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

• Chronic NK-Cell Lymphocytosis
• Indolent Large Granular NK-Cell LPD
• NK-Cell Lineage Granular Lymphocyte Proliferative Disorder

What is Chronic Lymphoproliferative Disorder of Natural Killer Cells? (Definition/Background information)

• Chronic Lymphoproliferative Disorder of Natural Killer Cells (or Chronic NK-Cell Lymphocytosis) is a rare type of potentially-cancerous condition that is generally asymptomatic. It is typically seen in middle-aged and older adults, predominantly in men
• There is considerable debate among scientists regarding this condition; some believe that it is a reactive, benign condition; while for others, it represents a low-grade malignancy
• Lymphoproliferative disorders (LPDs) are disorders in which there is uncontrolled production of (excess) lymphocytes due to several reasons. The term “lymphocytosis” indicates an increased number of lymphocytes in peripheral blood
• The cause and risk factors for Chronic Lymphoproliferative Disorder of NK-Cells are not well-established. But, the condition is seen to be associated with various underlying autoimmune disorders, infections, or even other lymphomas
• The notable signs and symptoms of Chronic Lymphoproliferative Disorder of Natural Killer Cells may include swollen liver, spleen, or lymph nodes; other organs may also be affected in some cases. Occasionally, few individuals may have severe anemia, leucopenia, and thrombocytopenia, which can lead to various complications and a poorer prognosis
• In case no symptoms are observed, the healthcare provider may choose to follow a ‘wait and watch’ approach. In individuals who present symptoms, Chronic Lymphoproliferative Disorder of Natural Killer Cells is typically treated using chemotherapy, blood transfusions, and other supportive measures
• The prognosis of Chronic Lymphoproliferative Disorder of Natural Killer Cells is normally good with adequate treatment, in most of the individuals. However, the outcome may be dependent upon the course of the underlying disorder or malignancy, if any

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 T-cell type or NK-cell type

Who gets Chronic Lymphoproliferative Disorder of Natural Killer Cells? (Age and Sex Distribution)

• Chronic Lymphoproliferative Disorder of Natural Killer Cells is an uncommon form of large granular lymphocyte leukemia
• The condition is generally seen during middle-age and older age; age range of 35-75 years and average age around 60 years
• Both males and females are affected; although, studies inform that males are affected much more than females (male-female ratio is 7:1)
• It can occur worldwide and all racial and ethnic groups may be affected

What are the Risk Factors for Chronic Lymphoproliferative Disorder of Natural Killer Cells? (Predisposing Factors)

The risk factors for Chronic Lymphoproliferative Disorder of Natural Killer Cells are not yet identified. However, the condition may be associated with the following underlying disorders: 

• 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 Chronic Lymphoproliferative Disorder of Natural Killer Cells? (Etiology)

Lymphocytes are a type of white blood cells that are responsible for providing immunity in the human body. Natural killer cells are a type of lymphocytes. When under certain circumstances, these lymphocytes grow and multiply abnormally, it results in lymphoproliferative disorders.

The cause of Chronic Lymphoproliferative Disorder of Natural Killer Cells is unknown.

• The condition may be caused by certain genetic mutations or defects
• Research studies have established a link between this cancer type and several other underlying conditions (that include infections, autoimmune disorders, and other cancers)
• TCR gene rearrangement in Chronic Lymphoproliferative Disorder of NK-Cells shows germline configuration

What are the Signs and Symptoms of Chronic Lymphoproliferative Disorder of Natural Killer Cells?

A majority of individuals may not have any symptoms of Chronic Lymphoproliferative Disorder of Natural Killer Cells, during the initial stages of the condition. In those with signs and symptoms, the following may be observed:

• ‘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
• Weakness/fatigue
• Dysfunction of nerve (peripheral neuropathy) - with numbness and tingling sensation
• Cutaneous vasculitis (inflammation of blood vessels on skin)
• Some individuals may have enlarged liver, spleen, or lymph nodes
• Skin lesions may be observed in some individuals

It is reported that Chronic NK-Cell Lymphocytosis does not present with symptoms in nearly 60% of the patients. However, depending upon the specific part of the body, or organ affected, the following specific signs and symptoms may be seen:

• 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 Chronic Lymphoproliferative Disorder of Natural Killer Cells Diagnosed?

In many cases, Chronic Lymphoproliferative Disorder of Natural Killer Cells is diagnosed incidentally. It may be definitively diagnosed by obtaining biopsy samples from the affected region and examining them under a microscope to detect the cancerous cells.

The diagnostic criterion for Chronic Lymphoproliferative Disorder of NK-Cells is the presence of increased number of NK cells in peripheral blood. This must be greater than 2x10^9/liter (or 2 billion per liter), for a period greater than 6 months, with no identifiable cause.

The following tests and procedures may be used in the diagnosis of this malignancy:

• A thorough physical examination and a complete medical history
• Assessment of presenting symptoms
• Blood tests that may include:
  • Complete blood cell count (CBC) blood test
  • Absolute large granular lymphocytes count on peripheral blood
  • Liver function blood test (LFT): Increased liver enzymes may be noted
  • Lactate dehydrogenase (LDH) blood test
  • Blood culture, on a case-by-case basis, to rule-out any infections
  • Immunoglobulin studies
  • 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 T-cell receptor (TCR) gene rearrangement clonality
  • In Chronic NK-Cell Lymphocytosis, TCR gene rearrangement shows germline configuration
• 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 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 also to detect residual levels of disease after treatment. This tool can help in diagnosing relapse and restart treatment as needed. Flow cytometric analysis shows the following phenotype of the tumor cells: CD3-, CD56+, and CD16+
• Radiological imaging may be performed:
  • 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 in order to rule-out other bone marrow conditions. The biopsy is sent to a laboratory for a pathological examination. 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
• 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. A diagnostic laparoscopy is also helpful in staging of the tumor. Nevertheless, this procedure is not very much used
• 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 Chronic Lymphoproliferative Disorder of NK-Cells 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 Chronic Lymphoproliferative Disorder of Natural Killer Cells?

The complications due to Chronic Lymphoproliferative Disorder of Natural Killer Cells may include: 

• 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
• Heavy bleeding due to severe thrombocytopenia
• Severe anemia requiring blood transfusions
• Severe leucopenia leading to recurrent infections
• Pure red cell aplasia (PRCA) is observed in some patients
• In some cases, it can transform to extranodal NK cell lymphoma, which is an aggressive lymphoma type
• 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 Chronic Lymphoproliferative Disorder of Natural Killer Cells Treated?

Typically, a ‘wait and watch’ approach is considered by the healthcare provider for Chronic Lymphoproliferative Disorder of Natural Killer Cells, if it presents no symptoms or only mild symptoms. If the condition becomes aggressive, then symptomatic treatment may be provided. Apart from this, a treatment of the underlying disorder/malignancy is also undertaken.

Systemic therapy is generally administered for Chronic Lymphoproliferative Disorder of NK-Cells that involves a combination of various treatment measures. These include the following:

• 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
• In order to prevent infections because the immune system is weakened by Chronic Lymphoproliferative Disorder of Natural Killer Cells or by its treatment, the patient is kept in an isolated ward and treated with appropriate antibiotics

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 Chronic Lymphoproliferative Disorder of Natural Killer Cells be Prevented?

Currently, the cause of Chronic Lymphoproliferative Disorder of Natural Killer Cells is unknown. Hence, it is not possible to prevent the condition. Nevertheless, considering the following factors may help in preventing cancers:

• Healthy diet and exercise, as well as avoidance of unnecessary exposure to chemicals, may help decrease the risk of cancer
• Avoiding or stopping smoking
• Undertaking proper and timely treatment of autoimmune disorders, viral infections, blood vessel inflammation, and any underlying malignancies
• Genetic testing in individuals with a family history of cancers
• 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 Chronic Lymphoproliferative Disorder of Natural Killer Cells? (Outcomes/Resolutions)

Chronic Lymphoproliferative Disorder of Natural Killer Cells is a rare type of blood cancer. The prognosis of the condition is generally good; usually, the condition does not progress aggressively.

• But, the prognosis is also based upon the presence and severity of other underlying disorders and malignancies
• Individuals with severe pancytopenia have generally poorer or worse prognosis than those with milder symptoms
• The prognosis depends upon a set of several factors, which include:
  • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
  • Individuals with bulky disease have a poorer prognosis
  • 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 tumor 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

Additional and Relevant Useful Information for Chronic Lymphoproliferative Disorder of Natural Killer Cells:

• The treatment for Chronic Lymphoproliferative Disorder of Natural Killer Cells can cause physical and emotional distress; supportive care and encouragement, help positively and can bring a measure of relief to the patients

The following article link will help you understand leukemia and lymphoma (blood cancer):

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