title: A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.
abstract: OBJECTIVE
  Approximately 5% of lung adenocarcinomas harbor an EML4-ALK gene fusion and define a unique tumor group that may be responsive to targeted therapy. However ALK-rearranged lung adenocarcinomas are difficult to detect by either standard fluorescence in situ hybridization or immunohistochemistry (IHC) assays. In the present study, we used novel antibodies to compare ALK protein expression in genetically defined lung cancers and anaplastic large cell lymphomas.
  
  
  METHODS
  We analyzed 174 tumors with one standard and two novel monoclonal antibodies recognizing the ALK protein. Immunostained tissue sections were assessed for the level of tumor-specific ALK expression by objective quantitative image analysis and independently by three pathologists.
  
  
  RESULTS
  ALK protein is invariably and exclusively expressed in ALK-rearranged lung adenocarcinomas but at much lower levels than in the prototypic ALK-rearranged tumor, anaplastic large cell lymphoma, and as a result, is often not detected by conventional IHC. We further validate a novel IHC that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK-rearranged lung adenocarcinomas in biopsy specimens, with excellent interobserver agreement between pathologists (kappa statistic, 0.94).
  
  
  CONCLUSIONS
  Low levels of ALK protein expression is a characteristic feature of ALK-rearranged lung adenocarcinomas. However, a novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Kenny
authors.initials: K
authors.lastname: Law
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Mark
authors.forename: David W
authors.initials: DW
authors.lastname: Cohen
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000911:Antibodies, Monoclonal; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D015588:Observer Variation; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
chemical_list: D000911:Antibodies, Monoclonal; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion