Nasal T/natural killer (NK)-cell lymphomas are derived from Epstein-Barr virus–infected cytotoxic lymphocytes of both NK- and T-cell lineage

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Abstract
The cellular nature of nasal T/natural killer (NK)‐cell lymphomas (NLs) remains controversial. It is still debatable whether these represent T‐cell lymphomas with extensive loss of surface antigens or are, in fact, true NK‐cell lymphomas. They are associated closely with Epstein‐Barr virus (EBV), to the extent that EBV‐encoded small non‐polyadenylated RNAs (EBER) expression can be used as a marker for the neoplastic cells. The cell lineage of this group of lymphomas was examined further by correlating immunophenotype, genotype and EBV status with the expression of cytotoxic granule‐associated proteins, perforin and T‐cell intracellular antigen‐1 (TIA‐1) in 13 cases of NL. Combined immunophenotypic and gene rearrangement analyses demonstrated that NLs can be identified clearly as either NK‐cell or T‐cell tumours. Nasal NK‐cell lymphomas lacked clonal rearrangement of both T‐cell receptor (TCR) γ and immunogloulin heavy chain (IgH) genes and were either CD3(Leu4)−CD56+ (8 cases) or CD3(Leu4)+CD56+ (2 cases), whereas nasal T‐cell lymphomas had rearranged TCRγ and germ‐line IgH genes and were either CD3(Leu4)+CD56+ (2 cases) or CD3(Leu4)+CD56− (1 case). Immunohistochemical (IH) studies showed that both perforin and TIA‐1 were expressed universally in NL, irrespective of NK‐ or T‐cell lineage. Dual labelling of TIA‐1 by IH and EBER by in situ hybridisation demonstrated that the granule proteins were expressed predominantly by the EBER+ tumour cells. Our results indicate that NLs are derived from EBV‐infected cytotoxic lymphocytes of both NK‐ and T‐cell lineage. We postulate that cytotoxic lymphocytes generated during the cellular immune response to EBV infection or re‐activation at the nasal region themselves may become targets for EBV infection and subsequent transformation. Int. J. Cancer 73:332–338, 1997.