title: ALK ambiguous-positive non-small cell lung cancers are tumors challenged by diagnostic and therapeutic issues.
abstract: Searching for ALK rearrangements using the approved fluorescent in situ hybridization (FISH) test and complementary immunohistochemistry (IHC) has become the rule to treat patients with advanced non‑small cell lung cancer (NSCLC) with anti‑ALK targeted therapy. The concordance between the two techniques is reported to be strong but imperfect. We report our experience with cases of ALK‑rearranged lung adenocarcinomas pointing out particularly ambiguous cases. FISH and IHC data on ALK but also c‑MET IHC as well as EGFR and KRAS mutation screening are considered, together with response to crizotinib treatment. We classified the 55 FISH ALK‑rearranged tumors into two groups according to the FISH and IHC results: a concordant FISH+IHC+ group (31 tumors) and an ambiguous group (24 tumors). These tumors were considered as 'ambiguous' ALK‑positive due to negative (21 tumors) or non‑contributive (3 tumors) IHC. In addition, the percentage of FISH-positive nuclei was between 15 and 20% in 17 tumors belonging to one or the other group (now called borderline tumors). We discuss the accuracy of the different tests with intent to determine whether ambiguous and borderline tumors are real positive ALK‑rearranged tumors. To conclude, ambiguous ALK‑positive lung cancers are challenging tumors with diagnosis and therapeutic issues that can justify parallel FISH, IHC and molecular screening strategy.
authors.affiliation: INSERM, U1078, F‑29200 Brest, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Uguen
authors.affiliation: Department of Pathology, Brest University Hospital, F‑29609 Brest, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Andrieu-Key
authors.affiliation: Department of Oncology, CHRU Brest, F‑29220 Brest, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Vergne
authors.affiliation: Department of Oncology, CHRU Brest, F‑29220 Brest, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Descourt
authors.affiliation: Department of Oncology, CHRU Brest, F‑29220 Brest, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Quéré
authors.affiliation: Department of Pathology, Brest University Hospital, F‑29609 Brest, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quintin-Roué
authors.affiliation: Department of Oncology, CHRU Brest, F‑29220 Brest, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Key
authors.affiliation: INSERM, U1078, F‑29200 Brest, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Guéguen
authors.affiliation: Department of Pathology, Brest University Hospital, F‑29609 Brest, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Talagas
authors.affiliation: INSERM, U1078, F‑29200 Brest, France.
authors.forename: Marc
authors.initials: M
authors.lastname: De Braekeleer
authors.affiliation: Department of Pathology, Brest University Hospital, F‑29609 Brest, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelles
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D000077547:Crizotinib; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)