Abstract
Patients with ALK gene rearrangements often manifest dramatic responses to crizotinib, an ALK inhibitor. Accurate identification of patients with ALK-positive non-small cell lung cancer (NSCLC) is essential for the clinical application of ALK-targeted therapy. However, assessing EML4-ALK rearrangement in NSCLC remains challenging in routine pathology practice. The aim of this study was to compare the diagnostic accuracy of FISH, immunohistochemistry (IHC), and real-time quantitative RT-PCR (QPCR) methodologies for detection of EML4-ALK rearrangement in NSCLC and to appraise immunohistochemistry as a pre-screening tool. In this study, a total of 473 paraffin-embedded NSCLC samples from surgical resections and biopsies were analyzed by IHC with ALK antibody. ALK rearrangement was further confirmed by FISH and QPCR. ALK protein expression was detected in twenty patients (20/473, 4.2%). Of the 20 ALK-positive cases by IHC, 15 cases were further confirmed as ALK rearrangement by FISH, and 5 cases were not interpretable. Also, we evaluated 13 out of the 20 IHC-positive tissues by QPCR in additional to FISH, and found that 9 cases were positive and 2 cases were equivocal, whereas 2 cases were negative although they were positive by both IHC and FISH. The ALK status was concordant in 5 out of 8 cases that were interpretable by three methods. Additionally, none of the 110 IHC-negative cases with adenocarcinoma histology showed ALK rearrangements by FISH. Histologically, almost all the ALK-rearranged cases were adenocarcinoma, except that one case was sarcomatoid carcinoma. A solid signet-ring cell pattern or mucinous cribriform pattern was presented at least focally in all ALK-positive tumors. In conclusion, our findings suggested that ALK rearrangement was associated with ALK protein expression. The conventional IHC assay is a valuable tool for the pre-screening of patients with ALK rearrangement in clinical practice and a combination of FISH and QPCR is required for further confirmation.
Highlights
Lung cancer remains the leading cause of cancer-related death worldwide [1,2], despite of improvements in detection methods and treatments
We examined anaplastic lymphoma kinase (ALK) gene rearrangement using immunohistochemistry in non-small cell lung cancer (NSCLC) clinical samples, and correlated the results with those obtained by fluorescence in situ hybridization (FISH) and quantitative reverse transcriptase-polymerase chain reaction (RT-polymerase chain reaction (PCR)) (QPCR)
No significant intratumoral staining heterogeneity was observed, signet-ring cells tended to exhibit weaker staining than the other cells, perhaps because cytoplasmic ALK protein was diminished by a large volume of mucus material
Summary
Lung cancer remains the leading cause of cancer-related death worldwide [1,2], despite of improvements in detection methods and treatments. Efforts are devoted to development of molecules against specific targets for specific tumor types. With continued improvement in our understanding of the molecular basis of lung cancer, a number of targeted therapies for NSCLC are being evaluated or developed. These therapies include angiogenesis inhibitors and signaling transduction inhibitors such as the epithelial growth factor receptor (EGFR)-targeted therapies [3]. The identification of the key oncogenes for lung cancer is a very important step toward the development of novel molecular-targeting agents
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