T-cell Large Granular Lymphocytic Leukemia



T-cell Large Granular Lymphocytic Leukemia


Kaaren K. Reichard, MD





Key Facts


Clinical Issues



  • Asymptomatic


  • Symptomatic: Recurrent infections (neutropenia)


  • Rheumatoid arthritis/other autoimmune diseases


  • Splenomegaly


  • Pure red cell aplasia


Microscopic Pathology



  • Peripheral blood



    • LGL lymphocytosis


    • LGLs generally > 2 × 109/L


  • Bone marrow (BM)



    • Extent of involvement is variable


    • Interstitial/intrasinusoidal patterns common


    • May be morphologically occult


    • Immunostains helpful to identify T-LGL infiltrate


Ancillary Tests



  • Immunophenotype



    • CD3(+), CD8(+), CD57(+), CD94(+), TCR-α/β(+)


    • Cytoplasmic granules TIA-1, perforin, GZMM(+)


    • Uniform expression of TCR-Vβ or KIR molecules


  • Molecular



    • T-cell receptor genes rearranged


Top Differential Diagnoses



  • Reactive/persistent LGL lymphocytosis


  • Chronic natural killer (NK) cell leukemia/lymphocytosis



    • Immunophenotype: CD2(+), CD3(-), CD16(+), CD56(+)


  • Aggressive NK cell leukemia



    • Epstein-Barr virus associated






Classic appearance of a large granular lymphocyte (LGL) is shown. LGLs constitute up to 15% of circulating white blood cells normally. Immunophenotyping shows that most are cytotoxic T cells.






CD3 immunostaining shows a marked increase in mature T cells in a case of T-LGL leukemia. The pattern of involvement is typically interstitial/intrasinusoidal and often morphologically occult.


TERMINOLOGY


Abbreviations



  • T-cell large granular lymphocytic leukemia (T-LGL leukemia)


Definitions



  • Persistent clonal proliferation of T-cell large granular lymphocytes (T-LGLs)


ETIOLOGY/PATHOGENESIS


Hypotheses



  • Chronic antigenic stimulation resulting in proliferation of T-cell large granular lymphocytes (T-LGLs)



    • Exogenous antigens such as HTLV


    • Endogenous autoantigens


  • Inhibition of apoptosis resulting in accumulation of T-LGLs



    • Dysregulation of FAS/FAS-L


Infectious Agents



  • Role of retroviral infection unclear


  • Most patients do not show evidence of HTLV-I or HTLV-II infection


  • Reactivity against small peptide derived from an HTLV-I envelope protein has been reported


Etiology of Neutropenia



  • FAS/FAS-L-induced premature apoptosis of granulocytic precursors


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Comprises 2-3% of chronic lymphocytic leukemias


  • Age



    • Median age: 60 years


    • Predominantly affects adults


  • Gender



    • No gender predilection


Site



  • Peripheral blood (PB)


  • Bone marrow (BM)


  • Spleen


  • Liver


Presentation



  • Asymptomatic



    • Incidental discovery of T-LGL lymphocytosis


  • Asymptomatic



    • Cytopenias



      • No clinically appreciated effects


    • Rheumatoid arthritis or autoimmune disorder (25-35% of patients)


    • Splenomegaly (20-50% of patients)


  • Symptomatic



    • Development of cytopenias



      • Neutropenia


      • Thrombocytopenia


      • Anemia: May be due to red cell aplasia


    • Development of recurrent infections



      • Often bacterial


      • Mucocutaneous


    • Splenomegaly


    • Systemic symptoms


  • LGL lymphocytosis: LGLs generally > 2 × 109/L


Laboratory Tests



  • Clinical examination


  • Complete blood cell count with differential


  • PB examination


  • BM examination if needed


  • Flow cytometry of PB &/or BM


  • T-cell receptor clonality studies



Natural History



  • Clinically heterogeneous


  • Some spontaneous regressions


  • Association with immune disorders


  • High proportion of patients will require treatment at some point


Treatment



  • Asymptomatic



    • Careful observation


  • Symptomatic



    • Methotrexate or cyclophosphamide or cyclosporine A



      • Treatment should be continued for at least 4 months to assess response


    • Corticosteroids



      • As monotherapy, not very effective long-term


      • Rapid improvements in symptoms/cytopenias if used in conjunction with methotrexate, cyclophosphamide, cyclosporine A


    • Prophylactic use of antibiotics if severe neutropenia


    • Hematopoietic growth factors



      • GM-CSF or G-CSF for neutropenia


      • Erythropoietin (EPO) for anemia


    • Clinical trial



      • As available


    • Progressive disease



      • Nucleoside analogues


      • Alemtuzumab: Anti-CD25 monoclonal antibody


      • Hematopoietic stem cell transplantation


Prognosis



  • Generally indolent


  • Related to control of cytopenias and associated symptoms


MICROSCOPIC PATHOLOGY


Peripheral Blood



  • LGL lymphocytosis



    • LGLs generally > 2 × 109/L


    • Occasional cases LGLs < 2 × 109/L


  • Circulating T-LGLs



    • Intermediate size


    • Round/slightly indented nucleus


    • Inconspicuous nucleoli


    • Abundant pale cytoplasm


    • Cytoplasmic azurophilic granules


  • Variable degrees/types of cytopenias


  • Generally unremarkable red blood cell, platelet, and myeloid morphology

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on T-cell Large Granular Lymphocytic Leukemia

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