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Most peripheral T-cell lymphomas (PTCL) express the alphabeta T-cell receptor (TCR) whereas rare PTCL express the gammadelta TCR. Most if not all gammadelta PTCL are extranodal lymphomas and among them, hepatosplenic gammadelta PTCL constitute a distinct clinicopathological entity. Besides alphabeta and gammadelta PTCL, there is a recently recognized group of extranodal, mainly nasal tumours, which display, in most instances, phenotypic and genotypic features of Natural-Killer cell non-Hodgkin's lymphomas (NK-NHL). Cytotoxic cells, including NK cells and cytotoxic alphabeta and gammadelta T lymphocytes may induce lysis of the target by using granule-associated cytotoxic proteins such as the T-cell intracellular antigen-1 (TIA-1), perforin and granzyme B. Expression of TIA-1 can be detected in all cytotoxic cells whereas granzyme B and perforin expression can be detected in high levels only in activated cytotoxic cells. Recently, several studies showed that the expression of these cytotoxic proteins in tumour cells of PTCL and NK-NHL is associated with a) extranodal site of clinicopathological presentation b) NK or Tgammadelta-cell phenotype c) CD30 expression in cutaneous T-cell lymphoproliferations and d) anaplastic morphology in nodal PTCL. This latter finding contrasts with the data that only rare Hodgkin lymphomas (HL) express cytotoxic proteins in Hodgkin and Reed-Sternberg cells. Altogether the data of the literature indicate that most extranodal T and NK-NHL are activated cytotoxic lymphomas with the notable exception of hepatosplenic gammadelta PTCL which represent tumours of non-activated cytotoxic cells. On this basis, it is suggested that the expression of cytotoxic proteins may be useful for the identification and classification of extranodal T and NK-cell lymphomas and, to some extent, for the differential diagnosis between HL and CD30+ anaplastic large cell lymphomas. Cytotoxic lymphomas are preferentially localized in extranodal sites such as skin, lung, upper respiratory and gastrointestinal tracts, which are continuously exposed to various antigens. Since cytotoxic T and NK cells are regarded as first line of defense in these sites, and some cytotoxic tumours such as nasal lymphomas and enteropathy-type intestinal lymphomas are associated with EBV and gliadin, respectively, it is likely that chronic antigen exposure may play a role in the pathogenesis of cytotoxic lymphomas occurring in mucosa and/or skin. Besides chronic antigenic stimulation, chronic immunosuppression may also have pathogenetic significance in cytotoxic lymphomas in view of their increased incidence in immunocompromised patients.

Lymphomas with T-cell phenotype represent a heterogeneous group of diseases differing in histopathology, tumour site, and cell origin. They include peripheral T-cell lymphomas (PTCLs) derived from alpha beta cells, but also some recently recognized entities such as gamma delta, hepatosplenic lymphomas and natural killer (NK) cell lymphomas. Only a few studies have investigated the possibility that at least some PTCLs could be derived from lymphocytes with cytotoxic potential. In order to investigate this possibility, 60 cases of PTCL, including 27 cases expressing the alpha beta T-cell receptor (TCR alpha beta), 15 TCR gamma delta cases and 18 cases expressing neither TCR (TCR silent), as well as 14 cases of NK-cell lymphomas, were studied by immunohistochemistry for the expression of TIA-1, perforin, and granzyme B proteins. Expression of TIA-1 is characteristic of cytotoxic cells regardless of their activation status, whereas expression of perforin and granzymes is highly increased in activated cytotoxic cells and correlates with the induction of cytolytic activity. All NK-cell lymphomas (11 sinonasal, three systemic cases) expressed TIA-1, perforin, and granzyme B in most tumour cells. All gamma delta PTCLs (15 cases) expressed TIA-1 protein in most tumour cells, with a different cytotoxic antigen profile in hepatosplenic gamma delta PTCL (TIA-1+, perforin-, granzyme B-) and in non-hepatosplenic gamma delta PTCLs (three nasal, one skin, one lung), the latter expressing the three cytotoxic proteins. Of the 45 cases of alpha beta and TCR silent PTCL, 15 (33 per cent) were considered to be derived from cytotoxic lymphocytes with expression of at least one cytotoxic protein (TIA-1, 15/45; perforin, 10/41; granzyme B, 14/38) in tumour cells. This cytotoxic protein expression appeared to be related to the site of localization, since 7/13 (54 per cent) extranodal and only 8/32 (25 per cent) nodal alpha beta and TCR silent PTCLs expressed TIA-1, and to histology, since this pattern was observed in a proportion of anaplastic (6/8, 75 per cent) and pleomorphic (8/17, 47 per cent) lymphomas, but not in AILD-type NHL (0/16). Taken together, our data suggest that NK-cell lymphomas and non-hepatosplenic gamma delta PTCLs represent tumours of activated cytotoxic NK cells and gamma delta T cells, respectively; that hepatosplenic gamma delta PTCLs represent tumours of non-activated cytotoxic gamma delta T cells; and that a small proportion of alpha beta and TCR silent PTCLs, mostly extranodal cases, or nodal anaplastic lymphomas, represent tumours of cytotoxic T cells.