What are the other Names for this Condition? (Also known as/Synonyms)

• LGL Leukemia
• LGLL (Large Granular Lymphocyte Leukemia)

What is Large Granular Lymphocyte Leukemia? (Definition/Background information)

• Large Granular Lymphocyte Leukemia (LGLL) represents a type of lymphoproliferative disorder. Lymphoproliferative disorders are disorders in which there is uncontrolled production of (excess) lymphocytes that occurs due to several reasons. LGLL could be either T-cell type or NK-cell (natural killer cell) type
• There are 4 main subtypes of Large Granular Lymphocyte Leukemia, which include:
  • Indolent T-Cell Large Granular Lymphocyte Leukemia: It is the most common form of LGL Leukemia
  • Aggressive Variant of T-Cell Large Granular Lymphocyte Leukemia
  • Aggressive Natural Killer Cell Leukemia
  • Chronic Lymphoproliferative Disorder of Natural Killer Cells
• It is important to subclassify Large Granular Lymphocyte Leukemia, since the treatment and prognosis can be significantly different among the various subtypes
• The cause of Large Granular Lymphocyte Leukemia is generally not known, although some research scientists believe that it is due to abnormal autoimmune responses, or initiated by certain viral infections
• Even though the symptoms depend on the specific subtype of Large Granular Lymphocyte Leukemia, commonly, fever, weight loss, appetite loss, reduced blood cell counts with a variety of symptoms, and swollen spleen and/or liver, are observed
• In most cases, the diagnosis involves symptom assessment, various blood tests, imaging scans, and biopsy studies. Flow cytometric analysis on peripheral blood and/or bone marrow specimen, along-with PCR tests may also aid in the diagnosis of Large Granular Lymphocyte Leukemia
• Large Granular Lymphocyte Leukemia is typically treated using chemotherapy, blood transfusions, steroid therapy, and other supportive measures. In severe cases, stem cell and bone marrow transplantations may be undertaken
• The prognosis depends mainly on the subtype of Large Granular Lymphocyte Leukemia. The prognosis of both the aggressive forms is poor despite treatment, since these are highly-malignant cancers and refractory to treatment. However, with adequate treatment, the prognosis of the indolent T-cell type and chronic lymphoproliferative disorder of NK-cell is good

General information on lymphocytes:

• Lymphocytes are the main white blood cells found in the lymph, which is the fluid of the lymphatic system; just as blood is the fluid of the circulatory system. Lymphocytes are made in bone marrow, and can develop into either B-cells or T-cells
• Large granular lymphocytes (LGLs) are present in peripheral blood in normal adults. The LGLs usually constitute 10-15% of the mononuclear cells in peripheral blood and they fight infections
• Lymph results from filtration of blood as it travels to and from tissues. Lymph is colorless because it lacks red blood cells; instead, it contains lymphocytes. It is central to the immune system
• There are 3 different kinds of lymphocytes:
  • T-lymphocytes or T cells: They help combat infections and abnormalities within the cells (cell-mediated immunity). They fight viruses and cancerous cells
  • B-lymphocytes or B cells: They produce antibodies that are bodily defense proteins, which target foreign invaders outside the cells (humoral immunity). They fight bacterial cells, cell fragments, and other immunogenic elements
  • Natural killer cells or NK cells: They perform diverse functions related to both cell-mediated and humoral immunity. They also scout for cancer cells, a process called immune surveillance
• Large Granular Lymphocyte Leukemias can be of the T-cell type or NK-cell type

Who gets Large Granular Lymphocyte Leukemia? (Age and Sex Distribution)

• Large Granular Lymphocyte Leukemias are relatively rare conditions; they constitute only between 2-5% of all T-cell or NK-cell leukemias
• The condition is generally seen in adults - young, middle-age, and older adults may be affected
• Both males and females are affected; although, a male predominance is seen with some subtypes of LGL Leukemias
• It can occur worldwide and all racial and ethnic groups may be affected

What are the Risk Factors for Large Granular Lymphocyte Leukemia? (Predisposing Factors)

No specific risk factors have been identified for Large Granular Lymphocyte Leukemia. However, some of the subtypes may be associated with the following conditions:

Indolent T-cell LGL Leukemia:

• Sjogren’s syndrome
• Systemic lupus erythematosus (SLE)
• Hashimoto’s thyroiditis

Aggressive NK-cell leukemia: 

• Epstein-Barr virus (EBV) infection
• Individuals of Asian origin may have a higher risk for the condition

Chronic lymphoproliferative disorder of NK-cells: 

• Autoimmune disorders
• Viral infections
• Inflammation of blood vessels (vasculitis)
• Underlying lymphomas or cancers in other parts of the body

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Large Granular Lymphocyte Leukemia? (Etiology)

The exact cause of Large Granular Lymphocyte Leukemia is unknown. Some researchers believe that it is due to an abnormal autoimmune response or one that is initiated by certain viral infections. Some believe that LGL leukemia is a persistent autoimmune disorder.

The following are noted with respect to the specific subtypes:

• Blood tests indicate positive results for the presence of human T-cell lymphotropic virus (HTLV) in the indolent T-cell type and chronic NK-cell type of LGL leukemia
• There is a strong association of aggressive NK-cell leukemia with Epstein-Barr virus (EBV) infection
• Less than 10% of the individuals with indolent T-cell LGL leukemia show chromosomal abnormalities
• TCR-β/γ (T-cell receptor-beta/gamma) gene rearrangement is noted in both the indolent type and aggressive variant of T-cell LGL leukemia
• TCR gene rearrangement in aggressive NK-cell leukemia and chronic lymphoproliferative disorder of NK-cells shows germline configuration

What are the Signs and Symptoms of Large Granular Lymphocyte Leukemia?

The signs and symptoms of Large Granular Lymphocyte Leukemia depend on the specific subtype of the condition. Also, up to 33% of individuals with the indolent T-cell type and nearly 60% of those with chronic lymphoproliferative disorder of NK-cells are asymptomatic.

The following common signs and symptoms of LGL Leukemia may be noted:

• ‘B’ symptoms that may include fever, night sweats, and weight loss
• Cytopenia (blood cell count reduction), which consists of the following:
  • Decreased red blood cells (anemia), causing fatigue, pale skin, and shortness of breath
  • Decreased white blood cells (leukopenia or leukocytopenia), causing an increased risk for infections
  • Decrease in platelet numbers (thrombocytopenia), resulting in easy bruising, prolonged bleeding, bleeding from the gums or nose, and presence of blood in stool
• Splenomegaly, or enlarged spleen
• Hepatomegaly, or enlarged liver
• Enlarged lymph nodes (lymphadenopathy) may be noted, with or without pain, in the aggressive T-cell variant and aggressive NK-cell type of LGL Leukemia
• Rheumatoid arthritis (RA), which can result in stiffening of joints, joint and muscular pain, and tiredness is seen with the indolent T-cell type of LGL Leukemia

In the aggressive forms of LGL Leukemias, involvement of other organs may be noted with the following signs and symptoms:

• There may be associated autoimmune disorders, which can cause joint and muscle pain, heat intolerance, recurrent rashes, abdominal pain, and a general feeling of illness
• If the brain is involved, then neurological symptoms such as the following may be observed:
  • Confusion
  • Tinnitus (ringing in the ears)
  • Hearing and visual impairment
• If the gastrointestinal (GI) tract is involved, then GI tract symptoms such as the following may be observed:
  • Ulcers
  • Diarrhea
  • Inflammation
  • GI bleeding
• Joint inflammation and fluid accumulation (edema) can occur, if the joints are affected

How is Large Granular Lymphocyte Leukemia Diagnosed?

Tests and procedures that could help in the diagnosis of Large Granular Lymphocyte Leukemia include:

• A thorough physical examination and a complete medical history
• Assessment of presenting symptoms
• Blood tests that may include:
  • Complete blood cell count (CBC)
  • Absolute large granular lymphocytes count on peripheral blood
  • Liver function blood test (LFT)
  • Blood culture, on a case-by-case basis, to rule-out any infections
  • Rheumatoid factor blood test
  • Antinuclear antibodies (ANA) test
  • Immunoglobulin studies
  • Anti-neutrophil antibodies blood tests
  • Southern blot techniques
• Molecular studies on peripheral blood and/or bone marrow specimen
• Polymerase chain reaction (PCR) test: It is used to measure the presence of certain biomarkers in blood or bone marrow cells. The test is ultrasensitive and detects extremely low amounts of biomarkers remaining in blood, which can be missed by cytogenetic methods, such as FISH, karyotype, or flow cytometry. PCR allows a more sensitive follow-up of patients in remission and can help determine whether additional treatment is necessary. Blood tests, such as PCR techniques and southern blot techniques, are used to determine TCR gene rearrangement clonality
• Flow cytometric analysis on peripheral blood and/or bone marrow specimen: Flow cytometry to identify cells as they flow through an instrument, called a flow cytometer. Flow cytometry measures the number and percentage of cells in a blood/bone marrow sample, and cell characteristics such as size, shape, and the presence of biomarkers on the cell surface. This method helps to sub-classify the condition and to detect residual levels of disease after treatment. This tool can help in diagnosing relapse and restart treatment as needed. Flow cytometric analysis can help provide information on different phenotypes of the tumor cells
• Radiological imaging may be performed that may include:
  • X-ray of the affected region
  • Ultrasound scan of the affected region
  • Computerized tomography (CT) scan of the abdomen or affected region
  • Vascular radiological studies
  • Whole body bone scan
  • Whole body CT-PET scans to determine if the cancer has spread to other organ systems
  • Brain MRIs are used if neurological symptoms are present, which can help determine if the cancer has spread to the brain, or to tissues that cover the brain
• Fluorescence in situ hybridization (FISH): It is a test performed on the blood or bone marrow cells to detect chromosome changes (cytogenetic analysis) in blood cancer cells. The test helps in identifying genetic abnormalities that may not be evident with an examination of cells under a microscope
• Immunophenotyping to identify a specific type of cell in a sample, which can help determine the best treatment course to be followed
• Bone marrow aspiration and biopsy is performed and sent to a laboratory for a pathological examination, to determine if the bone marrow is involved. Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, histochemical stains, molecular testing, and very rarely electron microscopic studies. However, a bone marrow biopsy is not needed in the early stages of the condition
• Lymph node biopsy, when enlarged lymph nodes are present, may be undertaken. The biopsies may be performed under general or local anesthesia. Normally, the entire lymph node is removed
• Lumbar puncture to determine if the brain is involved
• In addition, the cerebrospinal spinal fluid (CSF) may be collected by inserting a needle in the spine and subjected to microscopic, flow cytometric, PCR, and biochemical analysis, to diagnose central nervous system (CNS) involvement, if any
• Exploratory laparoscopy (diagnostic laparoscopy) may be required, if gastrointestinal symptoms are present. In this procedure, the abdomen is examined using a minimally-invasive technique, and a tissue biopsy and tissue for culture obtained. Minimally-invasive approaches help decrease complications and the length of stay at the hospital
• Differential diagnoses, to eliminate other conditions, such as Felty syndrome (that presents rheumatoid arthritis, neutropenia and splenomegaly), are often considered, before arriving at a definitive diagnosis

A definitive diagnosis of Large Granular Lymphocyte Leukemia is arrived at by a combination of blood tests, special molecular studies, and analysis of symptoms.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Large Granular Lymphocyte Leukemia?

The complications due to Large Granular Lymphocyte Leukemia depend on the specific subtype. The aggressive T-cell and NK-cell forms present more complications than the indolent T-cell and chronic NK-cell forms.

The following complications may be noted:

• Severe bleeding
• Severe anemia requiring blood transfusions
• Severe leucopenia leading to recurrent infections
• Loss of function of the organ (liver or spleen) that is involved
• Pure red cell aplasia (PRCA) observed in indolent T-cell and chronic NK-cell types
• Involvement of local and distant organs: The disorder can spread from the lymph nodes to other parts of the body, leading to a loss of function of the organ/area to which the cancer has spread
• Recurrence of the condition
• Severely decreased immunity can be a complication of the condition, which occurs even during its treatment. Due to this, individuals are more vulnerable to infections; there is an increased risk of developing serious complications from such infections
• If the condition spreads to the brain and central nervous system, it can give rise to:
  • Inflammation of the meninges or brain (that can be lethal)
  • Headache
  • Vision changes
  • Facial numbness
• If the abdomen is affected, it can cause intestinal obstruction that results in urine outflow obstruction and kidney damage

There may be complications related to chemotherapy used in treating the condition, which may include:

• Side effects such as dizziness, vomiting, appetite loss, mouth ulcers, and hair loss
• By damaging healthy cells, the individual is more open or vulnerable to secondary infections
• The treatment can also cause infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy

How is Large Granular Lymphocyte Leukemia Treated?

The healthcare provider may recommend a ‘wait and watch’ approach for asymptomatic indolent T-cell LGL Leukemia and chronic lymphoproliferative disorder of NK-cells, after a diagnosis is established. If the condition becomes aggressive, then symptomatic treatment may be provided. Apart from this, a treatment of the underlying disorder/malignancy is also undertaken.

In general, the treatment of Large Granular Lymphocyte Leukemia may involve the following measures:

• Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells
  • There can be severe side effects including fatigue, nausea, hair loss, anemia, high risk of infection, and drug-specific reactions
  • Lymphoproliferative disorders can be resistant to chemotherapy. It can also damage healthy cells
  • Chemotherapy can be administered as a pill, liquid, shot, or intravenously
• Targeted treatment with monoclonal antibody

Note: Men and women in child-bearing age would greatly benefit from counseling regarding fertility issues. Some chemotherapy agents can cause infertility in both men and women. There can be permanent damage to the testicles and ovaries, harming their ability to produce sperms or ova. In men, sperm banking can be considered before initiating therapy. In women, in many cases, due to urgency of starting chemotherapy, it is often difficult to perform ovum banking. However, if there is sufficient time prior to chemotherapy, ovum banking may be performed. The healthcare provider may help assess the risk-benefit analysis, depending upon each individual’s specific circumstances.

• Prednisone therapy - treatment with steroids on a case-by-case basis may be undertaken
• Administration of hematopoietic growth factors to treat decreased blood counts
• Blood transfusion
• Radiation: Radiation therapy is the use of high-energy radiation waves to kill cancer cells, by destroying their DNA
  • This treatment modality is generally used for early stage cancers. It is most commonly used in combination with chemotherapy
  • The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body
  • The side effects of radiation therapy include nausea, vomiting, fatigue, pain, risk of cancer later in life, and risk of heart disease
  • Radiation can damage healthy cells in addition to cancer cells, causing further complications
• Supportive treatment: Anti-nausea medications and antibiotics may be used as supportive therapy. In combination with other treatment measures, these can help combat the symptoms of immunodeficiency

Autologous and allogeneic stem cell transplant may be considered on a case-by-case basis, especially in younger individuals. Stem cell transplantations have resulted in cure in some individuals.

• Stem cell transplantation: This procedure involves the transplantation of healthy blood-forming stem cells into the body. The procedure is also called hematopoietic progenitor cell transplantation. Stem cells can be collected from the bone marrow, circulating (peripheral) blood, and umbilical cord blood. It may either involve an autologous stem cell transplantation, where stem cells are harvested from individuals before treatment and transplanted back into the patient after treatment, or involve an allogeneic stem cell transplantation, where stem cells donated by another matching person (usually a brother or sister) is used, if the condition recurs after stem cell transplant using one’s own cell. This is called as allogeneic stem cell transplant
• Bone marrow transplantation: Typically, systemic cases may be treated by administering high doses of chemotherapy or radiotherapy. But, high doses of chemotherapy drugs will also damage the bone marrow, preventing it from making any blood cells. Hence, before starting high-dose chemotherapy, the physicians may take out some of the patient’s bone marrow and freeze/preserve it. Collecting the bone marrow is called a bone marrow harvest. The bone marrow is then stored. After high dose chemotherapy or radiation, the bone marrow is thawed and injected back into patient through a drip (transfusion). This is called an autologous bone marrow transplant. Sometimes bone marrow donated by another matching person (usually a brother or sister) is used, if the condition recurs following transplant using one’s own cell. This is called as allogeneic bone marrow transplant

Allogeneic bone marrow and allogeneic stem cell transplants may have more side effects and complications, and this treatment may not be suitable for every individual. If allogeneic transplants come from a healthy donor with no malignant cells, then the chances of recurrence of the condition may be reduced.

The healthcare provider will determine the best course of treatment depending on one’s individual circumstances. Also, follow-up care with regular screening and check-ups are important post-treatment.

How can Large Granular Lymphocyte Leukemia be Prevented?

Currently, it is not possible to prevent Large Granular Lymphocyte Leukemia. However, controlling certain factors may help lower one’s general risk for the condition.

• Healthy diet and exercise, as well as avoidance of unnecessary exposure to chemicals, may help decrease its risk
• Avoiding smoking
• Using appropriate protective gear while working with X-rays or other radioactive sources
• In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, etc. should be well-documented and follow-up measures initiated

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, are mandatory. Often several years of active vigilance are crucial and necessary.

What is the Prognosis of Large Granular Lymphocyte Leukemia? (Outcomes/Resolutions)

The prognosis of Large Granular Lymphocyte Leukemia depends on the particular subtype of LGL Leukemia.

• The prognosis of both the aggressive subtypes of LGL Leukemia is generally poor despite treatment. Individuals, who show mild symptoms, may have a better prognosis than those who present severe symptoms
• The prognosis of the indolent T-cell subtype of and chronic NK-cell subtype of LGL Leukemia is good with timely and effective treatment
• In general, the prognosis depends upon a set of several factors, which include:
  • Stage of cancer: With lower-stage cancers, the prognosis is usually excellent with appropriate therapy. In advanced-stage cancers, the prognosis is generally poor
  • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
  • Involvement of vital organs may complicate the condition
  • Whether the condition is occurring for the first time, or is recurrent. Recurring conditions have worse prognosis compared to cases that do not recur 
  • Response to treatment: Conditions that respond to treatment have better prognosis compared to tumors that do not respond to treatment
  • Progression of the condition makes the outcome worse
• An early diagnosis and prompt treatment of the condition generally yields better outcomes than a late diagnosis and delayed treatment
• The combination chemotherapy drugs used, may have some severe side effects (such as cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor
• Progression to bone marrow failure is usually associated with short survival

Additional and Relevant Useful Information for Large Granular Lymphocyte Leukemia:

The following article link will help you understand leukemia and lymphoma:

http://www.dovemed.com/diseases-conditions/leukemia-and-lymphoma/