ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients

Chromosomal rearrangements involving the anaplastic lymphoma kinase gene (ALK) at 2p23 result in fusion with various partner genes leading to aberrant production of oncogenic protein products in multiple tumor types. Recently, the ALK protein inhibitor crizotinib was shown to be an effective therapy in patients with ALK-rearranged non-small cell lung cancer. The goal of this study was to determine the frequency of ALK alterations in adult renal cell carcinoma (RCC) and define associated clinicopathologic features and outcome. RCCs from a cohort of 534 consecutive surgically treated adult patients were analyzed for alterations of ALK by fluorescence in situ hybridization. ALK rearrangements were identified in 2 of 534 (<1%) RCCs. Both showed similar histologic features and the patients had a poor outcome. ALK copy number gain was identified in 54 (10%) RCCs. In clear cell type RCC (CCRCC), ALK copy number gain was significantly associated with tumor size (P=0.02) and nuclear grade (P<0.001), and with a worse 10-year cancer-specific survival vs similar patients lacking ALK copy number gain (P=0.03). ALK rearrangement is rare in adult RCC but may be associated with distinct histological features and poor outcome. Another potential mechanism to elevate ALK expression, increased ALK gene copy number, was observed in 10% of adult CCRCC, where it is associated with a higher tumor grade and poorer outcome. Additional studies are necessary to determine whether patients RCCs with ALK rearrangement and/or those with an increase in ALK copy number would benefit from ALK inhibitor treatment. Modern Pathology (2012) 25, 1516-1525; doi: 10.1038/modpathol.2012.107; published online 29 June 2012