NASAL-T NATURAL-KILLER (NK)-CELL LYMPHOMAS ARE DERIVED FROM EPSTEIN-BARR VIRUS-INFECTED CYTOTOXIC LYMPHOCYTES OF BOTH NK-CELL AND T-CELL LINEAGE

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 f act, true NK-cell lymphomas. They are associated closely with Epstein- Barr virus (EBV), to the extent that EBV-encoded small non-polyadenyla ted RNAs (EBER) expression can be used as a marker for the neoplastic cells. The cell lineage of this group of lymphomas was examined furthe r by correlating immunophenotype, genotype and EBV status with the exp ression of cytotoxic granule-associated proteins, perforin and T-cell intracellular antigen-1 (TIA-1) in 13 cases of NL. Combined immunophen otypic and gene rearrangement analyses demonstrated that NLs can be id entified clearly as either NK-cell or T-cell tumours. Nasal NK-cell ly mphomas lacked clonal rearrangement of both T-cell receptor (TCR) gamm a 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 TCR gamma and germ-line IgH genes and we re either CD3(Leu4)(+)CD56(+) (2 cases) or CD3(Leu4)(+)CD56(-)(I case) . Immunohistochemical (IH) studies showed that both perforin and TIA-1 were expressed universally in NL, irrespective of NK-or T-cell lineag e, Dual labelling of TlA-1 by IH and EBER by in situ hybridisation dem onstrated that the granule proteins were expressed predominantly by th e EBER+ tumour cells. Our results indicate that NLs are derived from E BV-infected cytotoxic lymphocytes of both NK- and T-cell lineage. We p ostulate that cytotoxic lymphocytes generated during the cellular immu ne response to EBV infection or re-activation at the nasal region them selves may become targets for EBV infection and subsequent transformat ion. (C) 1997 Wiley-Liss, Inc.