Monoclonal antibody HML-1 reactivity with adult T-cell leukaemia/lymphoma and other lymphomas

Human T-cell leukaemia/lymphoma virus type 1 (HTLV-1), a causative virus of adult T-cell leukaemia/lymphoma (ATLL), is known to be transmitted by breast-feeding. Using a monoclonal antibody HML-1 which labels human intestinal intra-epithelial T lymphocytes, we have immunohistochemically examined ATLL tissues in order to evaluate the possibility that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Previously this antibody was reported to react with intestinal T-cell malignant lymphomas but not with peripheral tumours, or any B-cell lymphomas. We investigated 181 patients with malignant lymphomas and found that 19 out of 113 ATLLs were positive for HML-1. T-cell malignant lymphomas excluding ATLL also reacted with HML-1 (7/24), but all the B-cell lymphomas 0/33) and non-neoplastic lymph node and skin lesions (0/10) were negative for HML-1. In patients with ATLL and other T-cell malignant lymphomas, the positivity level of HML-1 was relatively higher in stomach (3/7) and tonsil (2/6) than that in lymph nodes (15/100) and skin (8/47). We observed one HML-1 positive ATLL patient with tumour formation in the skin and lymphadenopathy and marked infiltration of the large intestine but minimal involvement of other organs. Although HML-1 was frequently expressed in gastric infiltration of ATLL, the level of positivity was too low in lymph nodes to support the hypothesis that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Some of the HML-1 positive ATLL cases co-expressed CD30. Furthermore, three of six cases of Ki-1 lymphoma (large anaplastic cell lymphoma) were positive for HML-1. We conclude that expression of HML-1 in ATLL reflects an activated state of the lymphoma cells, but not the intestinal origin of ATLL cells.     

Monoclonal antibody HML-1, a marker for intraepithelial T cells and lymphomas derived thereof, also recognizes hairy cell leukemia and some B-cell lymphomas

Current views regard monoclonal antibody HML-1 as an exquisite marker for intraepithelial T cells and primary intestinal and cutaneous T-cell lymphomas. We show that HML-1 reacted with 11 of 12 cases of hairy cell leukemia, with 1 of 13 cases of primary gastrointestinal B-cell lymphoma, and with an unclassified large-cell B lymphoma of the thoracic wall. We conclude that HML-1 is not restricted to the T-cell lineage and that the HML-1 antigen is expressed in a small subset of both T- and B-cell neoplasms.     

TIA-1 expression in lymphoid neoplasms. Identification of subsets with cytotoxic T lymphocyte or natural killer cell differentiation.

TIA-I is a 15-kd cytotoxic granule-associated protein expressed in natural killer (NK) cells and cytotoxic T lymphocytes. TIA-1 expression was evaluated by paraffin immunohistochemistry in 115 T- or NK-cell neoplasms, 45 B-cell neoplasms, and 45 Hodgkin''s lymphomas. TIA-1-positive granules were identified within the cytoplasm of neoplastic cells in 6/6 large granular lymphocytic leukemias, 11/11 hepatosplenic T-cell lymphomas, 15/15 intestinal T-cell lymphomas, 6/6 NK-like T-cell lymphomas of no special type, 2/2 NK-cell lymphomas, 8/9 nasal T/NK-cell lymphomas, 7/8 subcutaneous T-cell lymphomas, 4/5 pulmonary T- or NK-cell angiocentric lymphomas (lymphomatoid granulomatosis), 12/19 T-cell anaplastic large-cell lymphomas, 2/12 nodal peripheral T-cell lymphomas, 1/3 CD8+ cutaneous T-cell lymphomas, and 5/38 classical Hodgkin''s disease. All B-cell neoplasms, nodular lymphocyte-predominant Hodgkin''s disease (7 cases), CD4+ cutaneous T-cell lymphomas (6 cases), adult T-cell leukemia/lymphomas (3 cases), T-cell chronic or prolymphocytic leukemias (3 cases), and T-cell lymphoblastic leukemia/lymphomas (7-cases) were TIA-1 negative. These findings indicate that most large granular lymphocytic leukemias, hepatosplenic T-cell lymphomas, intestinal T-cell lymphomas, NK-like T-cell lymphomas, NK-cell lymphomas, nasal T/NK-cell lymphomas, subcutaneous T-cell lymphomas, pulmonary angiocentric lymphomas of T or NK phenotype, and anaplastic large-cell lymphomas are cytotoxic T-or NK-cell neoplasms.     

High frequency of Epstein–Barr virus in Chinese peripheral T-cell lymphoma

Forty-two cases of Chinese T-cell lymphoma were studied for expression of Epstein–Barr virus (EBV) encoded RNA (EBER-1) and EBV latent membrane protein-1 (LMP-1) using in situ hybridization and immunohistochemistry, respectively. EBV was detected in tumour cells in 24/39 peripheral T-cell lymphomas (62%), comprising 18/27 pleomorphic, medium and large cell lymphomas (67%), 4/6 angioimmunoblastic lymphadenopathy-like lymphomas (67%), 2/2 Lennert's lymphomas, 0/2 anaplastic large cell lymphomas, and 0/2 T-zone lymphomas. EBV was not found in three T-lymphoblastic lymphomas. EBV was associated with 12/24 nodal (50%) compared with 12/15 extranodal (80%) peripheral T-cell lymphomas. In EBV positive nodal lymphomas, 9/12 cases (75%) contained less than 10% EBER positive tumour cells. In EBV positive extranodal lymphomas, 9/11 cases (82%) showed EBV gene expression in more than 50% of the tumour cells, and in five of these almost all tumour cells were positive. Lymphomas of the nasopharynx (mainly midline granuloma-type) showed EBER-1 expression in nearly all tumour cells. LMP-1 was detected in 19/23 EBER positive peripheral T-cell lymphomas (83%). Our results show that EBV is strongly associated with peripheral T-cell lymphomas in Chinese. An important role for the virus is suggested in lymphomas of the nasopharynx. The significance of EBV in T-cell lymphomas that contain only a minor population of virally infected tumour cells is currently unclear.     

Expression of the Human Mucosal Lymphocyte Antigen, HML-1, by T Cells Activated with Mitogen or Specific Antigen In Vitro

Expression of the human mucosal lymphocyte antigen, HML-1 (CD103), recently identified as a novel ä^Eβ₇ integrin, was studied on peripheral blood lymphocytes activated with mitogen or specific antigen. HML-1 was up-regulated on PHA activated T-lymphoblasts cultured in 100IU/ml interleukin-2 (IL-2), reaching a peak of >50% positive cells at day 7, and expression was maintained at this level throughout the 28-day culture period. Following a transient decrease in the percentage of L-selectin cells, expression of this molecule was maintained on most PHA T-lymphoblasts. Cells activated by purified protein derivative of M. tuberculosis (PPD) or in mixed lymphocyte culture also up-regulated and maintained HML-1 expression for 14 days. In contrast, in all cases the percentage of CD25⁺ cells rose initially but subsequently declined over the same time periods. When freshly isolated cells from tonsil, spleen, mesenteric lymph node and lung were analysed, only lung contained significant numbers (39 × 6%) of HML-1⁺ cells. In both freshly isolated and activated cell populations the great majority of HML-1⁺ cells co-expressed CD8 although some HML-1⁺CD8^? cells were also present. Production of TGF-β₁ peaked early during T-lymphoblast and MLR cultures and was not related to induction of HML-1 expression. Immunoprecipitation studies showed that the HML-1 molecule expressed on 10-day PHA T-lymphoblasts was indistinguishable from that found on intestinal intraepithelial lymphocytes and that no α⁴β₇ integrin was expressed by these cells. Although HML-1 expression is essentially restricted to mucosal leucocytes in vivo, these experiments show that it is readily induced and maintained along with co-expression of L-selectin following CD8⁺ T-lymphocyte activation in vitro.     

T-cell receptor expression in the T-cell malignancies.

Twenty-eight cases with T-cell neoplasms (10 with T-cell acute lymphoblastic leukemia [T-ALL], 10 with T-lymphoblastic lymphoma, and 8 with peripheral T-cell lymphomas) and 2 cases with reactive lymph nodes were immunohistochemically stained with monoclonal antibodies beta F1, delta TCS1, and WT31; beta F1 antibody recognizes the beta-subunit of T-cell receptor (TCR), whereas delta TCS1 and WT31 recognize the delta- and alpha beta-subunits of TCR, respectively. Five cases with T-ALL, four with T-lymphoblastic lymphoma (T-LL), and seven with peripheral T-cell lymphomas were positive for beta F1. None showed positive reactivity for delta TCS1. One case with T-LL and four cases with peripheral T-cell lymphomas were positive for WT31. Of the nine cases positive for beta F1 among T-ALLs and T-LLs, six were also positive for CD1 (OKT6), whereas six of seven positive cases for CD1 were positive for beta F1. The authors therefore suggest that TCR beta is expressed in the immature T-cells just earlier than or around the same stage of differentiation as those expressing CD1. The authors' immuno-electron microscopy study revealed that positive reactivity for beta F1 was localized predominantly in the cytoplasm of the neoplastic cells in the cases with T-ALL, T-LL and peripheral T-cell lymphomas, and in the cytoplasm of the reactive T-cells. However, it was not localized on the surface membrane. In contrast, positive reactivity for WT31 was localized on the surface membrane of the neoplastic and reactive T-cells. Only half of the cases of peripheral T-cell lymphomas showed positive reactivity for WT31. The authors consider that it may not be a very useful antibody for the detection of TCR alpha beta on the T-cell neoplasms using frozen tissue sections.     

Reactivity of T cells in mycosis fungoides exhibiting marked epidermotropism with the monoclonal antibody HML-1 that defines a membrane molecule on human mucosal lymphocytes.

Twenty-eight cases of cutaneous T cell lymphomas of mycosis fungoides type, 8 of which showed a marked epidermotropism, were investigated for their reactivity with the monoclonal antibody HML-1. This reagent selectively recognizes human benign and malignant intestinal T lymphocytes, but not benign or malignant lymph node T cells. In all cases, the majority of nonepithelium-associated T cells present in the corium were HML-1 negative. In the eight cases with marked epidermotropism, the intraepidermal (IED) T cells were HML-1 positive in three cases, and HML-1 negative in the remaining five cases. The HML-1 positive IED T cells tended to be localized preferentially in the basal layers, whereas the HML-1 negative IED T cells were more diffusely distributed throughout all epidermal cell layers or formed intra-epidermal aggregates. These findings provide further evidence that mycosis fungoides is not a single entity, but represents a group of neoplasms originating from different T cell subsets that have in common their tropism to epidermis and/or dermis, and thus have a similar clinical presentation.     

Expression of monoclonal antibody HML-1-defined alpha E beta 7 integrin in cutaneous T cell lymphoma.

Considering that integrins may play a major role in the localization in distinct biological features as well as in the dissemination of several types of lymphomas, we studied the expression of the monoclonal antibody HML-1-defined alpha E beta 7 integrin (CD103) in the clinically and histologically determined stages of 53 mycosis fungoides (MF) skin biopsies and in 16 affected lymph nodes. Immunoperoxidase staining revealed HML-1 immunoreactivity with T cells in the early stages of disease (patch and plaque stage MF). HML-1 expression was more pronounced on infiltrating epidermal than on dermal T cells. In contrast to early stages, tumor stage MF and lymph nodes affected in the course of cutaneous T cell lymphoma were HML-1 negative. We found a strong association between HML-1 expression, epidermotropism of infiltrating T cells, and the stage of disease. We provide evidence that: 1) the loss of the HML-1 antigen on T cells in MF is a marker of poor prognosis and 2) because the HML-1 antigen is selectively expressed on T lymphocytes of epithelial sites such as gut and skin, our results are compatible with the view that alpha E beta 7 integrins perform homing receptor functions for epitheliotropic T cells.     

Nodal T/NK-cell lymphoma of nasal type: a clinicopathological study of six cases

Aims:  To investigate the clinicopathological features of six unusual cases of nodal CD56+ and Epstein–Barr virus (EBV)+ T/natural killer (NK)-cell lymphoma, a putative nodal counterpart of nasal NK/T-cell lymphoma (nodal T/NK-cell lymphoma of nasal type) in comparison with nasal NK/T-cell lymphoma with secondary lymph node involvement ( n  = 24) and peripheral T-cell lymphoma (PTCL) of cytotoxic molecule (CTM)+ and EBV+ type ( n  = 21).
Methods and results:  All cases of nodal T/NK-cell lymphoma of nasal type exhibited diffuse infiltration of pleomorphic medium-sized to large tumour cells, reminiscent of those in CTM+ EBV+ PTCL. The tumour cells had a typical phenotype of nasal NK/T-cell lymphoma: CD2+, CD3ε+, CD4−, CD5−, CD56+, T-cell intracellular antigen-1+, granzyme B+, perforin+ and EBV+. However, four of six cases demonstrated clonal T-cell receptor γ-gene rearrangement on polymerase chain reaction analysis, unlike nasal NK/T-cell lymphoma. Comparison of clinical parameters and overall survival among the three groups demonstrated only minor differences.
Conclusions:  Nodal T/NK-cell lymphoma may occupy the grey zone between extranodal nasal-type NK/T-cell lymphoma and nodal CTM+ PTCL in a spectrum of NK to T-cell lymphomas that are EBV+. The close relationship between NK/T-cell lymphomas and cytotoxic T-cell lymphomas was also substantiated.     

Discordant expression of CD3 and T-cell receptor beta-chain antigens in T-lineage lymphomas.

Using an immunoperoxidase technique that identifies both surface and cytoplasmic antigen expression, the authors examined 28 benign reactive lymphorproliferative lesions and 55 T-lineage lymphomas for reactivity with CD3 (Leu-4; T-cell receptor-associated antigen) and beta F1 antibodies, the latter recognizing nonpolymorphic determinants on T-cell receptor beta chains. Consistent with previous observations that these two antigens are co-expressed on the vast majority of thymocytes, peripheral blood T cells and tonsillar T cells, all 28 reactive lymphoproliferations showed essentially identical patterns of CD3 and beta F1 expression. In contrast, only 29 of 55 T-lineage lymphomas displayed coexpression of these antigens. Among 33 peripheral T-cell lymphomas, 11 cases showed CD3/beta F1 discordance (7 CD3+/beta F1-; 4 CD3-/beta F1+), and 5 showed absence of both these antigens. Nine of 22 T-lymphoblastic lymphomas showed CD3/beta F1 discordance (all CD3+/beta F1-), and 1 case was CD3-/beta F1-. These patterns of CD3/beta F1 expression, along with the patterns of CD2, CD4, CD5, CD7, and CD8 antigen expression in these neoplasms, indicate that T-cell lymphomas can manifest phenotypes not apparently reflective of normal T populations and suggest the presence of abnormal gene expression in these malignancies. The existence of aberrant phenotypes in T-cell neoplasia suggests caution in interpretation of investigations using T-lineage malignancies as models of normal T-cell biology. Finally, the identification of phenotypic abnormalities in T-lineage populations can be of great diagnostic usefulness in the delineation of benign versus malignant T-cell proliferations.     

Enhancement of CD3-induced activation of human intestinal intraepithelial lymphocytes by stimulation of the beta 7-containing integrin defined by HML-1 monoclonal antibody.

Intraepithelial lymphocytes (IEL) form a large population of T cells in close contact with the intestinal lumen and differ from lymphocytes in other lymphoid compartments by their predominant CD8+ phenotype and the strong expression of the recently characterized beta 7-containing integrin defined by the monoclonal antibody (mAb) HML-1. The aim of the present in vitro study was to investigate the possible role of the integrin defined by HML-1 in the activation of human IEL via the CD3-T cell receptor (TcR) pathway. The proliferative response of IEL to optimal concentrations of immobilized OKT3 was found to be similar to that of peripheral blood lymphocytes enriched in CD8+ cells. When co-immobilized with suboptimal concentrations of OKT3, antibodies directed against CD11a, CD29 and the beta 7-containing integrin defined by HML-1 exerted a strong synergistic effect on the proliferative response and on the expression of CD25 and CD71 antigens by human IEL. These data indicate that the CD3-TcR pathway is functional in human IEL and contrast with previous observations suggesting that the CD3-TcR pathway was difficult to elicit in human IEL. Furthermore, the present data show that the immune response of human IEL can be modulated via interactions between integrins expressed by IEL and their respective ligands in the mucosa and suggest that IEL's activation may depend on the level of expression of integrin ligands in the epithelium, particularly of the expression of the as yet unknown ligand for the IEL-specific integrin defined by HML-1.     

Leu-4 (CD3) antigen expression in the neoplastic cells from T-ALL and T-lymphoblastic lymphoma

The authors studied Leu-4 (CD3) antigen localization in the neoplastic cells from six cases with T-ALL, eight with T-lymphoblastic lymphoma (T-LL), and eight with peripheral T-cell lymphomas using immunoelectron microscopy (immuno-EM). Other various monoclonal antibody studies were also performed to detect the stages of differentiation of the neoplastic cells light microscopically. The authors' study indicated that cytoplasmic Leu-4 (cLeu-4) antigen expression appeared at the early stage of thymic T-cells, together with Leu-9 (CD7) and T101 (CD5). Their immuno-EM study also disclosed that the neoplastic cells at the early stage of thymocyte differentiation all had positive results for cLeu-4 but negative results for surface Leu-4 (sLeu-4). The Leu-4 antigen expression in the neoplastic cells at the stage of common thymocyte differentiation with OKT6- (CD1) positive phenotype was variable, showing cLeu-4+sLeu-4-, cLeu-4-sLeu-4+, and cLeu-4+sLeu-4+, depending on the cases investigated. From these results, they suggest that cLeu-4 antigen appears at the stage of early thymocyte differentiation, followed by predominant sLeu-4 expression at the stage of common thymocyte differentiation, and finally simultaneous expression of cLeu-4 and sLeu-4 at the stage of peripheral T-cells.     

A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes

A monoclonal antibody, HML-1, was produced by fusion of NSI myeloma cells with spleen cells of a mouse immunized with isolated human intestinal intraepithelial lymphocytes (IEL). Immunofluorescence studies of isolated cells, as well as immunoperoxidase staining of tissue sections, indicated that HML-1 labeled all the various subsets of human intestinal IEL, approximately 40% of lamina propria T cells, 30% mesenteric lymphoblasts and some lymphocytes in other mucosae, particularly IEL. Conversely, it revealed only rare cells in all other lymphoid compartments. Analysis by polyacrylamide gel gradient electrophoresis showed that HML-1 precipitated two major noncovalently bound components of approximate mol. masses of 105 and 150 kDa from human IEL. HML-1 thus defines a novel human membrane antigen present on a subpopulation of lymphocytes preferentially associated with epithelia, and particularly with the intestinal epithelium. The characteristics of this human antigen are very similar to those of an antigen we had previously described in the rat. The possible functional role of this novel class of lymphocyte membrane antigens as well as the nature of the mechanism that triggers their expression remain to be elucidated.     

Enteropathy-associated T cell lymphoma (malignant histiocytosis of the intestine) is recognized by a monoclonal antibody (HML-1) that defines a membrane molecule on human mucosal lymphocytes.

Enteropathy-associated T cell lymphoma (EATCL; malignant histiocytosis of the intestine) arises in patients with enteropathy, which in some cases is known to be a result of gluten sensitivity. The lymphoma arises in the intestine, where it may remain localized, although eventual dissemination is the rule. Intraepithelial tumour cells often are seen at the mucosal tumor margin. These features suggest that EATCL may be a tumor of intraepithelial lymphocytes. A monoclonal antibody (HML-1) has been produced recently that recognizes the entire intraepithelial lymphocyte population and 50% of lamina propria T cells but very few cells outside the mucosa. Immunocytochemistry has shown that all cases of enteropathy-associated T cell lymphoma studied are HML-1 positive and all peripheral T cell lymphomas and mucosal B cell lymphomas are HML-1 negative. This suggests strongly that EATCL is a tumor of mucosal T cells, possibly the intraepithelial T cell component.     

Acid alpha-naphthyl acetate esterase activity in human neoplastic lymphoid cells. Usefulness as a T-cell marker.

Previous studies have shown that a distinctive pattern of acid alpha-naphthyl acetate esterase (ANAE) activity (focal reaction product) characterizes normal human peripheral blood and tissue T lymphocytes but is absent from thymocytes and certain mitogen-stimulated T-cell blasts. In the present study mononuclear cell suspensions prepared from the peripheral blood and tissue specimens of 35 patients with lymphoid malignancies were simultaneously analyzed for surface immunoglobulin, sheep erythrocyte rosette formation, Ia antigens, and ANAE activity. The neoplastic cells from 16 patients with Ia+ SIg+ E- (B cell) malignancies, 4 patients with Ia+ SIg- E- (non-B, non-T) acute lymphoblastic leukemia, and 3 patients with Ia- SIg- E- (null cell) malignancies failed to exhibit ANAE activity. The neoplastic cells from 5 patients with Ia- SIg- E+ (T cell-derived) malignancies, including three cutaneous lymphomas, displayed characteristic T-pattern positivity, and in each case the percentage of E+ and ANAE+ cells was comparable. The neoplastic cells from 4 patients with Ia- SIg- E+ (T cell-derived) acute lymphoblastic leukemia were ANAE-. The expression of ANAE activity in T cell-derived malignancies may parallel its expression in the stages of normal T-cell differentiation and may prove to be a useful marker with which to sort out T-cell phenotypes.     

Expression of the diffuse B-cell lymphoma family molecule SWAP-70 in human B-cell neoplasms: immunohistochemical study of 86 cases.

SWAP-70 is a recently discovered member of the Dbl (diffuse B-cell lymphoma) family of signal transduction molecules that is abundantly expressed in B cells. SWAP-70 mediates lipid second-messenger signals to the cytoskeletal-organizing GTPase Rac, functioning as a guanine-nucleotide exchange factor. SWAP-70 is strongly expressed in germinal center B cells, with low-level expression in resting B-cells. Expression of SWAP-70 in neoplastic B cells has not been described. We report the immunohistochemical expression of SWAP-70 in 86 B-cell neoplasms. SWAP-70 was strongly expressed in 59 of the 86 cases: 2 of 10 (20%) precursor B-cell lymphoblastic leukemias, 2 of 2 (100%) precursor B-cell lymphoblastic lymphomas, 2 of 4 (50%) mantle cell lymphomas, 7 of 9 (78%) Burkitt lymphomas, 9 of 9 (100%) diffuse large B-cell lymphomas, 8 of 8 (100%) follicular lymphomas, 6 of 6 (100%) nodular lymphocyte predominant Hodgkin lymphomas, 0 of 8 (0%) classic Hodgkin lymphomas, 12 of 13 (92%) chronic lymphocytic leukemias, 3 of 3 (100%) nodal marginal zone lymphomas, 5 of 5 (100%) extranodal marginal zone lymphomas, 1 of 2 (50%) splenic marginal zone lymphomas, 2 of 3 (66%) hairy cell leukemias, and 0 of 4 (0%) plasma cell neoplasms. All 4 T-cell lymphomas were nonreactive for SWAP-70: 0 of 3 peripheral T-cell lymphomas and 0 of 1 anaplastic large cell lymphoma. These results suggest that a spectrum of neoplastic B cells maintains activation of this signal transduction pathway. This is the first report of the expression of a Dbl family molecule in human lymphoma and leukemia tissues.     

Expression of cytotoxic molecules in intestinal T-cell lymphomas

Intestinal T-cell lymphoma (ITCL) represents a subgroup of peripheral T-cell lymphomas which is thought to arise from αβ intraepithelial T-lymphocytes. Since these lymphocytes may contain cytotoxic molecules, the question of whether this also holds true for ITCL arises. Twenty ITCL cases were examined for the presence of granzyme B, perforin, and T-cell-restricted intracellular antigen (TIA-1)/granule membrane protein of 17 kD (GMP-17). Two molecules with restricted expression in cytotoxic cells, granzyme B and perforin, were detected by immunocytochemistry and by in situ hybridization with an isotopically labelled RNA probe, respectively. Immunocytochemistry was also performed with the antibody 2G9, which recognizes two molecules, one expressed by cytotoxic cells (TIA-1) and the other found in granulocytes and cytotoxic cells (GMP-17). Granzyme B, TIA-1/GMP-17, and perforin were found in the neoplastic cells of 16/19 cases, 19/20 cases, and 16/17 cases, respectively, of ITCL, but not in the tumour cells of the control group, which consisted of intestinal B-cell lymphomas (five cases) and CD8-negative peripheral nodal T-cell lymphomas (six cases). At least one of these molecules was expressed in the tumour cells of all ITCL cases. 2G9 proved to be the most sensitive immunohistological marker, since reactivity with this antibody was not only observed in the highest number of cases, but also found in high numbers of neoplastic cells in positive cases. In conclusion, ITCL appears to show cytotoxic differentiation in all cases. In conjunction with immunophenotypic and genotypic data, our results support a uniform derivation of this tumour from intraepithelial αβ cytotoxic T-lymphocytes. © 1997 John Wiley & Sons, Ltd.     

Expression of cyclin-dependent kinase 6 (cdk6) and frequent loss of CD44 in nasal-nasopharyngeal NK/T-cell lymphomas: comparison with CD56-negative peripheral T-cell lymphomas

Lymphomas involving the nasal and nasopharyngeal region mainly include CD56-positive natural killer (NK)/T-cell lymphomas, CD56-negative peripheral T-cell lymphomas (PTL), and B-cell lymphomas. Among these, the CD56-positive lymphoma, presumably of an NK/T-cell nature, is frequently seen in Asian, Mexican, and South American patients. NK cells are proposed to be closer developmentally to T cells than to other lymphoid cells, because bipotential common progenitor cells of NK/T-cell lineage have been isolated. In this study, we collected 47 cases of nasal lymphoma and investigated the phenotypic difference between NK/T-cell lymphoma and PTL by examining the pattern of the developmentally differentially expressed molecules cdk6 (cyclin-dependent kinase 6), CD44, CD117, and by examining the rearrangement of the T-cell receptor gene (TcR-GR). cdk6, an essential regulator of the cell cycle in G1 progression, was over-expressed in a subset of cortical thymocytes, but absent in mature thymocytes. In contrast, CD44, a glycosylated adhesion molecule, was absent in cortical thymocytes, but present in mature thymocytes and peripheral activated T cells. We found both over-expression of nuclear cdk6 (n-cdk6) and frequent absence of CD44 in nasal CD56-positive NK/T-cell lymphomas, in contrast to most nasal CD56-negative PTL, which were CD44-immunoreactive with weak or no expression of n-cdk6. Almost all tested cases of NK/T-cell lymphoma displayed a germ-line configuration of TcR, without evidence of gene rearrangement. Thus, there seems to be a useful distinction between the classical NK/T type of nasal lymphoma (CD56+/n-cdk6+/CD44-/TcR-GR-) and PTL (CD56-/n-cdk6-/CD44+/TcR-GR+) involving the nasal region. The presence of Epstein-Barr virus does not seem to be a good marker for distinguishing between NK/T lymphoma and PTL involving the nasal region.     

Histological and immunophenotypical characteristics of peripheral T-cell lymphomas

Histopathologic features of immunohistochemically confirmed 37 nodal peripheral T-cell lymphomas are described. Unspecified and 10 angioimmunoblastic T-cell lymphomas were analyzed. The most demonstrative histological features of both types of lymphomas were spectrum of small, medium and large lymphoid cells, lymphoid cells with irregular nuclei, presence of clusters of clear cells, arborizing endothelial venules, increased number of histiocytes, eosinophils and plasma cells. Isolated paracortical expantion, compartmentalization of neoplastic infiltrate and large atypical Reed-Stemberg-like cells were occasional findings. Delineation between peripheral T-cell lymphoma, unspecified and angioimmunoblastic T-cell lymphoma needs evaluation of follicular dendritic cell pattern. The results suggest that detection of histopathologic features typical for peripheral T-cell lymphomas gives an opportunity to compose optimal panel for immunotyping which is absolutely necessary.     

A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites.

It has been proposed that the skin is a functionally unique compartment of the immune system, although little direct evidence supporting this hypothesis has been presented. Here we show that lymphocyte populations at cutaneous sites can be differentiated from otherwise similar populations at noncutaneous sites by their preferential expression of an epitope defined by the MAb HECA-452. This MAb recognizes a predominantly 200-kd cell-surface glycoprotein present on about 16% of peripheral blood T cells, including both CD4+ and CD8+ T cells (17% and 11% HECA-452+, respectively), as well as TCR-delta-bearing T cells (32%+). Most thymocytes (99%) lacked HECA-452 antigen expression, and essentially all the HECA-452+ peripheral blood T cells were found in the adhesion molecule high, CD45R low putative memory cell subset, findings suggesting that HECA-452 expression develops peripherally as a consequence of antigenic stimulation. However, the HECA-452 antigen is not a conventional activation antigen because it was not upregulated with mitogen stimulation of peripheral blood T cells. Most significantly, among 54 diverse specimens of normal/reactive lymphoid tissues and sites of chronic inflammation, there was a clear association of lymphocyte HECA-452 expression and cutaneous location. In extracutaneous sites (n = 38) only about 5% of lymphocytes within the T-cell areas of these tissues expressed this antigen, whereas in inflammatory skin lesions (n = 16), 85% were HECA-452+. The association of HECA-452 expression and cutaneous location was also seen in a series of T-cell lymphomas. The malignant cells of 16 of 18 cases of epidermotropic (patch/plaque) stage mycosis fungoides were HECA-452+, as well as 2 of 7 nonmycosis fungoides peripheral T-cell lymphomas in skin. In contrast, this antigen was not expressed in thymic (lymphoblastic) lymphomas (n = 14), nonepidermotropic (tumor) stage mycosis fungoides (n = 5), and noncutaneous peripheral T-cell lymphomas (n = 15). Among lymphocytes, the preferential expression of the HECA-452 determinant by cutaneous T cells supports the hypothesis that the skin constitutes a immunologically unique lymphoid tissue and suggests that this molecule may play a role in either lymphocyte homing to skin or in lymphocyte interactions with the epidermis.