Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...

(LGLs) in the peripheral

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

. 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 cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

s). In a study based in the US, the average age of diagnosis was 66.5 years whereas in a French study the median age at diagnosis was 59 years (with an age range of 12–87 years old). 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. Due to lack of presenting symptoms, the disorder is likely to be underdiagnosed in the general population.

Signs and symptoms

This disease is known for an indolent clinical course and incidental discovery. The most common physical finding is moderate

splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulat ...

B symptoms B symptoms are a set of symptoms, namely fever, night sweats, and unintentional weight loss, that can be associated with both Hodgkin lymphoma and non-Hodgkin lymphoma. These symptoms are not specific to lymphomas, especially each one considered ...

are seen in a third of cases, and recurrent

infections An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

due to

anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...

and/or

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

are seen in almost half of cases.

Rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome. Signs and symptoms of

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

are commonly found, due to the association between T-LGLL and erythroid

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.

Sites of involvement

The leukemic cells of T-LGLL can be found in peripheral

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

, and

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. Nodal involvement is rare.

Cause

The postulated cells of origin of T-LGLL leukemia are transformed CD8+

T-cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

with clonal rearrangements of β chain

T-cell receptor The T-cell receptor (TCR) is a protein complex, located on the surface of T cells (also called T lymphocytes). They are responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. ...

genes for the majority of cases and a CD8-

with clonal rearrangements of γ chain

genes for a minority of cases.

Diagnosis

Laboratory findings

The requisite lymphocytosis of this disease is typically 2-20 billion/L. Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.

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 Perforin-1 Perforin (PRF), encoded by the PRF1 gene, is a pore-forming toxic protein housed in the secretory granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Together, these cells are known as cytotoxic lymphocytes (CLs). ...

and

granzyme B Granzyme B (GrB) is one of the serine protease granzymes most commonly found in the granules of natural killer cells (NK cells) and cytotoxic T cells. It is secreted by these cells along with the pore forming protein perforin to mediate apoptos ...

Flow cytometry Flow cytometry (FC) is a technique used to detect and measure the physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the ...

is also commonly used.

Bone marrow

Bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

involvement in this disease is often present, but to a variable extent.

Bone marrow biopsy Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of condit ...

is commonly used for diagnosis. The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs.

Immunophenotype

The neoplastic cells of this disease display a mature

immunophenotype Immunophenotyping is a technique used to study the protein expressed by cells. This technique is commonly used in basic science research and laboratory diagnostic purpose. This can be done on tissue section (fresh or fixed tissue), cell suspensio ...

, with the majority of cases showing a

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...

CD8 CD8 (cluster of differentiation 8) is a transmembrane protein, transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell Cell signaling, signaling and aid ...

+ T-cell subset

versus other permutations of those markers. Variable expression of CD11b,

CD56 Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discover ...

, and

CD57 3-beta-glucuronosyltransferase 1 (B3GAT1) is an enzyme that in humans is encoded by the ''B3GAT1'' gene, whose enzymatic activity creates the CD57 epitope on other cell surface proteins. In immunology, the CD57 antigen (CD stands for cluster of d ...

are observed. Immunohistochemistry for

TIA-1 TIA1 or Tia1 cytotoxic granule-associated rna binding protein is a 3'UTR mRNA binding protein that can bind the 5'TOP sequence of 5'TOP mRNAs. It is associated with programmed cell death (apoptosis) and regulates alternative splicing of the gene ...

, and

are usually positive.

Genetic findings

Clonal rearrangements of the

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

Treatment

First line treatment is immunosuppressive therapy. A weekly dosage of

Methotrexate Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...

(with or without daily

Prednisone Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium ...

) may induce partial or complete response in some patients while others may require

Cyclosporine Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, ecz ...

Cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...

. Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia. Experimental data suggests that treatment with calcitrol (the active form of

vitamin D Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...

) may be useful in treating T-cell LGL due to its ability to decrease pro-inflammatory cytokines.

Prognosis

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

Epidemiology

T-LGLL is a rare form of

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

, 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 The Fred Hutchinson Cancer Center, formerly known as the Fred Hutchinson Cancer Research Center and also known as Fred Hutch or The Hutch, is a cancer research institute established in 1975 in Seattle, Washington (state), Washington. History ...

. Specimens from patients with LGLL are banked at the

University of Virginia The University of Virginia (UVA) is a Public university#United States, public research university in Charlottesville, Virginia, United States. It was founded in 1819 by Thomas Jefferson and contains his The Lawn, Academical Village, a World H ...

for research purposes, the only bank for such purposes.

References

External links

{{Hematological malignancy histology Lymphocytic leukemia