Large granular lymphocytic leukemia

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Large granular lymphocytic leukemia
SpecialtyHematology, oncology

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.[1]

It is divided in two main categories: T-cell LGL leukemia (T-LGLL) and natural-killer (NK)-cell LGL leukemia (NK-LGLL). As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).[2]

In a study based in the US, the average age of diagnosis was 66.5 years[3] whereas in a French study the median age at diagnosis was 59 years (with an age range of 12–87 years old).[4] In the French study, only 26% of patients were younger than 50 years which suggests that this disorder is associated with older age at diagnosis.[4] Due to lack of presenting symptoms, the disorder is likely to be underdiagnosed in the general population.[5]

Signs and symptoms

Painful ulcer on the right ventral tongue with irregular margins[6]

This disease is known for an indolent clinical course and incidental discovery.[1] The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to anaemia and/or neutropenia[7] are seen in almost half of cases.[8][9][10][11]

Rheumatoid arthritis is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome.[12] Signs and symptoms of anemia are commonly found, due to the association between T-LGLL and erythroid hypoplasia.[13]

Sites of involvement

The leukemic cells of T-LGLL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.[1][8]


The postulated cells of origin of T-LGLL leukemia are transformed CD8+ T-cell with clonal rearrangements of β chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of γ chain T-cell receptor genes for a minority of cases.[1]


Laboratory findings

The requisite lymphocytosis of this disease is typically 2-20x109/L.[13]

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.[11][14][15][16]

Peripheral blood

The neoplastic lymphocytes seen in this disease are large in size with azurophilic granules that contains proteins involved in cell lysis such as perforin and granzyme B.[17] Flow cytometry is also commonly used.[18]

Bone marrow

Bone marrow involvement in this disease is often present, but to a variable extent. Bone marrow biopsy is commonly used for diagnosis. The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs.[1]


The neoplastic cells of this disease display a mature T-cell immunophenotype, with the majority of cases showing a CD4-/CD8+ T-cell subset immunophenotype versus other permutations of those markers.[9][10] Variable expression of CD11b, CD56, and CD57[11] are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.[1]

Type Immunophenotype
Common type (80% of cases) CD3+, TCRαβ+, CD4-, CD8+
Rare variants CD3+, TCRαβ+, CD4+, CD8-
CD3+, TCRαβ+, CD4+, CD8+
CD3+, TCRγδ+, CD4 and CD8 variable

Genetic findings

Clonal rearrangements of the T-cell receptor (TCR) genes are a necessary condition for the diagnosis of this disease. The gene for the β chain of the TCR is found to be rearranged more often than the γ chain. of the TCR.[15][19]

Current evidence suggests that patients with STAT3 mutations are more likely to respond to methotrexate therapy.[20]


First line treatment is immunosuppressive therapy. A weekly dosage of Methotrexate (with or without daily Prednisone) may induce partial or complete response in some patients while others may require Cyclosporine or Cyclophosphamide.[7]

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.[21]

Experimental data suggests that treatment with calcitrol (the active form of vitamin D) may be useful in treating T-cell LGL due to its ability to decrease pro-inflammatory cytokines.[22]


The 5 year survival has been noted as 89% in at least one study from France of 201 patients with T-LGL leukemia.[4]


T-LGLL is a rare form of leukemia, comprising 2-3% of all cases of chronic lymphoproliferative disorders.[citation needed]


LGLL was discovered in 1985 by Thomas P. Loughran Jr. while working at Fred Hutchinson Cancer Research Center.[23] Specimens from patients with LGLL are banked at the University of Virginia for research purposes, the only bank for such purposes.[24]


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External links