title: ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.
abstract: BACKGROUND
  ALK rearrangement is particularly observed in signet-ring sub-type adenocarcinoma. Since fluorescence in situ hybridization (FISH) is not suitable for mass screening, we aimed to characterize the predictive utility of tumour morphology and ALK immunoreactivity to identify ALK rearrangement, in a primary lung adenocarcinoma dataset enriched for signet-ring morphology, compared with that of other morphology.
  
  
  METHODS
  7 adenocarcinomas from diagnostic archives reported with signet-ring morphology were assessed and compared with 11 adenocarcinomas without signet-ring features over the same time period. Growth patterns were reviewed, ALK expression was assessed by standard immunohistochemistry using ALK1 clone and Envision detection (Dako), and ALK rearrangement was assessed by FISH (Abbott Molecular). Associations between groups and predictive utility of tumour morphology and ALK expression using FISH as gold standard were calculated.
  
  
  RESULTS
  2 excision lung biopsy cases with pure (100%) signet-ring morphology and solid patterns demonstrated diffuse moderate cytoplasmic ALK immunoreactivity (2+) and harboured ALK rearrangements (p=0.007), unlike 5 mixed-signet-ring and 11 non-signet-ring adenocarcinomas, which showed negative or 1+ immunoreactivity; and did not harbour ALK rearrangements (p>0.1). ALK expression was not associated with ALK copy number. 6 of 7 cases with signet ring morphology stained for TTF-1. Pure signet-ring morphology and moderate ALK expression were both associated with ALK rearranged tumours.
  
  
  CONCLUSIONS
  ALK rearrangement is strongly associated with ALK immunoreactivity, and was seen only in tumours with pure signet-ring morphology and solid growth pattern. Tumour morphology, growth pattern and ALK immunoreactivity appear to be good indicators of ALK rearrangement, with TTF-1 positivity aiding in proving primary pulmonary origin.
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK. sanjay.popat@rmh.nhs.uk
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Toon
authors.initials: T
authors.lastname: Min
authors.forename: John
authors.initials: J
authors.lastname: Swansbury
authors.forename: Melissa
authors.initials: M
authors.lastname: Dainton
authors.forename: James G
authors.initials: JG
authors.lastname: Croud
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Rice
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology* / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D001706:Biopsy; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology*; D014157:Transcription Factors; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases