title: Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 and KRAS 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 in PIK3CA, CDKN2A, 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.
authors.forename: Brandon R
authors.initials: BR
authors.lastname: Driver
authors.forename: Bryce P
authors.initials: BP
authors.lastname: Portier
authors.forename: Dina R
authors.initials: DR
authors.lastname: Mody
authors.forename: Michael
authors.initials: M
authors.lastname: Deavers
authors.forename: Eric H
authors.initials: EH
authors.lastname: Bernicker
authors.forename: Min P
authors.initials: MP
authors.lastname: Kim
authors.forename: Bin S
authors.initials: BS
authors.lastname: Teh
authors.forename: Jose F
authors.initials: JF
authors.lastname: Santacruz
authors.forename: Lisa
authors.initials: L
authors.lastname: Kopas
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Munden
authors.affiliation: 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.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Cagle
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000235:genetics / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018287:Carcinoma, Large Cell / Q000145:classification* / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000145:classification* / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010865:Pilot Projects; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014944:World Health Organization
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human