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Vol 2, No 3 (2009)
Other materials agreed with the Editors
Published online: 2009-06-22
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Characteristics of T-cell large granular lymphocyte proliferations

Monika Prochorec-Sobieszek
Journal of Transfusion Medicine 2009;2(3):81-135.

open access

Vol 2, No 3 (2009)
ROZPRAWA HABILITACYJNA
Published online: 2009-06-22

Abstract

T-cell large granular lymphocyte (T-LGL) proliferations are considered rare probably due to the lack of knowledge about this disorder as the cause of unexplained neutropenia and lymphocytosis, associated with autoimmune and hematological diseases. These proliferations may occur either as transient, reactive expansion of polyclonal CD8+ cytotoxic T lymphocytes or chronic oligoclonal or monoclonal T-LGL lymphocytosis. They may also fit the criteria of clinically overt T-LGL leukemia.
Since publications on T-LGL proliferations are rather infrequent and often involve small groups of patients, while diagnostic problems are quite frequent, personal studies were undertaken. The aim was a multidirectional clinical, histopathological and immnunohistochemical trephine biopsy studies as well as flow cytometry of peripheral blood and bone marrow of 55 patients with T-LGL lymphocytosis. The bone marrow samples were also evaluated for T-cell receptor (TCR) and immunoglobulin (IG) variable genes rearrangements. All this contributed to better knowledge of the clinical presentation and pathology of this often overlooked disease.
T-LGL proliferations occurred in 0.4% of patients evaluated in Department of Pathomorphology with suspicion of lymphoproliferations and/or cytopenia. T-LGL leukemia was recognized in 43 cases, 12 patients had reactive T-LGL lymphocytosis. The following clinical symptoms were observed in 71% of T-LGL leukemia patients: splenomegaly (in 43% of cases), recurrent infections mainly of respiratory tract (26%), fatigue (19%) and skin lesions (12%). All patients presented with chronic cytopenias: neutropenia (93%), leucopenia (33%), anemia (29%) and thrombocytopenia (38%). Patients with symptomatic reactive T-LGL lymphocytosis had similar clinical features and abnormalities in laboratory results to T-LGL leukemia patients except for lower T-LGL lymphocytosis (p = 0.000) and less frequent neutropenia (p = 0.036).
An important feature of T-LGL leukemia were B-cell processes with reactive activation, clonal evolution and proliferation. Autoimmune diseases were present in 50% of T-LGL leukemia patients, most often rheumatoid arthritis (RA) in 36% of cases; some (7%) corresponding to unclassified arthritis. Serological abnormalities (autoantibodies and polyclonal hypergammaglobuinemia) were observed in 71% of patients, both with diagnosed autoimmune disease or asymptomatic. Lymphoid nodules as a morphological parameter of B cell activation were present in bone marrow in 56% of cases. Moreover, 18% of patients demonstrated both TCR and IG kappa and lambda variable genes rearrangements characteritic for monoclonal B cells. Chronic B cell lymphoproliferations developed in 2 patients (chronic lymphocytic leukemia and marginal zone lymphoma). The association of T-LGL proliferations with B-cell pathology suggests their common pathogenesis most probably depending on chronic (auto)antigenic stimulation.
Patients with T-LGL leukemia and associated autoimmune disease displayed more often splenomegaly, leucopenia, severe neutropenia, higher incidence of autoantibodies, polyclonal hipergammaglobulinemia and lower count of T-LGL (p = 0.000) than T-LGL patients without associated disease. More than half of T-LGL leukemia and autoimmune disease patients did not fulfill the quantitative diagnostic criteria concerning the number of T-LGL, which suggests a clonal reaction to the underlying disease. However, the histopathological pattern of bone marrow infiltration, T-cell immunophenotype and frequency of rearrangements of individual regions of TCR genes were similar in both groups. Felty's syndrome displayed a spectrum of T-LGL proliferations from reactive, polyclonal through oligoclonal and monoclonal to T-LGL leukemia. Monoclonal lymphocytosis was most frequently observed (80%). It indicates that ongoing autoimmune process may terminate in clonal proliferation.
Histopathological and immunohistochemical evaluation of bone marrow biopsies was of important value in T-LGL proliferations diagnosis. Characteristic for T-LGL leukemia were infiltrations of T lymphocytes forming interstitial clusters (100% of cases) or in intravascular linear location (64%) expressing CD3+ (100%), CD4 (91%), CD8+ (85%), CD57+ (85%), granzym B+ (88%). Reactive lymphoid nodules (56%) and lowered granulocyte precursors with left-shifted maturation (53%) were also present. Histopathological pattern and immunofenotype of bone marrow infiltration in T-LGL leukemia patients differ from patients with reactive T-LGL lymphocytosis by frequency of linear intravascular (p = 0.000) and interstitial with cluster formation (p = 0.000) infiltrations of T cells, and granzyme B expression (p = 0.002). The effect of selected morphological and immunophenotypical parameters on the clinical course of the disease was also investigated. No correlation was observed between the extent of bone marrow infiltration with T-LGL leukemia cells, pattern of bone marrow infiltration (interstitial alone v. interstitial and intravascular), cytolytic T-cell phenotype (granzyme B+ v. granzyme B) and the presence of anemia, leucopenia, neutropenia, thrombocytopenia, constitutional symptoms and recurrent infections. Only correlation between the presence of lymphoid nodules in the bone marrow and polyclonal hypergammaglobuinemia was noted.
Assessing phenotypic aberrancies by flow cytometry allowed to distinguish reactive from leukemic T-LGL populations. T-LGL leukemia cells demonstrated abnormalities (dim or negative) of one (100%) or two and more (66%) T-cell antigens: CD5 (81%), CD7 (67%), CD43 (80%), CD2 (19%), CD3 (13%) and the presence of one of the isoforms of CD45 molecule (CD45RA in 89% of cases). These abnormalities did not occur in reactive T-LGL. T-LGL leukemic cells showed varied expression of natural killer cells antigens such as CD16 (89%), CD56 (24%) and CD57 (74%). These antigens also appeared on reactive T-LGL, so they were of no importance for differentiation. However, CD16 expression was more frequent on leukemic cells (p=0.006). Immunophenotypic variants of T-LGL leukemia with CD4 (9% of patients), TCRgd (31%) or CD56 (24%) expression had no impact on the clinical presentation of the disease. For T-LGL TCRgd+ leukemia, the frequency of double negative CD4/CD8 phenotype (p = 0.007) and CD56 expression (p = 0.02) was higher as compared to common TCRab+ leukemia. Monoclonal as well as polyclonal T-LGL CD4+ lymphocytosis was associated with small B-cell lymphomas, which determined the clinical course of the disease.
Most frequently, 71% T-LGL leukemia patients revealed simultaneous rearrangements of TCRB and TCRG genes. The rearrangements occurred at a random pattern with VgIf,Vg10-Jg region most frequently rearranged (82% of cases). In about 1/3 of cases, biclonal or biallelic TCR genes rearrangements were present. Classic cytogenetic tests showed normal kariotypes. During 17 months of follow-up the disease remained indolent in the majority of T-LGL leukemia patients. Ten percent of patients died, mainly due to infections related to T-LGL leukemia-associated neutropenia. The overall response rate to therapy was 61%. Good response was for cyclosporine A with a complete hematologic remission in 1/9 cases, partial response (PR) in 8/9 cases as well as for methotrexate (PR in 5/8 patients). Both were administered either in monotherapy or in combination with prednisone and/or granulocyte-colony stimulating factor.
Clinically and biologically T-LGL leukemia is at the border of reactive and neoplastic processes. The disease is indolent, unlike neoplastic diseases and with no cytogenetic abnormalities specific for such diseases, but with confirmed clonality and invasion expressed by organ infiltration. T-LGL leukemia may be easily overlooked or not considered due to only minimal involvement of organs or the presence of a variety of other disorders, mainly autoimmune and hematologic, with their symptoms dominating in the clinical picture. The association of this type of leukemia with numerous diseases suggests that T-LGL monoclonal lymphocytosis, which sometimes does not fulfill the quantitative criteria for leukemia, may be a clonal reaction to the underlying disease. Thus, T-LGL leukemia diagnosis should not be based on one type of testing only. Histopathological and cytometric studies reveal certain disease-specific features, but TCR genes rearrangements need to be confirmed. On the other hand, the high sensitivity of molecular biology tests may reveal populations of monoclonal cells that do not meet the diagnostic criteria for T-LGL leukemia. The appearance of clinical symptoms observed both in leukemia and reactive T-LGL lymphocytosis is crucial for the starting treatment.

Abstract

T-cell large granular lymphocyte (T-LGL) proliferations are considered rare probably due to the lack of knowledge about this disorder as the cause of unexplained neutropenia and lymphocytosis, associated with autoimmune and hematological diseases. These proliferations may occur either as transient, reactive expansion of polyclonal CD8+ cytotoxic T lymphocytes or chronic oligoclonal or monoclonal T-LGL lymphocytosis. They may also fit the criteria of clinically overt T-LGL leukemia.
Since publications on T-LGL proliferations are rather infrequent and often involve small groups of patients, while diagnostic problems are quite frequent, personal studies were undertaken. The aim was a multidirectional clinical, histopathological and immnunohistochemical trephine biopsy studies as well as flow cytometry of peripheral blood and bone marrow of 55 patients with T-LGL lymphocytosis. The bone marrow samples were also evaluated for T-cell receptor (TCR) and immunoglobulin (IG) variable genes rearrangements. All this contributed to better knowledge of the clinical presentation and pathology of this often overlooked disease.
T-LGL proliferations occurred in 0.4% of patients evaluated in Department of Pathomorphology with suspicion of lymphoproliferations and/or cytopenia. T-LGL leukemia was recognized in 43 cases, 12 patients had reactive T-LGL lymphocytosis. The following clinical symptoms were observed in 71% of T-LGL leukemia patients: splenomegaly (in 43% of cases), recurrent infections mainly of respiratory tract (26%), fatigue (19%) and skin lesions (12%). All patients presented with chronic cytopenias: neutropenia (93%), leucopenia (33%), anemia (29%) and thrombocytopenia (38%). Patients with symptomatic reactive T-LGL lymphocytosis had similar clinical features and abnormalities in laboratory results to T-LGL leukemia patients except for lower T-LGL lymphocytosis (p = 0.000) and less frequent neutropenia (p = 0.036).
An important feature of T-LGL leukemia were B-cell processes with reactive activation, clonal evolution and proliferation. Autoimmune diseases were present in 50% of T-LGL leukemia patients, most often rheumatoid arthritis (RA) in 36% of cases; some (7%) corresponding to unclassified arthritis. Serological abnormalities (autoantibodies and polyclonal hypergammaglobuinemia) were observed in 71% of patients, both with diagnosed autoimmune disease or asymptomatic. Lymphoid nodules as a morphological parameter of B cell activation were present in bone marrow in 56% of cases. Moreover, 18% of patients demonstrated both TCR and IG kappa and lambda variable genes rearrangements characteritic for monoclonal B cells. Chronic B cell lymphoproliferations developed in 2 patients (chronic lymphocytic leukemia and marginal zone lymphoma). The association of T-LGL proliferations with B-cell pathology suggests their common pathogenesis most probably depending on chronic (auto)antigenic stimulation.
Patients with T-LGL leukemia and associated autoimmune disease displayed more often splenomegaly, leucopenia, severe neutropenia, higher incidence of autoantibodies, polyclonal hipergammaglobulinemia and lower count of T-LGL (p = 0.000) than T-LGL patients without associated disease. More than half of T-LGL leukemia and autoimmune disease patients did not fulfill the quantitative diagnostic criteria concerning the number of T-LGL, which suggests a clonal reaction to the underlying disease. However, the histopathological pattern of bone marrow infiltration, T-cell immunophenotype and frequency of rearrangements of individual regions of TCR genes were similar in both groups. Felty's syndrome displayed a spectrum of T-LGL proliferations from reactive, polyclonal through oligoclonal and monoclonal to T-LGL leukemia. Monoclonal lymphocytosis was most frequently observed (80%). It indicates that ongoing autoimmune process may terminate in clonal proliferation.
Histopathological and immunohistochemical evaluation of bone marrow biopsies was of important value in T-LGL proliferations diagnosis. Characteristic for T-LGL leukemia were infiltrations of T lymphocytes forming interstitial clusters (100% of cases) or in intravascular linear location (64%) expressing CD3+ (100%), CD4 (91%), CD8+ (85%), CD57+ (85%), granzym B+ (88%). Reactive lymphoid nodules (56%) and lowered granulocyte precursors with left-shifted maturation (53%) were also present. Histopathological pattern and immunofenotype of bone marrow infiltration in T-LGL leukemia patients differ from patients with reactive T-LGL lymphocytosis by frequency of linear intravascular (p = 0.000) and interstitial with cluster formation (p = 0.000) infiltrations of T cells, and granzyme B expression (p = 0.002). The effect of selected morphological and immunophenotypical parameters on the clinical course of the disease was also investigated. No correlation was observed between the extent of bone marrow infiltration with T-LGL leukemia cells, pattern of bone marrow infiltration (interstitial alone v. interstitial and intravascular), cytolytic T-cell phenotype (granzyme B+ v. granzyme B) and the presence of anemia, leucopenia, neutropenia, thrombocytopenia, constitutional symptoms and recurrent infections. Only correlation between the presence of lymphoid nodules in the bone marrow and polyclonal hypergammaglobuinemia was noted.
Assessing phenotypic aberrancies by flow cytometry allowed to distinguish reactive from leukemic T-LGL populations. T-LGL leukemia cells demonstrated abnormalities (dim or negative) of one (100%) or two and more (66%) T-cell antigens: CD5 (81%), CD7 (67%), CD43 (80%), CD2 (19%), CD3 (13%) and the presence of one of the isoforms of CD45 molecule (CD45RA in 89% of cases). These abnormalities did not occur in reactive T-LGL. T-LGL leukemic cells showed varied expression of natural killer cells antigens such as CD16 (89%), CD56 (24%) and CD57 (74%). These antigens also appeared on reactive T-LGL, so they were of no importance for differentiation. However, CD16 expression was more frequent on leukemic cells (p=0.006). Immunophenotypic variants of T-LGL leukemia with CD4 (9% of patients), TCRgd (31%) or CD56 (24%) expression had no impact on the clinical presentation of the disease. For T-LGL TCRgd+ leukemia, the frequency of double negative CD4/CD8 phenotype (p = 0.007) and CD56 expression (p = 0.02) was higher as compared to common TCRab+ leukemia. Monoclonal as well as polyclonal T-LGL CD4+ lymphocytosis was associated with small B-cell lymphomas, which determined the clinical course of the disease.
Most frequently, 71% T-LGL leukemia patients revealed simultaneous rearrangements of TCRB and TCRG genes. The rearrangements occurred at a random pattern with VgIf,Vg10-Jg region most frequently rearranged (82% of cases). In about 1/3 of cases, biclonal or biallelic TCR genes rearrangements were present. Classic cytogenetic tests showed normal kariotypes. During 17 months of follow-up the disease remained indolent in the majority of T-LGL leukemia patients. Ten percent of patients died, mainly due to infections related to T-LGL leukemia-associated neutropenia. The overall response rate to therapy was 61%. Good response was for cyclosporine A with a complete hematologic remission in 1/9 cases, partial response (PR) in 8/9 cases as well as for methotrexate (PR in 5/8 patients). Both were administered either in monotherapy or in combination with prednisone and/or granulocyte-colony stimulating factor.
Clinically and biologically T-LGL leukemia is at the border of reactive and neoplastic processes. The disease is indolent, unlike neoplastic diseases and with no cytogenetic abnormalities specific for such diseases, but with confirmed clonality and invasion expressed by organ infiltration. T-LGL leukemia may be easily overlooked or not considered due to only minimal involvement of organs or the presence of a variety of other disorders, mainly autoimmune and hematologic, with their symptoms dominating in the clinical picture. The association of this type of leukemia with numerous diseases suggests that T-LGL monoclonal lymphocytosis, which sometimes does not fulfill the quantitative criteria for leukemia, may be a clonal reaction to the underlying disease. Thus, T-LGL leukemia diagnosis should not be based on one type of testing only. Histopathological and cytometric studies reveal certain disease-specific features, but TCR genes rearrangements need to be confirmed. On the other hand, the high sensitivity of molecular biology tests may reveal populations of monoclonal cells that do not meet the diagnostic criteria for T-LGL leukemia. The appearance of clinical symptoms observed both in leukemia and reactive T-LGL lymphocytosis is crucial for the starting treatment.
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Keywords

T-cell large granular lymphocyte leukemia; histopathology; immunophenotype; rearrangements of T-cell receptor genes; clonal heterogeneity; autoimmune disorders

About this article
Title

Characteristics of T-cell large granular lymphocyte proliferations

Journal

Journal of Transfusion Medicine

Issue

Vol 2, No 3 (2009)

Article type

Other materials agreed with the Editors

Pages

81-135

Published online

2009-06-22

Bibliographic record

Journal of Transfusion Medicine 2009;2(3):81-135.

Keywords

T-cell large granular lymphocyte leukemia
histopathology
immunophenotype
rearrangements of T-cell receptor genes
clonal heterogeneity
autoimmune disorders

Authors

Monika Prochorec-Sobieszek

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