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Lymphoma - Non B cell neoplasms

T/NK cell disorders

T-cell large granular lymphocytic leukemia


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 31 October 2011, last major update September 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● T-cell large granular lymphocytic leukemia (T-LGL) is a heterogeneous disorder characterized by a persistent (>6 months) increase in the number of peripheral blood large granular lymphocytes (LGL), usually 2-20 x 109/L, without a clearly identified cause (WHO 2008, Blood 1997;89:256)

Epidemiology
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● Uncommon; 2-3% of mature lymphocytic leukemias
● M:F ratio 1:1
● No clearly defined age peak, majority between 45-75 years (73%)

Etiology
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● Possibly due to sustained immune stimulation
● Frequently associated with autoimmune disorders
● Absence of homeostatic apoptosis (high levels of FAS/FASL) suggests activation of pro-survival pathways
● Rarely occurs as a form of post-transplant lymphoproliferative disorders
● Clonal populations of T-LGL also seen in association with low grade B cell malignancies (HCL, CLL), but no progression to clinical disease

Sites
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● Peripheral blood, bone marrow, liver, spleen
● Lymph node involvement – very rare

Clinical features
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● Modest lymphocytosis (usually between 2-20 x 109/L) and often severe neutropenia with or without anemia; splenomegaly in 50%
● May have rheumatoid factor, rheumatoid arthritis, autoantibodies, circulating immune complexes and hypergammaglobulinemia
● Severe anemia due to red cell aplasia may occur
● CD4+ cases are often associated with an underlying malignancy (30%)

Case reports
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● 39 year old man with tumor of donor origin after bone marrow transplant (Am J Clin Pathol 2003;120:626)
● 69 year old man with dim CD20 expression in tumor cells (Int J Clin Exp Pathol 2010;3:798)
● Patients with pure red cell aplasia (Haematologica 1998;83:664)
● Concurrent with CMML (Cytometry B Clin Cytom 2010;Dec 2)
● Associated with Sjögren syndrome (Acta Haematol 2010;124:5 )
● Associated with MDS (Am J Clin Pathol 2009;131:347)

Treatment and prognosis
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● Indolent course in most cases, median survival 13 years in study with 68 patients
● Morbidity and mortality mostly due to cytopenias, especially neutropenia, and other accompanying diseases
● If treatment is necessary: cyclosporine A, cyclophosphamide, corticosteroids, methotrexate, pentostatin

Postulated normal counterpart
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● CD8-positive T-cell subset for the common type
● Subset of T lymphocytes for the rare TCRγδ-positive type

Micro description
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Peripheral blood: medium/large lymphocytes with abundant cytoplasm containing coarse azurophilic granules
Bone marrow: variable cellularity, myeloid series shifted to immaturity, mild to moderate reticulin fibrosis, interstitial/intrasinusoidal involvement highlighted by CD8; non-neoplastic nodular aggregates of B cells surrounded by a rim of CD4+ T-cells
Spleen: red pulp infiltration/expansion and hyperplastic white pulp

Micro images
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Peripheral blood


Bone marrow-CD8


Bone marrow-Granzyme B


Non-neoplastic nodule


Spleen

Cytochemistry
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● Granules positive for acid phosphatase and β glucuronidase

Positive stains
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● CD3, CD8, TCRαβ, CD16 & CD57 (80%), CD94 and KIR isoforms (>50%), TIA1, granzyme B, granzyme M
● Uncommon: CD4+ TCRαβ-positive cases; TCRγδ-positive cases (60% CD8+, 40% CD4-/CD8-)

Negative stains
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● CD4, loss of CD5 and CD7

Flow cytometry images
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Various images

EM description
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● Parallel tubular arrays

Genetics and molecular
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● T-cell receptor gene rearrangement
● No consistent karyotypic abnormalities

Differential diagnosis
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Reactive hyperplasia: no T cell receptor gene rearrangement

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > T-cell large granular lymphocytic leukemia


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