☆ 4.1 Article

The Role of Immunohistochemical Analysis in the Evaluation of EML4-ALK Gene Rearrangement in Lung Cancer

APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY (2015)

Journal

APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY

Volume 23, Issue 4, Pages 239-244

Publisher

LIPPINCOTT WILLIAMS & WILKINS

DOI: 10.1097/PAI.0000000000000088

Keywords

EML4-ALK; lung; adenocarcinoma; immunohistochemistry; fluorescence in situ hybridization

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Abstract

Background: Among the mutations described in non-small cell lung carcinoma is a rearrangement resulting from an inversion within chromosome 2p leading to the formation of a fusion gene, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK). Fluorescence in situ hybridization (FISH) is the gold standard for the detection of ALK gene rearrangements. However, molecular methods are not readily available in all pathology laboratories. Immunohistochemistry (IHC) using an antibody directed against the EML4-ALK fusion protein provides a widely available alternative method of detection. We assessed whether IHC is a comparable and cost-effective alternative to FISH analysis for the detection of ALK gene rearrangements. Design: A total of 110 non-small cell lung carcinoma cases (63 surgical/biopsy and 47 cytology specimens), previously tested for ALK gene rearrangements by FISH [7 (6.4%) positive for the rearrangement], were probed for the EML4-ALK fusion protein using a monoclonal EML4-ALK antibody, clone 5A4. Cells were considered to stain positive for ALK if >5% of cells showed cytoplasmic staining of at least grade 1 intensity (scale: 0 to 3). A cost analysis was performed using ALK IHC as a screening test. Results: The sensitivity and specificity of the EML4-ALK IHC stain compared with ALK FISH analysis were 100% and 96%, respectively. All 7 FISH-positive cases stained positive by IHC, whereas 4 FISH-negative cases demonstrated positive staining. One of the 4 FISH-negative, IHC-positive cases harbored an EML4-ALK rearrangement by RT-PCR yielding 3 false-positive results overall. The kappa agreement between IHC and FISH methods is 0.76 (substantial/excellent). The potential savings of implementing the ALK IHC as a screening method would be $10,418.21. Conclusions: Sensitivity of the EML4-ALK IHC stain is excellent (100%) but due to its suboptimal specificity, IHC cannot reliably supplant FISH analysis for the detection of ALK gene rearrangements. IHC shows promise as a screening tool to prevent unnecessary costly FISH analysis.

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Case Report: ALK rearranged locally advanced lung adenocarcinoma showing inconsistent radiographic findings and pathological responses during neoadjuvant alectinib therapy

Peijun Cao, Qingchun Zhao, Yongwen Li, Ruifeng Shi, Guangsheng Zhu, Zihe Zhang, Hongbing Zhang, Minghui Liu, Sen Wei, Hongyu Liu, Jun Chen

Summary: In this study, a patient with locally advanced lung adenocarcinoma received neoadjuvant chemotherapy and alectinib treatment, and then underwent thoracoscopic left lower lung lobectomy. After chemotherapy, the lymph nodes enlarged again and the patient was switched to alectinib therapy, but no significant lesion changes were detected on imaging. However, the pathological findings indicated extensive necrosis in the tumor area with no residual tumor cells and massive chronic inflammatory cell infiltration, which was inconsistent with the imaging results. The possibility of intratumoral immune heterogeneity was discussed as a potential explanation for this paradoxical response.

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