Correlation of novel ALK^ATI 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, fluorescence in-situ hybridisation 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.