Differential Expression of RORγt and T-bet in ALK-Negative Anaplastic Large Cell Lymphoma: Implications for Biological Heterogeneity and Differential Diagnosis.

ALK-negative anaplastic large cell lymphoma (ALK-negative ALCL) frequently expresses cytotoxic molecules, which may complicate its distinction from peripheral T-cell lymphoma NOS (PTCL-NOS), particularly in cytotoxic molecule-positive cases. Among these, nodal EBV-negative cytotoxic T-cell lymphoma (CTL) represents an important diagnostic consideration. We evaluated the clinicopathological features of ALK-negative ALCL in comparison with nodal EBV-negative CTL and ALK-positive ALCL, with a focus on the immunohistochemical expression of master transcription factors (RORγt, T-bet, and GATA3). RORγt expression was significantly more frequent in ALK-negative ALCL than in nodal EBV-negative CTL (11/21 [52%] vs. 2/25 [8%]; P=0.001), and was uniformly present in ALK-positive ALCL (10/10 [100%]; P=0.012 vs. ALK-negative ALCL). In contrast, T-bet expression was less frequent in ALK-negative ALCL (2/21 [10%]) than in nodal EBV-negative CTL (9/25 [36%]; P=0.045), and was absent in all ALK-positive ALCL cases. RORγt and T-bet expression were largely mutually exclusive across the cohort, with only one overlapping case. GATA3 expression was absent in all evaluable cases of nodal EBV-negative CTL and ALK-positive ALCL, and was detected in only 2 of 19 ALK-negative ALCL cases (11%). These findings suggest that ALK-negative ALCL shows a distinct transcription factor profile characterized by frequent RORγt expression and infrequent T-bet expression, in contrast to nodal EBV-negative CTL. Assessment of these markers may provide a useful adjunct in the differential diagnosis of cytotoxic T-cell lymphomas, particularly in diagnostically challenging cases.