Large granular lymphocytic leukemia

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-LGL)L. As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).^[2]

It is also known by the following terms: proliferation of large granular lymphocytes (LGLs), LGL leukemia, Tγ-lymphoproliferative disorder, and, in common with other T cell leukemias such as T-cell prolymphocytic leukemia, T-cell chronic lymphocytic leukemia.^[1]

Signs and symptoms

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 the associated neutropenia are seen in almost half of cases.^[3][4][5][6]

Rheumatoid arthritis is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome.^[7] Signs and symptoms of anemia are commonly found, due to the association between T-LGLL and erythroid hypoplasia.^[8]

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][3]

Cause

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]

Diagnosis

Laboratory findings

The requisite lymphocytosis of this disease is typically 2-20x10⁹/L.^[8]

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.^{[6][9][10][11]}

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.^[12]

Bone marrow

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

Immunophenotype

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.^[4][5] Variable expression of CD11b, CD56, and CD57^[6] are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.^[1]

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.^[10][13]

Treatment

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.^[14]

Prognosis

The 5 year survival has been noted as 89% in at least one study from France of 201 patients with T-LGL leukemia.^[15]

Epidemiology

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

History

LGLL was discovered in 1985 by Thomas P. Loughran Jr. while working at Fred Hutchinson Cancer Research Center.^[16] Specimens from patients with LGLL are banked at the University of Virginia for research purposes, the only bank for such purposes.^[17]

References