EVALUATION OF ALK IMMUNOHISTOCHEMISTRY AS AN ALTERNATIVE TO FISH FOR DETECTING ALK REARRANGEMENTS IN NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Background: ALK rearrangements define a therapeutically actionable subtype of non-small cell lung cancer (NSCLC). Immunohistochemistry (IHC) detects ALK protein expression, whereas fluorescence in situ hybridization (FISH) detects rearrangements at the genomic locus. Their diagnostic equivalence is influenced by assay validation and clinically relevant discordance. Objective: To assess ALK IHC performance relative to FISH and evaluate its suitability as a primary or alternative diagnostic strategy in NSCLC. Methods: Database searches identified 976 records. After removal of 214 duplicates and 12 additional records, 750 records were screened; 55 full-text reports were assessed for eligibility and six independent primary studies contributed 3,326 paired IHC–FISH specimens. Sensitivity and specificity were synthesized separately using inverse-variance random-effects models of logit proportions with a Paule–Mandel variance estimator. Study-level accuracy, heterogeneity, leave-one-study-out estimates and methodological quality were assessed. Results: Among 3,326 paired specimens, 261 were IHC-positive/FISH-positive, 25 were IHC-positive/FISH-negative, 40 were IHC-negative/FISH-positive and 3,000 were negative on both assays. Pooled sensitivity was 86.2% (95% CI 81.7–89.7%) and pooled specificity was 98.3% (95% CI 95.0–99.4%). The crude aggregate agreement was 98.0%; specificity varied substantially between studies (I²=84.3%). Independent molecular investigations showed that some IHC-positive/FISH-negative cancers harbor clinically actionable ALK fusions. Conclusion: Validated ALK IHC is a practical alternative to routine FISH for many NSCLC specimens, but a negative or equivocal IHC result should not be regarded as infallible. Orthogonal molecular testing remains valuable when staining is weak, technical quality is uncertain or clinicopathological and molecular findings disagree.