Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma

Abstract

Anaplastic large cell lymphoma (ALCL) can be classified genetically based on rearrangements (R) of the ALK , TP63 , and/or DUSP22 genes. ALK- R defines a specific entity, ALK-positive ALCL, while DUSP22- R and TP63- R define subgroups of ALK-negative ALCLs with distinct clinicopathologic features. ALK -R and TP63 -R produce oncogenic fusion proteins that can be detected by immunohistochemistry. ALK immunohistochemistry is an excellent surrogate for ALK- R and screening with p63 immunohistochemistry excludes TP63- R in two third of ALCLs. In contrast, DUSP22 -R does not produce a fusion protein and its identification requires fluorescence in situ hybridization. However, DUSP22- R ALCL has a characteristic phenotype including negativity for cytotoxic markers and phospho-STAT3 Y705 . Recently, we also identified overexpression of the LEF1 transcription factor in DUSP22- R ALCL. Here, we sought to validate this finding and examine models for predicting DUSP22- R using immunohistochemistry for LEF1 and TIA1 or phospho-STAT3 Y705 . We evaluated these 3 markers in our original discovery cohort (n=45) and in an independent validation cohort (n=46) of ALCLs. The correlation between DUSP22- R and LEF1 expression replicated strongly in the validation cohort ( P <0.0001). In addition, we identified and validated a strategy using LEF1 and TIA1 immunohistochemistry that predicted DUSP22- R with positive and negative predictive values of 100% after exclusion of indeterminate cases and would eliminate the need for fluorescence in situ hybridization in 65% of ALK-negative ALCLs. This approach had similar results in identifying DUSP22- R in the related condition, lymphomatoid papulosis. Together with previous data, these findings support a 4-marker immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic subtyping of ALCL.