{gamma}{delta} T-cell neoplasms: a clinicopathological study of 11 cases

T. Saito1, Y. Matsuno2, R. Tanosaki1, T. Watanabe1, Y. Kobayashi1 and K. Tobinai1,+

1 Hematology Division and 2 Clinical Laboratory Division, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan

Received 25 October 2001; revised 21 March 2002; accepted 10 April 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The majority of T-cell neoplasms express T-cell antigen receptor (TCR) {alpha}ß on their cell surface, and a few cases show the TCR {gamma}{delta} phenotype. Recently, a variety of {gamma}{delta} T-cell neoplasm was recognized; however, its clinicopathological features have not been extensively analyzed. Here we report the results of a clinicopathological study of 11 cases of {gamma}{delta} T-cell neoplasm.

Patients and methods:

During the 11-year period from 1989 to 1999, 104 patients with T-cell neoplasms were examined by flow cytometric analysis and/or immunohistochemical analysis. Tumor cells from all 104 patients expressed one or more of the T-cell antigens—CD2, CD3, CD5 and CD7. Forty-nine of the 104 cases of T-cell neoplasms were examined immunophenotypically for TCR {alpha}ß/{gamma}{delta} subsets.

Results:

Expression of TCR {gamma}{delta} on tumor cells was found in five (33%) of 15 patients with precursor T-cell lymphoblastic leukemia/lymphoma, one (25%) of four with T-cell granular lymphocytic leukemia and five (26%) of 19 with peripheral T-cell lymphoma (PTCL), whereas no expression was found in 11 patients with adult T-cell leukemia-lymphoma. Primary sites of the five patients with {gamma}{delta} PTCL were as follows: lymph node, three; skin, one and liver, tonsil and skin, one. The courses of the three patients with {gamma}{delta} PTCL of nodal onset were very short (3, 5 and 9 months, respectively), and they were all resistant to combination chemotherapies.

Conclusions:

Although {gamma}{delta} T-cell neoplasm constitutes a heterogeneous population, it is important to examine the expression of TCR with the view to identifying possible poor prognostic subgroups, such as primary nodal {gamma}{delta} T-cell lymphoma.

Key words: {gamma}{delta} T-cell neoplasm, nodal {gamma}{delta} T-cell lymphoma, T-cell receptor


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
T-cell antigen receptor (TCR) is a complex of molecules consisting of an antigen-binding heterodimer of either {alpha}ß or {gamma}{delta} chains. Although the structure of TCR {gamma}{delta} is similar to that of TCR {alpha}ß, {gamma}{delta} T-cells exhibit a more limited diversity and a tissue-restricted repertoire [1, 2]. Human {gamma}{delta} T-cells account for 1–10% of normal circulating peripheral blood T lymphocytes, 2–4% of T-cells in normal lymph nodes, 3–5% of medullary thymocytes and 15% of splenic T lymphocytes [3, 4]. The physiological function of {gamma}{delta} T-cells remains elusive, although some evidence has been accumulated indicating that {gamma}{delta} T-cells play a role against a broad spectrum of invasive microorganisms. In addition, certain hematopoietic tumor cells (e.g. Burkitt’s lymphoma cell line Daudi or myeloma cell line RPMI 8226) are specifically recognized and lysed by these T-cells in vitro [5, 6].

The majority of T-cell neoplasms express TCR {alpha}ß on their cell surface, and a few cases show the TCR {gamma}{delta} phenotype. Previous studies have suggested that the analysis of TCR expression might contribute to delineating clinicopathological features and prognosis of precursor T-cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) [710]. Recently, a variety of clinicopathological spectrums of post-thymic {gamma}{delta} T-cell neoplasms were recognized, including hepatosplenic, cutaneous, intestinal, thyroidal and nodal onsets [1119]. In the Revised European–American Lymphoma (REAL) Classification [20], hepatosplenic {gamma}{delta} T-cell lymphoma was listed as a distinct entity derived from {gamma}{delta} T-cell. Although hepatosplenic {gamma}{delta} T-cell lymphoma was recognized as a lymphoma subset of poor prognosis, the clinicopathological characteristics of other types of {gamma}{delta} T-cell neoplasms, especially primary nodal {gamma}{delta} T-cell lymphoma, are still unknown.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
During the 11-year period from 1989 to 1999, tumor cells from 104 patients with T-cell neoplasms were examined by flow cytometric analysis and/or immunohistochemical analysis at the National Cancer Center Hospital (Tokyo, Japan). They were diagnosed as having T-ALL/LBL (n = 29), T-cell granular lymphocytic leukemia (T-GLL; n = 7), peripheral T-cell lymphoma (PTCL; n = 38) and adult T-cell leukemia-lymphoma (ATL; n = 30). All patients expressed one or more of the T-cell antigens: CD2, CD3, CD5 and CD7. Fifteen of 29 T-ALL/LBL, 19 of 38 PTCL, four of seven T-GLL and 11 of 30 ATL were examined immunophenotypically for TCR {alpha}ß/{gamma}{delta} subsets.

Immunophenotypical analysis by flow cytometry
Neoplastic specimens were obtained from bone marrow in all T-ALL/T-LBL, peripheral blood in T-GLL, pleural effusion in one PTCL (Case 7), lymph node in two PTCL (Cases 8 and 9), tonsil in one PTCL (Case 10) and skin in one PTCL (Case 11). Immunophenotypical analyses were performed by flow cytometry (EPICS XL-MCL, Beckman Coulter, Miami, FL, USA). Multiparametric analysis was performed using two or three fluorescent signals (antibodies conjugated to fluorescein isothiocyanate, phycoerythrin and peridinin chlorophyll). Antibodies recognizing CD3 (UCHT 1, Immunotech, Marseille, France), CD4 (T4, Immunotech), CD8 (T8, Immunotech), CD19 (B4, Immunotech), CD20 (B-Ly1, DAKO, Carpinteria, CA, USA), CD25 (ACT-1, DAKO), TCR {alpha}ß [WT31, Becton Dickinson (BD), San Jose, CA, USA] and TCR {gamma}{delta} ({delta}TCS-1 and/or TCR {delta}1; BD) were used in this analysis. We determined the immunophenotype of neoplastic cells to be a {gamma}{delta} T-cell phenotype when the percentage of TCR {gamma}{delta}-expressing cells was >40%.

Cytological, histological and immunohistological analyses
Peripheral blood or bone marrow from T-ALL/LBL and T-GLL were evaluated for cytological findings. Histological sections from patients with PTCL were evaluated for pattern of the infiltrate, vascular proliferation, necrosis and cytological composition. All cases of PTCL were studied using paraffin-section immunohistochemistry using the avidin–biotin complex method and primary antibodies to the following antigens: CD3 (PS1; Novocastra, Newcastle upon Tyne, UK), CD4 (1F6; Novocastra), CD8 (4B11; Novocastra), CD20 (L26; DAKO, Glostrup, Denmark) and CD45 (2B11+PD7/26; DAKO). In addition, three cases of primary nodal {gamma}{delta} T-cell lymphoma were also studied for granzyme-B (GrB-7; Monosan, Uden, The Netherlands) and T-cell intracellular antigen-1 (TIA-1; 26gA10F5, Immunotech).

In-situ hybridization (ISH) analysis
Detection of Epstein–Barr virus (EBV) RNA was performed by ISH using EBER-1 oligonucleotides on formalin-fixed, paraffin-embedded sections as previously described [18].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Immunophenotypical features
Expression of TCR {gamma}{delta} on neoplastic cells was found in five (33%) of 15 T-ALL/LBL, one (25%) of four T-GLL, and five (26%) of 19 PTCL (including three cases of primary nodal {gamma}{delta} T-cell lymphoma), whereas no expression was found in 11 patients with ATL. Patient characteristics and the results of immunophenotypical analysis on 11 cases of {gamma}{delta} T-cell neoplasms are listed in Tables 1 and 2, respectively. Their subset phenotypes were CD48 in eight ({gamma}{delta} T-ALL/LBL, five; {gamma}{delta} T-GLL, one; {gamma}{delta} PTCL, two) and CD4+8 in three ({gamma}{delta} PTCL, three; including two cases of primary nodal {gamma}{delta} T-cell lymphoma).


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Table 1. Patient characteristics and clinical features of {gamma}{delta} T-cell neoplasms
 

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Table 2. Immunophenotypical analysis
 
Cytological, immunohistological features and EBV analysis
Morphological and immunohistological features of {gamma}{delta} T-cell neoplasms were not very different from those of their TCR {alpha}ß-expressing counterparts. Although three cases of primary nodal {gamma}{delta} T-cell lymphoma were classified as peripheral T-cell lymphoma according to the REAL Classification, two of them revealed remarkable vascular proliferation. In Case 8, the lymph node showed diffuse proliferation of lymphoma cells with preservation of non-neoplastic lymphoid follicles (‘T-zone’ pattern; Figure 1A). Vascular proliferation and necrosis were remarkable. The tumor cells predominantly consisted of medium-sized cells to large cells. Nuclear/cytoplasmic ratio of lymphoma cells was high, and nuclei occasionally showed a prominent indentation (Figure 1B). In Case 9, the lymph node architecture was effaced by diffuse infiltration of lymphoma cells accompanied by vascular proliferation (Figure 1C). On the other hand, Case 7 showed infiltration of large lymphoma cells without extensive vascular proliferation. Among the three cases of primary nodal {gamma}{delta} T-cell lymphoma, autopsy was only permitted in Case 8. His disease was widely spread, including systemic lymph nodes and liver at autopsy, and lymphoma cell infiltration in the liver was present mainly in portal areas.



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Figure 1. Histological demonstration of two cases of primary nodal {gamma}{delta} T-cell lymphoma. (A) Primary nodal {gamma}{delta} T-cell lymphoma showing the diffuse proliferation of lymphoma cells with a T-zone pattern [Case 8; hematoxylin and eosin (H&E); original magnification, x100]. (B) High nuclear/cytoplasmic ratio of lymphoma cells with deep indentation is shown (Case 8; H&E; original magnification, x400). (C) Lymph node architecture was effaced by the diffuse large cell lymphoma with vascular proliferation (Case 9; H&E; original magnification, x100).

 
Immunohistochemical analysis showed cytotoxic molecules, granzyme-B or TIA-1, to be positive in two patients (Cases 7 and 9). In-situ hybridization analysis showed the presence of EBV in tumor cells (scattered pattern) in one (Case 7) of three cases (Table 2).

Clinical features
Clinical presentations and follow-up results of 11 patients with {gamma}{delta} T-cell neoplasms are summarized in Table 1. All patients were seronegative both for human T-cell leukemia virus type-I and human immunodeficiency virus.

All five patients with {gamma}{delta} T-ALL/LBL received multiagent chemotherapy, and achieved an initial complete response (CR) except for one (Case 5). Three patients received allogeneic (Case 1) or autologous (Cases 3 and 4) bone marrow transplantations (BMTs). However, they recurred 3, 38 and 10 months after transplant and died 29, 60 and 14 months after initial diagnosis, respectively. The other two patients (Cases 2 and 5) lived for a shorter period of time than the patients who received BMT.

One patient with {gamma}{delta} T-GLL (Case 6) was followed up without any therapy for >4 years, and disease progression was not observed [21].

Five patients were diagnosed as having {gamma}{delta} PTCL. The primary sites were lymph nodes alone in three patients (Cases 7–9), liver, tonsil and skin in one (Case 10), and skin in one (Case 11). Three patients (Cases 7–9) were diagnosed as having primary nodal {gamma}{delta} T-cell lymphoma. Their clinical courses are described below.

Case 7
A 64-year-old Japanese male was admitted in April 1991 because of cervical lymphadenopathy. A cervical lymph node biopsy was performed and he was diagnosed as having PTCL in clinical stage (CS) IIA according to the Ann Arbor Classification. At this point, we could not diagnose him as having primary nodal {gamma}{delta} T-cell lymphoma because, at this time, analysis of TCR {alpha}ß/{gamma}{delta} phenotype was not carried out. He was classified into the low risk group according to the international prognostic index (IPI) [22]. He received one course of LSG9 (vincristine, vindesine, cyclophosphamide, prednisolone, doxorubicin, bleomycin, etoposide, procarbazine and methotrexate) therapy followed by involved-field irradiation for 5 weeks (50 Gy). Although he achieved an initial CR, the disease recurred as systemic lymphadenopathy with pleural effusion. Lymphoma cells in the pleural effusion were analyzed by flow cytometry and he was diagnosed as having primary nodal {gamma}{delta} T-cell lymphoma. He died 9 months after diagnosis.

Case 8
A 66-year-old Japanese male was admitted in October 1998 because of bilateral submandibular, cervical and left inguinal lymphadenopathy. A cervical lymph node biopsy was performed and he was diagnosed as having primary nodal {gamma}{delta} T-cell lymphoma in CS IIIA. He was classified into the low-intermediate risk group. He received five courses of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) therapy, one course of ESHAP (etoposide, methyl prednisolone, cytosine arabinoside and cisplatin) therapy [23], and another salvage chemotherapy consisting of vindesine, nimustine, mitoxantorone, etoposide and prednisolone, followed by irradiation for 2 weeks (11 Gy). However, he was refractory to chemo-radiotherapy and died with systemic lymphadenopathy and hepatomegaly 5 months after diagnosis.

Case 9
A 79-year-old Japanese male was admitted in October 1998 because of bilateral cervical and inguinal lymphadenopathy. This patient had a history of lung tuberculosis. A cervical lymph node biopsy was taken and he was diagnosed as having primary nodal {gamma}{delta} T-cell lymphoma in CS IIIA. He was classified into the low-intermediate risk group. He received one course of CHOP therapy and two courses of EPOCH (etoposide, prednisolone, vincristine, doxorubicin, and cyclophosphamide) therapy [24]. However, he was refractory to them and died with systemic lymphadenopathy three months after diagnosis.

The remaining two patients with {gamma}{delta} PTCL were diagnosed as having hepatosplenic {gamma}{delta} T-cell lymphoma (Case 10) and mycosis fungoides derived from {gamma}{delta} T-cell (Case 11). Although Case 10 received multiagent chemoradiotherapy and achieved an initial CR, the disease recurred 7 months later and he died 3 years after diagnosis. Skin tumors without lymphadenopathy were initially noted in Case 11. This patient was followed up without therapy. However, 8 years later he was found to have abdominal lymphadenopathy and received multiagent chemotherapy. Although he achieved a partial response, the disease recurred and he died of overwhelming disease progression 9 years after initial presentation.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In 1986, Bank et al. [25] discovered the TCR {gamma}{delta}. Following their initial description, several studies on T-ALL/LBL, T-GLL and PTCL with the TCR {gamma}{delta} phenotype have been reported [719, 21]. Indeed, {gamma}{delta} T-cell neoplasms show a broad clinicopathological spectrum, except for ATL, in the present study. In addition, TCR {gamma}{delta} was expressed on the tumor cells of 33% of patients with T-ALL/LBL, 25% with T-GLL and 26% with PTCL. Compared with the frequency of the TCR {gamma}{delta} phenotype in T-cells from normal peripheral blood (1–10%) and lymph nodes (2–4%), the incidence of {gamma}{delta} T-cell neoplasms was relatively high. However, similar results were reported in T-ALL/LBL (50%) [10] and in PTCL (3.4–10.5%) [1315]. It is presumed that {gamma}{delta} T-cell neoplasm is not such a rare disease.

Since Ichinohasama et al. [17] first reported a case of nodal {gamma}{delta} T-cell lymphoma in 1996, several cases of {gamma}{delta} T-cell lymphoma with lymph node involvement have been documented [18, 19, 26, 27]. However, primary nodal {gamma}{delta} T-cell lymphoma without extranodal involvement (e.g. hepatosplenomegaly, bone marrow involvement) is extremely rare [1719] and its clinicopathological features have not been extensively analyzed. Histological features of primary nodal {gamma}{delta} T-cell lymphoma in this series were characterized by the diffuse proliferation of medium- to large-size cells with irregular nuclei [17, 18; Cases 7–9]. Occasionally, the predominant involvement of the T-zone area with residual B-cell follicles was observed [18; Case 8], and prominent vascular proliferation was also found [17; Cases 8 and 9].

Immunophenotypically, in contrast with normal {alpha}ß T-cells in which the vast majority are either CD4+CD8 or CD4CD8+, only 1–4% of normal {gamma}{delta} T-cells express CD4 and 5–10% express CD8 [2]. In the present study, all patients with {gamma}{delta} T-cell neoplasm, with three exceptions, had a CD4CD8 phenotype. On the other hand, two (Cases 8 and 9) of the three cases of primary nodal {gamma}{delta} T-cell lymphoma expressed the CD4+CD8 phenotype. This rare subset of {gamma}{delta} T-cell neoplasm phenotypes was previously reported in one other case [17]. In this study, the monoclonal antibodies {delta}TCS-1 and/or TCR {delta}1 were used to identify TCR {gamma}{delta} phenotype. TCR {delta}1 binds to a {delta} constant region determinant of the {gamma}{delta} heterodimer of TCR and {delta}TCS-1 binds to distinct {delta} variable region-encoded determinants [7]. Although only six cases (Cases 1, 3, 4, 5, 7 and 11) were analyzed using both monoclonal antibodies, all but two cases (Cases 7 and 11) with {gamma}{delta} PTCL showed a {delta}TCS-1/TCR {delta}1+ phenotype.

It is known that cytotoxic lymphocytes, such as NK-cells and cytotoxic T-cells, contain unique proteins within their intracytoplasmic azurophilic granules including granzyme-B and TIA-1. Their expression has been studied in a large series of non-Hodgkin’s lymphomas, and it was reported that TIA-1 and granzyme-B cytoplasmic granules were detected in 70% of anaplastic large-cell lymphomas and 23% of PTCL [28]. However, the expression of these cytotoxic molecules in primary nodal {gamma}{delta} T-cell lymphoma has not been extensively analyzed. Ohshima et al. [19] reported a case of primary nodal {gamma}{delta} T-cell lymphoma with cytotoxic molecules (TIA-1+/granzyme-B). In the present study, two cases (Cases 7 and 9) demonstrated a strong cytoplasmic staining for the cytotoxic granule-associated protein, suggesting that the lymphoma cells were derived from activated cytotoxic T-cells. Lymphoma cells from Case 9 were positive for granzyme-B, but negative for TIA-1. Although TIA-1 is supposed to be constitutively expressed in cytotoxic cells, a similar expression pattern (TIA-1/granzyme-B+) in T-cell neoplasms was reported in a previous report [28].

Previously, the nasal and nasal-type NK-cell lymphoma was identified as a tumor associated with EBV [29, 30]. Although it was recently suggested that EBV is associated with the lymphomagenesis of primary nodal {gamma}{delta} T-cell lymphoma [18, 19], further investigations are required.

Another important finding of the present study is that the prognosis of primary nodal {gamma}{delta} T-cell lymphoma may be dismal. In the present study, all three patients were resistant to combination chemotherapies, and died with disease progression within 1 year of diagnosis. Although the small number of patients in the present study makes it difficult to establish its poor prognosis, and further comparative clinicopathological studies with its TCR {alpha}ß-expressing counterparts are needed, it is important to examine the expression of TCR when we diagnose as PTCL in view of identifying the possibly poor prognostic subgroups, including primary nodal {gamma}{delta} T-cell lymphoma.


    Acknowledgements
 
This study was supported by the Grants-in-Aid for Cancer Research (9–10 and 11–8) from the Ministry of Health, Labor and Welfare of Japan.


    Footnotes
 
+ Correspondence to: Dr K. Tobinai, Hematology Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81-3-3542-2511; Fax: +81-3-3542-3815; E-mail; ktobinai{at}ncc.go.jp Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Falini B, Flenghi L, Pileri S et al. Distribution of T cells bearing a different form of the T cell receptor {gamma}/{delta} in normal and pathological human tissues. J Immunol 1989; 143: 2480–2488.[Abstract/Free Full Text]

2. Groh V, Porcelli S, Fabbi M et al. Human lymphocytes bearing T cell receptor {gamma}/{delta} are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med 1989; 169: 1277–1294.[Abstract]

3. de Villartay JP, Pullman AB, Andrade R et al. {gamma}/{delta} Lineage relationship within a consecutive series of human precursor T-cell neoplasms. Blood 1989; 74: 2508–2518.[Abstract]

4. Picker L, Brenner M, Michie S, Warnke RA. Expression of T cell receptor {delta} chains in benign and malignant T lineage lymphoproliferations. Am J Pathol 1988; 132: 401–405.[Abstract]

5. Fisch P, Malkovsky M, Kovats S et al. Recognition by human V9/V2 T cells of a GroEL homolog on Daudi Burkitt’s lymphoma cells. Science 1990; 250: 1269–1273.[ISI][Medline]

6. Bukowski JF, Morita CT, Tanaka Y et al. V2V2 TCR-dependent recognition of nonpeptide antigens and Daudi cells analyzed by TCR gene transfer. J Immunol 1995; 154: 998–1006.[Abstract/Free Full Text]

7. Falini B, Flenghi L, Fagioli M et al. T-lymphoblastic lymphomas expressing the non-disulfide-linked form of the T-cell receptor {gamma}/{delta}: characterization with monoclonal antibodies and genotypic analysis. Blood 1986; 74: 2501–2507.[Abstract]

8. Alfsen C, Beiske K, Holte H et al. T-cell receptor {gamma}{delta}+/CD3+48 T-cell acute lymphoblastic leukemias: a report of five cases. Blood 1991; 77: 2023–2030.[Abstract]

9. Campana D, Couston-Smith E, Behm F, Goorha R. Normal and aberrant T-cell receptor protein expression in T-cell acute lymphoblastic leukemia. Recent Results Cancer Res 1993; 131: 19–30.[Medline]

10. Schott G, Sperling C, Schrappe M et al. Immunophenotypic and clinical features of T-cell receptor {gamma}{delta}+ T-lineage acute lymphoblastic leukemia. Br J Haematol 1998; 101: 753–755.[ISI][Medline]

11. Farcet JP, Gualard P, Marolleau J-P et al. Hepatosplenic T-cell lymphoma: Sinusal/Sinusoidal localization of malignant cells expressing the T-cell receptor {gamma}{delta}. Blood 1990; 75: 2213–2219.[Abstract]

12. Arnulf B, Copie-Bergman C, Delfau-Larue MH et al. Nonhepatosplenic {gamma}{delta} T-cell lymphoma: A subset of cytotoxic lymphomas with mucosal or skin location. Blood 1998; 91: 1723–1731.[Abstract/Free Full Text]

13. Yamaguchi M, Ohno T, Nakamine H et al. {gamma}{delta} T-cell lymphoma: A clinicopathologic study of six cases including extrahepatosplenic type. Int J Hematol 1999; 69: 186–195.[ISI][Medline]

14. Picker LJ, Brenner MB, Michie S, Warnke RA. Expression of T cell receptor {delta} chains in benign and malignant T lineage lymphoproliferations. Am J Pathol 1988; 132: 401–405.[Abstract]

15. Gaulard P, Bourquelot P, Kanavaros P et al. Expression of the {alpha}/ß and {gamma}/{delta} T-cell receptors in 57 cases of peripheral T-cell lymphomas. Am J Pathol 1990; 137: 617–628.[Abstract]

16. Yamaguchi M, Ohno T, Kita K. {gamma}{delta} T-cell lymphoma of the thyroid gland. N Engl J Med 1997; 336: 1391–1392.[Free Full Text]

17. Ichinohasama R, Miura I, Takahashi T et al. Peripheral CD4+/CD8 {gamma}{delta} T cell lymphoma: a case report with multiparameter analyses. Hum Pathol 1996; 27: 1370–1377.[ISI][Medline]

18. Kagami Y, Nakamura S, Suzuki R et al. A nodal {gamma}/{delta} T-cell lymphoma with an association of Epstein–Barr virus. Am J Surg Pathol 1997; 21: 729–736.[ISI][Medline]

19. Ohshima K, Suzumiya J, Sugihara M et al. Clinical, immunohistochemical and phenotypic features of aggressive nodal cytotoxic lymphomas, including {alpha}/ß, {gamma}/{delta} T-cell and natural killer cell types. Virchows Arch 1999; 435: 92–100.[ISI][Medline]

20. Harris NL, Jaffe ES, Stein H et al. A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–1392.[Free Full Text]

21. Saito T, Togitani K, Murakami J et al. Granular lymphocytic leukemia derived from {gamma}{delta} T-cell expressing cytotoxic molecules. Leuk Res 2001; 25: 259–261.[ISI][Medline]

22. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–994.[Abstract/Free Full Text]

23. Velasquez WS, Mclaughlin P, Tucker S et al. ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994; 12: 1169–1176.[Abstract]

24. Wilson WH, Bryant G, Bates S et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol 1993; 11: 1573–1582.[Abstract]

25. Bank I, DePinho RA, Brenner MB et al. A functional T3 molecule associated with a novel heterodimer on the surface of immature human thymocytes. Nature 1986; 322: 179–181.[ISI][Medline]

26. Charton-Bain MC, Brousset P, Bouabdallah R et al. Variation in the histological pattern of nodal involvement by {gamma}/{delta} T-cell lymphoma. Histopathology 2000; 36: 233–239.[ISI][Medline]

27. Wong KF, Chan JKC, Matutes E et al. Hepatosplenic {gamma}{delta} T-cell lymphoma, a distinct aggressive lymphoma type. Am J Surg Pathol 1995; 19: 718–726.[ISI][Medline]

28. Kagami Y, Suzuki R, Taji H et al. Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients. Am J Surg Pathol 1999; 23: 1184–1200.[ISI][Medline]

29. Kanavaros P, Lescs MC, Briere J et al. Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein–Barr virus. Blood 1993; 81: 2688–2695.[Abstract]

30. Harabuchi Y, Imai S, Wakashima J et al. Nasal T-cell lymphoma causally associated with Epstein–Barr virus. Cancer 1996; 77: 2137–2149.[ISI][Medline]





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