title: Multicenter ALK testing in non-small-cell lung cancer: results of a round robin test.
abstract: BACKGROUND
  The anaplastic lymphoma kinase (ALK) inhibitor crizotinib has recently received approval for the treatment of patients with locally advanced or metastatic ALK-positive non-small-cell lung cancer (NSCLC). As the therapeutic prescription postulates the detection of ALK rearrangements, reliable diagnostic approaches are of utmost importance. With this study, we present the data of the first German ALK-round robin test based on genomic DNA in situ hybridization (ISH). The application of immunohistochemistry (IHC) for ALK protein detection was optional and not required for certification.
  
  
  METHODS
  Two tissue microarrays, each consisting of the same 10 NSCLC but in different arrangement of the cases, were generated (five unequivocally ALK-positive and five unequivocally ALK-negative cases). ISH-based results and optional IHC data had to be submitted within 10 working days. A successful participation (certification) was reached if at least 19 of the 20 possible points were scored (2 points for a correct case classification).
  
  
  RESULTS
  Fifty-three of 59 participants (89.8%) provided their data for ISH-ALK detection within the submission period. Thirty-two of 53 participants (60.3%) received at least 19 points required for certification. Remarkably, the range of cells with aberrant ALK signal configuration was broad in ALK-negative (0-13%) and in ALK-positive cases (15-95%). Thirty-five participants supported the round robin test with optional ALK IHC results, which displayed a great heterogeneity in the ALK ISH-positive cases.
  
  
  CONCLUSIONS
  In essence, our ALK ISH round robin test clearly demonstrates that there is accumulating need for improvement of ALK testing. Although ISH may be regarded as a well-established procedure, its broad application in a diagnostic setting is challenging and requires standardized methods and harmonized interpretation to achieve sound results for therapeutic decisions. The same is true for ALK IHC which, however if standardized, might improve the diagnostic approach.
authors.affiliation: *Institute of Pathology, Humboldt University Berlin, Campus Charité Mitte, Charité Universitätsmedizin, Berlin, Germany; and †Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Laffert
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases