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Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy.

Prochorec-Sobieszek M, Rymkiewicz G, Makuch-Łasica H, Majewski M, Michalak K, Rupiński R, Warzocha K, Maryniak R - Arthritis Res. Ther. (2008)

Bottom Line: Bone marrow trephines from T-LGL leukemia patients showed interstitial clusters and intrasinusoidal linear infiltrations of CD3+/CD8+/CD57+/granzyme B+ lymphocytes, reactive lymphoid nodules, and decreased or normal granulocyte precursor count with left-shifted maturation.RA and neutropenia patients represented a continuous spectrum of T-LGL proliferations, although monoclonal expansions were most frequently observed.The histopathological pattern and immunophenotype of bone marrow infiltration as well as molecular characteristics were similar in T-LGL leukemia patients with and without arthritis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathomorphology, Institute of Hematology and Transfusion Medicine, I, Gandhi 14, 02-776 Warsaw, Poland. monika.prochorec@interia.pl

ABSTRACT

Introduction: The purpose of this study was to analyze the data of patients with T-cell large granular lymphocyte (T-LGL) lymphocytosis associated with inflammatory arthropathy or with no arthritis symptoms.

Methods: Clinical, serological as well as histopathological, immunohistochemical, and flow cytometric evaluations of blood/bone marrow of 21 patients with T-LGL lymphocytosis were performed. The bone marrow samples were also investigated for T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangements by polymerase chain reaction with heteroduplex analysis.

Results: Neutropenia was observed in 21 patients, splenomegaly in 10, autoimmune diseases such as rheumatoid arthritis (RA) in 9, unclassified arthritis resembling RA in 2, and autoimmune thyroiditis in 5 patients. T-LGL leukemia was recognized in 19 cases. Features of Felty syndrome were observed in all RA patients, representing a spectrum of T-LGL proliferations from reactive polyclonal through transitional between reactive and monoclonal to T-LGL leukemia. Bone marrow trephines from T-LGL leukemia patients showed interstitial clusters and intrasinusoidal linear infiltrations of CD3+/CD8+/CD57+/granzyme B+ lymphocytes, reactive lymphoid nodules, and decreased or normal granulocyte precursor count with left-shifted maturation. In three-color flow cytometry (FCM), T-LGL leukemia cells demonstrated CD2, CD3, and CD8 expression as well as a combination of CD16, CD56, or CD57. Abnormalities of other T-cell antigen expressions (especially CD5, CD7, and CD43) were also detected. In patients with polyclonal T-LGL lymphocytosis, T cells were dispersed in the bone marrow and the expression of pan-T-cell antigens in FCM was normal. Molecular studies revealed TCRB and TCRG gene rearrangements in 13 patients and TCRB, TCRG, and TCRD in 4 patients. The most frequently rearranged regions of variable genes were Vbeta-Jbeta1, Jbeta2 and Vgamma If Vgamma10-Jgamma. Moreover, in 4 patients, additional rearrangements of IG kappa and lambda variable genes of B cells were also observed.

Conclusion: RA and neutropenia patients represented a continuous spectrum of T-LGL proliferations, although monoclonal expansions were most frequently observed. The histopathological pattern and immunophenotype of bone marrow infiltration as well as molecular characteristics were similar in T-LGL leukemia patients with and without arthritis.

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Histopathological features of bone marrow in patients with arthritis and T-cell large granular lymphocyte (T-LGL) lymphocytosis. (a) Patient 1 with rheumatoid arthritis (RA) and T-LGL leukemia. Staining for CD57 demonstrates intrasinusoidal linear arrays and interstitial clusters of T cells (EnVision stain, ×100). (b) Granzyme B highlights cytotoxic granules in these cells (EnVision stain, ×200). (c) Patient 10 with polyclonal T-LGL lymphocytosis. Staining for CD8 shows dispersed T cells (EnVision stain, ×200). (d) Patient 9 with unclassified arthritis, T-LGL leukemia, and IGKV and IGLV gene rearrangements. CD3 staining shows interstitial and nodular infiltration of T cells (EnVision stain, ×100). (e) Patient 9. The lymphoid nodule contains few CD20+ B cells (EnVision stain, ×200). (f) Patient 7 with RA and T-LGL leukemia. A decreased count of granulocytic precursors (myeloperoxydase+) is shown (EnVision stain, ×200). IGKV, immunoglobulin kappa variable; IGLV, immunoglobulin lambda variable
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Figure 1: Histopathological features of bone marrow in patients with arthritis and T-cell large granular lymphocyte (T-LGL) lymphocytosis. (a) Patient 1 with rheumatoid arthritis (RA) and T-LGL leukemia. Staining for CD57 demonstrates intrasinusoidal linear arrays and interstitial clusters of T cells (EnVision stain, ×100). (b) Granzyme B highlights cytotoxic granules in these cells (EnVision stain, ×200). (c) Patient 10 with polyclonal T-LGL lymphocytosis. Staining for CD8 shows dispersed T cells (EnVision stain, ×200). (d) Patient 9 with unclassified arthritis, T-LGL leukemia, and IGKV and IGLV gene rearrangements. CD3 staining shows interstitial and nodular infiltration of T cells (EnVision stain, ×100). (e) Patient 9. The lymphoid nodule contains few CD20+ B cells (EnVision stain, ×200). (f) Patient 7 with RA and T-LGL leukemia. A decreased count of granulocytic precursors (myeloperoxydase+) is shown (EnVision stain, ×200). IGKV, immunoglobulin kappa variable; IGLV, immunoglobulin lambda variable

Mentions: Morphological and immunohistochemical bone marrow characteristics are summarized in Table 3. The bone marrow was hypercellular in 11 patients, normocellular in 5 patients, and hypocellular in 5 patients. Sections stained with monoclonal antibodies revealed interstitial infiltrates of small lymphocytes with slightly irregular nuclei and scanty cytoplasm, which formed small clusters and aggregates in all patients with TCR gene rearrangements. Moreover, in 14 of them, the infiltrates also had a clear intrasinusoidal linear component (Figure 1a). These infiltrations were subtle and difficult to notice on standard hematoxylin and eosin stain. T cells were CD3+, CD8+, granzyme B+, and CD4- in 16 patients (Figure 1b). Three patients had different phenotypes of T cells: CD3+/CD4-/CD8-, CD3+/CD4+/CD8-, and CD3+/CD4+/CD8+. CD57 staining gave variable results and was positive in 12 patients, positive in only some T cells in 5 patients, and negative in 2 patients. In two cases (patients 10 and 11) with polyclonal T-LGL lymphocytosis, CD3+CD8+CD57+/-/granzyme B+/- lymphocytes were dispersed in the bone marrow and did not form clusters or intravascular infiltrations (Figure 1c). Reactive intertrabecular lymphoid nodules were detected in 14 of 21 examined patients (Figure 1d). B cells in the center of these nodules expressed CD20 and, in 2 cases, formed germinal centers (Figure 1e). They were surrounded by small CD3+ T lymphocytes expressing predominantly CD4+ and only a few CD8+ cells. Myeloperoxydase stain showed decreased granulocyte precursors with left-shifted maturation in 12 patients, normal in 7 patients, and increased in 2 patients (Figure 1f). Red cell precursors revealed normal maturation. In most cases, the megakaryocyte count and their morphology were normal.


Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy.

Prochorec-Sobieszek M, Rymkiewicz G, Makuch-Łasica H, Majewski M, Michalak K, Rupiński R, Warzocha K, Maryniak R - Arthritis Res. Ther. (2008)

Histopathological features of bone marrow in patients with arthritis and T-cell large granular lymphocyte (T-LGL) lymphocytosis. (a) Patient 1 with rheumatoid arthritis (RA) and T-LGL leukemia. Staining for CD57 demonstrates intrasinusoidal linear arrays and interstitial clusters of T cells (EnVision stain, ×100). (b) Granzyme B highlights cytotoxic granules in these cells (EnVision stain, ×200). (c) Patient 10 with polyclonal T-LGL lymphocytosis. Staining for CD8 shows dispersed T cells (EnVision stain, ×200). (d) Patient 9 with unclassified arthritis, T-LGL leukemia, and IGKV and IGLV gene rearrangements. CD3 staining shows interstitial and nodular infiltration of T cells (EnVision stain, ×100). (e) Patient 9. The lymphoid nodule contains few CD20+ B cells (EnVision stain, ×200). (f) Patient 7 with RA and T-LGL leukemia. A decreased count of granulocytic precursors (myeloperoxydase+) is shown (EnVision stain, ×200). IGKV, immunoglobulin kappa variable; IGLV, immunoglobulin lambda variable
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483444&req=5

Figure 1: Histopathological features of bone marrow in patients with arthritis and T-cell large granular lymphocyte (T-LGL) lymphocytosis. (a) Patient 1 with rheumatoid arthritis (RA) and T-LGL leukemia. Staining for CD57 demonstrates intrasinusoidal linear arrays and interstitial clusters of T cells (EnVision stain, ×100). (b) Granzyme B highlights cytotoxic granules in these cells (EnVision stain, ×200). (c) Patient 10 with polyclonal T-LGL lymphocytosis. Staining for CD8 shows dispersed T cells (EnVision stain, ×200). (d) Patient 9 with unclassified arthritis, T-LGL leukemia, and IGKV and IGLV gene rearrangements. CD3 staining shows interstitial and nodular infiltration of T cells (EnVision stain, ×100). (e) Patient 9. The lymphoid nodule contains few CD20+ B cells (EnVision stain, ×200). (f) Patient 7 with RA and T-LGL leukemia. A decreased count of granulocytic precursors (myeloperoxydase+) is shown (EnVision stain, ×200). IGKV, immunoglobulin kappa variable; IGLV, immunoglobulin lambda variable
Mentions: Morphological and immunohistochemical bone marrow characteristics are summarized in Table 3. The bone marrow was hypercellular in 11 patients, normocellular in 5 patients, and hypocellular in 5 patients. Sections stained with monoclonal antibodies revealed interstitial infiltrates of small lymphocytes with slightly irregular nuclei and scanty cytoplasm, which formed small clusters and aggregates in all patients with TCR gene rearrangements. Moreover, in 14 of them, the infiltrates also had a clear intrasinusoidal linear component (Figure 1a). These infiltrations were subtle and difficult to notice on standard hematoxylin and eosin stain. T cells were CD3+, CD8+, granzyme B+, and CD4- in 16 patients (Figure 1b). Three patients had different phenotypes of T cells: CD3+/CD4-/CD8-, CD3+/CD4+/CD8-, and CD3+/CD4+/CD8+. CD57 staining gave variable results and was positive in 12 patients, positive in only some T cells in 5 patients, and negative in 2 patients. In two cases (patients 10 and 11) with polyclonal T-LGL lymphocytosis, CD3+CD8+CD57+/-/granzyme B+/- lymphocytes were dispersed in the bone marrow and did not form clusters or intravascular infiltrations (Figure 1c). Reactive intertrabecular lymphoid nodules were detected in 14 of 21 examined patients (Figure 1d). B cells in the center of these nodules expressed CD20 and, in 2 cases, formed germinal centers (Figure 1e). They were surrounded by small CD3+ T lymphocytes expressing predominantly CD4+ and only a few CD8+ cells. Myeloperoxydase stain showed decreased granulocyte precursors with left-shifted maturation in 12 patients, normal in 7 patients, and increased in 2 patients (Figure 1f). Red cell precursors revealed normal maturation. In most cases, the megakaryocyte count and their morphology were normal.

Bottom Line: Bone marrow trephines from T-LGL leukemia patients showed interstitial clusters and intrasinusoidal linear infiltrations of CD3+/CD8+/CD57+/granzyme B+ lymphocytes, reactive lymphoid nodules, and decreased or normal granulocyte precursor count with left-shifted maturation.RA and neutropenia patients represented a continuous spectrum of T-LGL proliferations, although monoclonal expansions were most frequently observed.The histopathological pattern and immunophenotype of bone marrow infiltration as well as molecular characteristics were similar in T-LGL leukemia patients with and without arthritis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathomorphology, Institute of Hematology and Transfusion Medicine, I, Gandhi 14, 02-776 Warsaw, Poland. monika.prochorec@interia.pl

ABSTRACT

Introduction: The purpose of this study was to analyze the data of patients with T-cell large granular lymphocyte (T-LGL) lymphocytosis associated with inflammatory arthropathy or with no arthritis symptoms.

Methods: Clinical, serological as well as histopathological, immunohistochemical, and flow cytometric evaluations of blood/bone marrow of 21 patients with T-LGL lymphocytosis were performed. The bone marrow samples were also investigated for T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangements by polymerase chain reaction with heteroduplex analysis.

Results: Neutropenia was observed in 21 patients, splenomegaly in 10, autoimmune diseases such as rheumatoid arthritis (RA) in 9, unclassified arthritis resembling RA in 2, and autoimmune thyroiditis in 5 patients. T-LGL leukemia was recognized in 19 cases. Features of Felty syndrome were observed in all RA patients, representing a spectrum of T-LGL proliferations from reactive polyclonal through transitional between reactive and monoclonal to T-LGL leukemia. Bone marrow trephines from T-LGL leukemia patients showed interstitial clusters and intrasinusoidal linear infiltrations of CD3+/CD8+/CD57+/granzyme B+ lymphocytes, reactive lymphoid nodules, and decreased or normal granulocyte precursor count with left-shifted maturation. In three-color flow cytometry (FCM), T-LGL leukemia cells demonstrated CD2, CD3, and CD8 expression as well as a combination of CD16, CD56, or CD57. Abnormalities of other T-cell antigen expressions (especially CD5, CD7, and CD43) were also detected. In patients with polyclonal T-LGL lymphocytosis, T cells were dispersed in the bone marrow and the expression of pan-T-cell antigens in FCM was normal. Molecular studies revealed TCRB and TCRG gene rearrangements in 13 patients and TCRB, TCRG, and TCRD in 4 patients. The most frequently rearranged regions of variable genes were Vbeta-Jbeta1, Jbeta2 and Vgamma If Vgamma10-Jgamma. Moreover, in 4 patients, additional rearrangements of IG kappa and lambda variable genes of B cells were also observed.

Conclusion: RA and neutropenia patients represented a continuous spectrum of T-LGL proliferations, although monoclonal expansions were most frequently observed. The histopathological pattern and immunophenotype of bone marrow infiltration as well as molecular characteristics were similar in T-LGL leukemia patients with and without arthritis.

Show MeSH
Related in: MedlinePlus