Correlation of novel ALKATI with ALK immunohistochemistry and clinical outcomes in metastatic melanoma

Aims Recently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALK(ATI)), has been described in melanoma and is susceptible to targeted ALK-inhibitor therapy. Clinical outcomes of patients with ALK(ATI)mutated melanoma as well as correlation with immunohistochemical (IHC) methods have not yet been described. Methods and results Clinicopathological characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescencein-situhybridisation and RNA-based digital molecular analysis assays were performed on archival tissue from 173 stage III and 192 stage IV tumours. ALK(ATI)was identified in 12.7 and 4.8% stage III and IV tumours, respectively. Discrete presentations of the ALK(ATI)are seen: isolated ALK(ATI)(n = 20) and mixed ALK(ATI)(combined ALK(ATI)and ALK(WT);n = 7). Isolated ALK(WT)expression (n = 4) was seen with no ALK fusions. Stage III patients showed improved survival with ALK(ATI)expression compared to those with ALK(WT)or no expression [5-year survival 80, 95% confidence interval (CI) = 57-100% versus 43%, 95% CI = 34-55%,P = 0.013]. Clinicopathological characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (n = 12) has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALK(ATI). Conclusion Presence of ALK(ATI)is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALK(ATI)for targeted therapy.