title: Pulmonary large cell carcinoma lacking squamous differentiation is clinicopathologically indistinguishable from solid-subtype adenocarcinoma.
abstract: BACKGROUND
  Pulmonary large cell carcinoma (LCC) includes tumors not readily diagnosed as adenocarcinoma (ADC) or squamous cell carcinoma on morphologic grounds, without regard to immunophenotype, according to the World Health Organization (WHO). This ambiguous designation may cause confusion over selection of mutation testing and directed therapies. Several groups have proposed the use of immunohistochemistry (IHC) to recategorize LCC as ADC or squamous cell carcinoma; however, it remains unclear if strictly defined LCCs are a clinicopathologically distinct lung tumor subset.
  
  
  OBJECTIVE
  To compare the pathologic, molecular, and clinical features of 2 morphologically similar tumors: solid-subtype ADC and LCC.
  
  
  METHODS
  Tumors were included on the basis of solid growth pattern; tumors with squamous or neuroendocrine differentiation were excluded. Solid ADC (n = 42) and LCC (n = 57) were diagnosed by using WHO criteria (5 intracellular mucin droplets in ≥2 high-power fields for solid ADC) and tested for KRAS, EGFR, and ALK alterations.
  
  
  RESULTS
  Both solid ADC and LCC groups were dominated by tumors with "undifferentiated"-type morphology and both had a high frequency of thyroid transcription factor 1 expression. KRAS was mutated in 38% of solid ADCs versus 43% of LCCs (P = .62). One ALK-rearranged and 1 EGFR-mutated tumor were detected in the solid ADC and LCC groups, respectively. There were no significant differences in clinical features or outcomes; the prevalence of smoking in both groups was greater than 95%.
  
  
  CONCLUSIONS
  Other than a paucity of intracellular mucin, LCC lacking squamous or neuroendocrine differentiation is indistinguishable from solid-subtype ADC. We propose the reclassification of these tumors as mucin-poor solid adenocarcinomas.
authors.affiliation: Published as an Early Online Release June 5, 2013. From the Department of Pathology (Drs Hwang, Bruce, and Sholl, and Mr Szeto) and Center for Advanced Molecular Diagnostics (Mr Szeto and Drs Bruce and Sholl), Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts (Drs Hwang and Sholl); and the Department of Pathology, Banner MD Anderson Cancer Center, Gilbert, Arizona (Dr Perry).
authors.forename: David H
authors.initials: DH
authors.lastname: Hwang
authors.forename: David P
authors.initials: DP
authors.lastname: Szeto
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Perry
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Bruce
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018287:Carcinoma, Large Cell / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D003937:Diagnosis, Differential; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D014157:Transcription Factors; D014944:World Health Organization; D018631:ras Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D009077:Mucins; D011518:Proto-Oncogene Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins