Large granular lymphocyte (LGL) comprises about 10-15% of normal peripheral blood mononuclear cells. Morphologically they are bigger than a normal lymphocyte and have azurophilic granules in their cytoplasm. LGL can be further divided into CD3- and CD3+ cells depending on their cell lineage. The LGL identified in the peripheral blood of normal individuals are usually CD3 -, lack CD3/TCR complex and mediate MHC-restricted killing. The CD3+ LGL express CD3/TCR complex and represent activated cytotoxic T cells (2). Therefore clonal proliferation of LGL can either arise from NK or T cell lineage (3). These lympho proliferative disorders range from reactive process to indolent and aggressive neoplasm.
T-cell large granular lymphocyte leukemia (T-LGL) is a heterogeneous disorder that is characterized by lymphocytosis of large granular cells in the peripheral blood usually between 2 - 20x109/L, is persistent for more than 6 months and has no identifiable cause (1). The hallmark of T-LGL is the expansion of a discrete or clonal population of cytolytic lymphocytes in the peripheral blood. They represent 2 - 3% of all cases of small lymphocytic leukemia. They usually involve the peripheral blood, bone marrow, liver, and spleen.
The problem of identifying T-LGL from a benign granular lymphocytic process is difficult based just on the morphology of the lymphocytes, since they do not have any distinguishing features. This is especially true with hematoxylin and eosin stained bone marrow biopsy specimens where the granular lymphocytes often do not have any distinctive cytologic features (4). Immunohistochemistry of bone marrow biopsy therefore helps in highlighting interstitial clusters of LGL cells. The important antibodies that help in identifying these cells include CD 57, CD 3, TIA-1 and granzyme B (7). However the presence of a population of T - large granular lymphocyte is not synonymous with T-cell malignancy, since minor T-cell clones can be found in oligoclonal immune reactions, especially in the elderly and immunosuppressed individuals Therefore other criteria such as an increase in blood LGL population, demonstration of T-cell clonality, and demonstration of a distinct peripheral blood T-cell population by flow cytometry are needed (5).
The median age of onset of T-LGL is about 55 years. Clinically they can present with various hematologic abnormalities that include chronic neutropenia, anemia, cyclic neutropenia, pure red cell aplasia, autoimmune hemolytic anemia, ITP, aplastic anemia, and MDS (6). One of the prominent features of T-LGL is its association with autoimmune diseases especially rheumatoid arthritis and Felty's syndrome. Many of the cases have serologic abnormalities, which include positive rheumatoid factor, ANA, high levels of circulating immune complexes, polyclonal hypergammaglobulinemia, and high levels of b2-microglobulin (6).
The above case highlights some of the distinctive characteristics and difficulties associated with T-LGL. Our patient had a history of rheumatoid arthritis, which has a strong association with T-LGL. Although morphologically it was difficult to make a diagnosis, immunohistochemistry on the bone marrow biopsy, flow cytometry, and molecular studies helped in identifying the clonal population present. In our case the cytogenetics results were also interesting because an unbalanced translocation was noted between chromosomes 14 and 15. This resulted in a trisomy 14q and a possible involvement of 14q11, which is the region where the Ta/Td are mapped. The rearrangement of these genes is frequently associated with T-cell leukemia/lymphoma (8). It also highlights the fact that it is important to examine the peripheral blood smear where it is frequently possible to pick up the large granular cells and a diagnosis of a large granular lymphocyte leukemia can be considered, which might otherwise be overlooked in a bone marrow biopsy specimen.
Contributed by Leena Lourduraj, MD and Lydia C Contis, MD