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
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Abstract |
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The majority of T-cell neoplasms express T-cell antigen receptor (TCR) ß on their cell surface, and a few cases show the TCR
phenotype. Recently, a variety of
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
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 antigensCD2, CD3, CD5 and CD7. Forty-nine of the 104 cases of T-cell neoplasms were examined immunophenotypically for TCR ß/
subsets.
Results:
Expression of TCR 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
PTCL were as follows: lymph node, three; skin, one and liver, tonsil and skin, one. The courses of the three patients with
PTCL of nodal onset were very short (3, 5 and 9 months, respectively), and they were all resistant to combination chemotherapies.
Conclusions:
Although 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
T-cell lymphoma.
Key words: T-cell neoplasm, nodal
T-cell lymphoma, T-cell receptor
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Introduction |
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The majority of T-cell neoplasms express TCR ß on their cell surface, and a few cases show the TCR
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
T-cell neoplasms were recognized, including hepatosplenic, cutaneous, intestinal, thyroidal and nodal onsets [1119]. In the Revised EuropeanAmerican Lymphoma (REAL) Classification [20], hepatosplenic
T-cell lymphoma was listed as a distinct entity derived from
T-cell. Although hepatosplenic
T-cell lymphoma was recognized as a lymphoma subset of poor prognosis, the clinicopathological characteristics of other types of
T-cell neoplasms, especially primary nodal
T-cell lymphoma, are still unknown.
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Patients and methods |
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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 ß [WT31, Becton Dickinson (BD), San Jose, CA, USA] and TCR
(
TCS-1 and/or TCR
1; BD) were used in this analysis. We determined the immunophenotype of neoplastic cells to be a
T-cell phenotype when the percentage of TCR
-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 avidinbiotin 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 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 EpsteinBarr virus (EBV) RNA was performed by ISH using EBER-1 oligonucleotides on formalin-fixed, paraffin-embedded sections as previously described [18].
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Results |
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Clinical features
Clinical presentations and follow-up results of 11 patients with 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 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 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 PTCL. The primary sites were lymph nodes alone in three patients (Cases 79), liver, tonsil and skin in one (Case 10), and skin in one (Case 11). Three patients (Cases 79) were diagnosed as having primary nodal
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 T-cell lymphoma because, at this time, analysis of TCR
ß/
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
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 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 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 PTCL were diagnosed as having hepatosplenic
T-cell lymphoma (Case 10) and mycosis fungoides derived from
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.
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Discussion |
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Since Ichinohasama et al. [17] first reported a case of nodal T-cell lymphoma in 1996, several cases of
T-cell lymphoma with lymph node involvement have been documented [18, 19, 26, 27]. However, primary nodal
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
T-cell lymphoma in this series were characterized by the diffuse proliferation of medium- to large-size cells with irregular nuclei [17, 18; Cases 79]. 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 ß T-cells in which the vast majority are either CD4+CD8 or CD4CD8+, only 14% of normal
T-cells express CD4 and 510% express CD8 [2]. In the present study, all patients with
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
T-cell lymphoma expressed the CD4+CD8 phenotype. This rare subset of
T-cell neoplasm phenotypes was previously reported in one other case [17]. In this study, the monoclonal antibodies
TCS-1 and/or TCR
1 were used to identify TCR
phenotype. TCR
1 binds to a
constant region determinant of the
heterodimer of TCR and
TCS-1 binds to distinct
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
PTCL showed a
TCS-1/TCR
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-Hodgkins 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 T-cell lymphoma has not been extensively analyzed. Ohshima et al. [19] reported a case of primary nodal
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 T-cell lymphoma [18, 19], further investigations are required.
Another important finding of the present study is that the prognosis of primary nodal 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
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
T-cell lymphoma.
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Acknowledgements |
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Footnotes |
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