nonkeratinizing squamous cell carcinoma based on immunopositivity for adenocarcinoma markers or squamous cell carcinoma markers, respectively. Large cell carcinomas that are negative for adenocarcinoma and squamous cell carcinoma immunomarkers are now classified as large cell carcinoma with null immunohistochemical features (LCC-N). Although a few studies investigated the mutation profile of large cell carcinomas grouped by immunostain profile before the publication of the new WHO classification, investigation of tumors previously diagnosed as large cell carcinoma and reclassified according to the 2015 WHO classification has not, to our knowledge, been reported.
Objective.—To determine the mutation profiles of pulmonary large cell carcinomas reclassified by WHO 2015 criteria.
Design.—Archival cases of non–small cell lung carcinoma with large cell carcinoma morphology (n = 17) were reclassified according to 2015 WHO criteria. To determine mutation profile, we employed Ion Torrent (Life Technologies, Carlsbad, California)–based next-generation sequencing (50 genes; more than 2800 mutations) in addition to real-time quantitative reverse transcription polymerase chain reaction for ALK translocation detection.
Results.—Two of 17 cases (12%) were reclassified as LCC-N, and both had mutations—BRAF D594N in one case andKRAS G12C in the other case. Seven of 17 cases (41%) were reclassified in the adenocarcinoma with solid pattern group, which showed one KRAS G12C and one EGFR E709K + G719C double mutation in addition to mutations in TP53. Eight of 17 cases (47%) were reclassified in the nonkeratinizing squamous cell carcinoma group, which showed mutations inPIK3CACDKN2A, and TP53. No ALK translocations or amplifications were detected.
Conclusions.—The adenocarcinoma with solid pattern group showed mutations typical of adenocarcinoma, whereas the nonkeratinizing squamous cell carcinoma group showed mutations typical of squamous cell carcinoma. Both LCC-N cases had mutations associated with adenocarcinoma, supporting the hypothesis that LCC-N is related to adenocarcinoma.

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