The low rate of ALK rearrangement positivity by FISH—as evidenced by the low correlations between the rates of neoplastic nuclei by FISH and PFS following initial ALK inhibitors in ALK-rearranged Sq-LC, and by IHC negativity (cases 2 and 4) suggest that tumor tissues from patients with ALK-rearranged Sq-LC may contain heterogeneous tumor components including the original Sq-LC without ALK rearrangement and an independent oncogene-addiction phenotype, which are attributable to EML4–ALK mutations. This evidence concerns the gene EML4 and laryngotracheoesophageal cleft.