Hepatosplenic γδ T-cell lymphoma: Ultrastructural, immunophenotypic, and functional evidence for cytotoxic T lymphocyte differentiation

Hepatosplenic γδ T cell lymphoma (TCL) is a rare, aggressive subset of peripheral TCL that presents with hepatosplenomegaly and cytopenias. Detailed clinicopathological, ultrastructural, and cytogenetic analyses of these lymphomas are limited; functional characteristics of these lymphomas are unknown. We have undertaken a clinicopathological, immunophenotypic, ultrastructural, cytogenetic, and functional analysts of three hepatosplenic γδ TCLs. All patients presented with massive hepatosplenomegaly and anemia, thrombocytopenia, or severe neutropenia; terminal blastlike transformation occurred in one patient. Combination chemotherapy had no response in two patients, but induced complete remission in one. γδ T cell receptor (TCR) expression and clonal TCRδ gene rearrangements were documented in each case. Two different subsets of γδ TCL were identified based on δ chain variable region usage; two lymphomas were Vδ1+, whereas the third was negative for both V 1/2 and Vδ2. Cytogenetic analysis was performed on two lymphomas; isochromosome 7q and probable trisomy 8 was shown in one of the Vδ1+ lymphomas, whereas the Vδ1 negative lymphoma had 14p+ with t(1;14)(q21;p13). NK cell-associated antigens (CD11c, CD16, or CD56) and cytotoxic T lymphocyte (CTL) effector proteins (perforin, granzyme B, TIA-1, and Fas ligand) were expressed by each lymphoma; dense core cytolytic granules were observed by electron microscopy in both lymphomas studied. Functional studies performed in two cases showed TCR-mediated cytolysis of P815 x 2 FcR+ cells induced by anti-CD3 in a redirected cytolysis assay in one of the CD56+, Vδ1+ lymphomas, whereas IFNγ secretion was induced by anti-CD3 in the CD56-, Vδ1 negative lymphoma. These studies show that hepatosplenic γδ TCLs have CTL differentiation, retain functional activity in vitro, and are derived from at least two δ T cell subsets.