French multicentric validation of ALK rearrangement diagnostic in 547 lung adenocarcinomas.
Anaplastic lymphoma kinase (ALK) gene rearrangements in lung adenocarcinoma result in kinase activity targetable by crizotinib. Although fluorescence in situ hybridisation (FISH) is the reference diagnostic technique, immunohistochemistry (IHC) could be useful for pre-screening. Diagnostic yields of ALK IHC, FISH and quantitative reverse transcriptase PCR performed in 14 French pathology/molecular genetics platforms were compared. 547 lung adenocarcinoma specimens were analysed using 5A4 and D5F3 antibodies, two break-apart FISH probes and TaqMan kits. Clinicopathological data were recorded. 140 tumours were ALK rearranged (FISH with ≥15% of rearranged cells) and 400 were ALK FISH negative (<15%). FISH was not interpretable for seven cases. ALK patients were young (p=0.003), mostly females (p=0.007) and light/nonsmokers (p<0.0001). 13 cases were IHC negative but FISH ≥15%, including six cases with FISH between 15% and 20%; eight were IHC positive with FISH between 10% and 14%. Sensitivity and specificity for 5A4 and D5F3 were 87% and 92%, and 89% and 76%, respectively. False-negative IHC, observed in 2.4% of cases, dropped to 1.3% for FISH >20%. Variants were undetected in 36% of ALK tumours. Discordances predominated with FISH ranging from 10% to 20% of rearranged cells and were centre dependent. IHC remains a reliable pre-screening method for ALK rearrangement detection.
Département d'Anatomie et de Cytologie Pathologiques, Pôle de Biologie et de Pathologie, CHU A. Michallon, and Université Joseph Fourier, INSERM U823, Institut Albert Bonniot, Grenoble, France SLantuejoul@chu-grenoble.fr.
Sylvie
S
Lantuejoul
Service d'Anatomie Pathologique, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.
Isabelle
I
Rouquette
Département de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, INSERM S1147, Paris, France.
Hélène
H
Blons
Service d'Anatomie et de Cytologie Pathologiques, Registre MESONAT, CHU Côte de Nacre, U1086 INSERM-UCBN "Cancers et Préventions", Caen, France.
Nolwenn
N
Le Stang
Laboratoire de Pathologie Clinique et Expérimentale et Biobanque, Hôpital Pasteur, Centre Hospitalo-Universitaire de Nice, Université de Nice Sophia Antipolis, Nice, France.
Marius
M
Ilie
Service d'Anatomie Pathologique, Service de Biologie des Tumeurs, CHU Haut-Levêque, Pessac, France.
Hugues
H
Begueret
Institut de Pathologie, Centre de Biologie Pathologie Génétique, CHRU de Lille, Lille, France.
Valerie
V
Grégoire
Laboratoire de Pathologie Clinique et Expérimentale et Biobanque, Hôpital Pasteur, Centre Hospitalo-Universitaire de Nice, Université de Nice Sophia Antipolis, Nice, France.
Paul
P
Hofman
Service d'Anatomie Pathologique, Service de Biologie des Tumeurs, CHU Haut-Levêque, Pessac, France.
Audrey
A
Gros
Laboratoire d'Anatomie Pathologique, Hôpital Nord, Marseille, France.
Stephane
S
Garcia
Service d'Anatomie et de Cytologie Pathologiques, Hôpital Central, Nancy, France.
Nathalie
N
Monhoven
Service d'Anatomie et Cytologie Pathologiques, Hôpital de la Croix Rousse, Lyon, France.
Mojgan
M
Devouassoux-Shisheboran
Service d'Anatomie et de Cytologie Pathologiques, Hôpitaux universitaire Paris centre, Paris, France.
Audrey
A
Mansuet-Lupo
Service d'Anatomie et de Cytologie Pathologiques, Hôpital Louis Pradel, Bron, France.
Françoise
F
Thivolet
Service d'Anatomie et de Cytologie Pathologiques, Hôpital Tenon, Paris, France.
Martine
M
Antoine
Service d'Anatomie et de Cytologie Pathologiques, Hôpital Central, Nancy, France.
Jean-Michel
JM
Vignaud
Service d'Anatomie Pathologique, Centre Jean Perrin, Clermont-Ferrand, France.
Frederique
F
Penault-Llorca
Service d'Anatomie et de Cytologie Pathologiques, Registre MESONAT, CHU Côte de Nacre, U1086 INSERM-UCBN "Cancers et Préventions", Caen, France.
Françoise
F
Galateau-Sallé
Département d'Anatomie et de Cytologie Pathologiques, Pôle de Biologie et de Pathologie, CHU A. Michallon, and Université Joseph Fourier, INSERM U823, Institut Albert Bonniot, Grenoble, France.
Anne
A
McLeer-Florin
D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D005188:False Negative Reactions; D005260:Female; D005602:France; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D055815:Young Adult
D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases