A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.
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.
Mino-Kenudson
Mari
M
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
Chirieac
Lucian R
LR
Law
Kenny
K
Hornick
Jason L
JL
Lindeman
Neal
N
Mark
Eugene J
EJ
Cohen
David W
DW
Johnson
Bruce E
BE
Jänne
Pasi A
PA
Iafrate
A John
AJ
Rodig
Scott J
SJ
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
D000911:Antibodies, Monoclonal; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion