Anaplastic large cell lymphomas with equivocal DUSP22 FISH results: recommendations for clinical reporting and diagnostic evaluation

Anaplastic large cell lymphoma (ALCL), one of the most common T-cell lymphomas, shows unifying pathological features but is clinically and genetically heterogeneous. One genetic subgroup, characterized by recurrent DUSP22 rearrangements (R), has distinct morphologic, immunophenotypic, and molecular features and can be identified in routine pathology practice using a breakapart (BAP) fluorescence in situ hybridization (FISH) probe. However, some cases show equivocal BAP-FISH findings (BAP-FISH^EQ) and the features of these cases are poorly understood. Here, we sought to characterize DUSP22 BAP-FISH^EQ ALCLs further. First, we applied an immunohistochemistry (IHC) algorithm using TIA1, pSTAT3^Y705, and LEF1, which can predict DUSP22-R with high accuracy. Among 37 BAP-FISH^EQ ALCLs, 18 (49%) were IHC-algorithm positive (IHC^POS), 8 (21%) were IHC-algorithm negative (IHC^NEG), and 11 (30%) were IHC^EQ. In 32 BAP-FISH^EQ cases, we also applied a dual-color, dual-fusion (D-FISH) probe for t(6;7)(p25.3;q32.3), which accounts for 45% of DUSP22-R ALCLs. Among BAP-FISH^EQ cases, D-FISH was positive in 10/18 IHC^POS cases (56%), 0/9 IHC^EQ cases (0%), and 0/5 IHC^NEG cases (0%). Median survival in BAP-FISH^EQ ALCLs was 105 months, intermediate between BAP-FISH^POS ALCLs (median survival not reached) and BAP-FISH^NEG ALCLs (19 months). Thus, DUSP22 BAP-FISH^EQ ALCLs are clinicopathologically heterogeneous, likely due to an admixture of cases with an unbalanced DUSP22-R and cases with focal deletions without rearrangement. For clinical reporting, we recommend that DUSP22 BAP-FISH^EQ ALCLs be reported as equivocal, and not be grouped with BAP-FISH^POS ALCLs. Clinical adoption of an IHC algorithm, possibly supplemented by t(6; 7) D-FISH, could facilitate genetic subtyping in about two-thirds of BAP-FISH^EQ ALCLs.