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

• Primary CNS Lymphoma

What is Primary Central Nervous System Lymphoma? (Definition/Background Information)

• Primary Central Nervous System (CNS) Lymphoma is a non-Hodgkin’s B-cell lymphoma that usually arises within the brain. Primary CNS Lymphoma is mostly observed in AIDS patients
• This type of lymphoma first involves the brain and spinal cord (the central nervous system) and later can involve other parts of the body including the lymph nodes and bone marrow. Most Primary CNS Lymphomas are diffuse large B-cell lymphoma subtypes, which is an aggressive subtype of lymphoma
• Currently, immunosuppressive therapy (administered for organ transplant) and AIDS, has been identified as risk factors for Primary Central Nervous System Lymphoma. The cause of the condition is unknown, though genetic mutations have been implicated
• The condition can cause headaches, fatigue, convulsions, and other general signs and symptoms, such as fever, weight loss, and appetite loss. In case of severe complications, various vital organs may be affected
• Chemotherapy, surgery, radiation therapy, and other treatment measures may be used for treating Primary Central Nervous System Lymphoma based on the assessment by the physician
• The prognosis depends on many factors including the subtype and stage of lymphoma, progression of the condition, response to treatment, and overall health of the individual
• In general, the prognosis of Primary Central Nervous System Lymphoma is poor in individuals with AIDS, and is guarded in healthy individuals with normal immune system (those who do not have AIDS)

General information on lymphoma and lymphocytes:

• Lymphoma is a type of cancer stemming from uncontrollably dividing lymphocytes (type of white blood cells). There are two types of lymphomas:
  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma
• 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
• 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

Who gets Primary Central Nervous System Lymphoma? (Age and Sex Distribution)

• Primary Central Nervous System Lymphoma is typically observed in individuals with AIDS; 1 in 5 lymphomas in AIDS patients is Primary CNS Lymphoma
• AIDS is more common in younger adults than other age groups due to their risky behaviors, such as multiple partners, usage of injectable drugs, etc.
• Primary CNS Lymphoma occurring in individuals with normal immune system is between the ages 50-60 years. Even though the condition is rare in such individuals, the incidence is increasing; the cause for this is unknown
• However, individuals of any age group and gender (male or female) may be affected
• It can occur worldwide and all racial and ethnic groups may be affected

What are the Risk Factors for Primary Central Nervous System Lymphoma? (Predisposing Factors)

• The primary risk factor for Primary Central Nervous System Lymphoma is HIV infection resulting in AIDS. This leads to poor immune system in the affected individual
• Therapy using immunosuppressants for organ transplant (such as for kidney or liver transplant) is another important risk factor
• Studies have shown that the condition may be also associated with Epstein-Barr virus infection (in about 90% of the cases)

In general, the following factors may contribute towards lymphoma formation and development:

• Advanced age; older individuals commonly have a higher risk
• Individuals with weak immune system (due to various health conditions)
• Family history of immune disease
• The presence of any systemic disease
• Smoking
• Exposure to radiation and industrial chemicals
• Chemotherapy
• X-ray, CT scan exposure
• Profession involving radiation exposure, which may include nuclear plant workers, pilots, astronauts, etc.
• Certain medications and drugs

International Prognostic Index: According to some scientists, the International Prognostic Index may not be very helpful in evaluating Primary CNS Lymphoma. However, some scientists believe that it is helpful in some cases, to determine the prognosis.

The International Prognostic Index, for aggressive non-Hodgkin lymphoma, lists a few factors that determine the overall risk:

• Age over 60 years
• Elevated level of serum lactate dehydrogenase - LDH (a type of enzyme)
• Performance status, i.e. the overall health condition of the individual, which could range from being fully active (low risk) to being completely disabled (very high risk)
• Individual, who have already suffered from lymphoma, or other types of blood cancers, may have a relapse or a recurrence
• Presence of an immunodeficiency syndrome, like AIDS, is a high risk factor
• Those infected with Epstein-Barr virus are also prone to this lymphoma type

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 Primary Central Nervous System Lymphoma? (Etiology)

Lymphocytes are a type of white blood cells that are responsible for providing immunity in the human body. B-cells and T-cells are the two different types of lymphocytes. When under certain circumstances, the lymphocytes grow and multiply abnormally, it leads to a condition called as lymphoma, which is a most common type of cancer. There are 2 types of lymphoma:

• Hodgkin lymphoma
• Non-Hodgkin lymphoma

The exact cause of Primary Central Nervous System Lymphoma, a non-Hodgkin’s lymphoma, is unknown. There may be certain genetic defects, such as translocation, which is a juxtaposition of regions of the chromosomes. This may result in:

• Change of regulatory elements of certain cancer-causing genes called as oncogenes, which can lead to increased production of their mRNA (overexpression), thus increasing their protein levels
• Exchange of protein coding regions of gene, giving rise to new proteins that can stimulate the inappropriate growth of cells
• It is believed that the abnormal development of lymphocytes gives rise to cancerous cells leading to the formation of this condition. Nevertheless, how this occurs and the factors that cause it remain under investigation

It is also known that there is a strong link between Primary CNS Lymphoma and Epstein-Barr virus infection in AIDS-infected individuals.

What are the Signs and Symptoms of Primary Central Nervous System Lymphoma?

A majority of tumors are in individuals with poor or decreased immune system; rarely, individuals with a normal immune system can get Primary Central Nervous System Lymphoma. In such individuals, the tumors are not usually associated with EBV.

Primary Central Nervous System Lymphoma may be present as a mass in the brain (or spinal cord) and may cause the following neurological signs and symptoms, depending on its location:

• Headaches
• Nausea and vomiting
• Convulsions
• Decreased brain function
• Difficulty in speech, hearing, and decreased vision
• Loss of sensation in different parts of body
• Difficulty in muscle movements in various parts of body
• Memory loss
• ‘B’ symptoms that may include fever, night sweats, and 10% weight loss over a period of 6 months

Additionally, there may also be the following general signs and symptoms:

• Fatigue and weakness, headache
• Anemia (low red blood cell count)
• Frequent infections
• Low blood pressure
• Enlarged lymph nodes that may be painless

When the involvement of other organs occurs, the signs and symptoms may be based on the specific organs that are affected.

How is Primary Central Nervous System Lymphoma Diagnosed?

Primary Central Nervous System Lymphoma diagnosis is generally performed by obtaining biopsy samples from the affected region and examining them under a microscope to detect the cancerous cells. The following tests and procedures may help in the diagnosis of Primary CNS Lymphoma:

• A thorough physical examination and a complete medical history, which is very important
• The presence of HIV infection can be diagnosed through blood tests including:
  • HIV ELISA (enzyme-linked  immunosorbent assay)
  • Western blot test
  • CD4 lymphocyte count
  • HIV RNA level (viral load test)
• Blood tests that may include:
  • Complete blood cell count (CBC) blood test
  • Absolute lymphocyte count on peripheral blood
  • Liver function blood test (LFT)
  • Lactate dehydrogenase (LDH) blood test
  • Blood chemistry study
• Radiological imaging may be performed specific to location of the involved organ, and to determine the extent of lymphoma in the body including:
  • Plain x-ray of the skull
  • CT or CAT scan with contrast of the head and neck region
  • MRI scan of the brain
  • Brain angiography
  • Vascular radiological studies
  • Whole body bone scan
  • Whole body CT-PET scans to determine how far the lymphoma has spread, by checking the size and metabolic rate (a reflection of uncontrolled growth) of lymph nodes, throughout the body. This can also help determine, if the cancer has spread to other organ systems
• Lumbar puncture
• Cerebrospinal fluid (CSF) tap: 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
• Flow cytometry of the cerebrospinal fluid 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
• Tissue biopsy from the affected region: In rare situations when a diagnosis cannot be confirmed, a brain biopsy is undertaken
  • A biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
  • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
  • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, flow cytometric analysis and very rarely, electron microscopic studies, to assist in the diagnosis
• The biopsy may be performed through any of the following procedures:
  • Needle biopsy of the tumor through a burr hole: A needle biopsy may not be helpful, because one may not be able to visualize the different morphological areas of the tumor. Hence, a needle biopsy as a diagnostic tool has certain limitations, and an open surgical biopsy is preferred
  • Stereotactic core biopsy of the tumor: Here a computer-assisted guidance system helps in the location of the tumor. The biopsy needle is placed in the tumor and core of tumors are taken
  • Open biopsy of the tumor by opening the skull using craniotomy method

The following tools may be used for the analysis of tissue or fluid that has confirmed malignant cells:

• 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
• Polymerase chain reaction (PCR): 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
• 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

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. The bone marrow aspiration and biopsy is performed to assess the stage of the lymphoma, which can help in treatment purposes.

Note: Differential diagnoses, to eliminate other tumor types are often considered, before arriving at a definitive diagnosis.

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 Primary Central Nervous System Lymphoma?

The complications due to Primary Central Nervous System Lymphoma may include:

• Involvement of local and distant organs: It can lead to systemic or disseminated disease in some cases
• Loss of function of the organ/area to which cancer has spread due to systemic involvement
• Invasion to nearby brain tissue affecting brain function
• In case of a relapse, this lymphoma is known to affect several organs such as the lungs, kidney, breast, GI tract, and liver (extranodal locations)
• Weakened immune system (or immunosuppression) can be a complication, which can become more severe during treatment. Due to this, individuals are more vulnerable to infections; there is an increased risk of developing serious complications from such infections
• Occasionally, the tumor can transform into a more aggressive form or subtype of lymphoma

The complications due to AIDS may include:

• Dementia, polyneuropathy
• Coronary artery disease
• Stroke
• Cancer in other parts of the body
• Severe and recurrent infections
• Treatment-related complications may include Cushing’s disease, metabolic syndrome, and abnormal fat deposition

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

The treatment measures can also give rise to secondary cancers, such as skin cancer.

How is Primary Central Nervous System Lymphoma Treated?

A combination of measures may be used to treat Primary Central Nervous System Lymphoma. The treatment also depends upon the stage, overall health, age, and subtype of lymphoma. Staging is important because different treatment regimens are necessary, depending on the progression of the lymphoma.

Treatment for HIV infection and AIDS may be undertaken through the following measures:

• Antiretroviral therapy to suppress the multiplication of the virus in the body
• HAART or highly-active antiretroviral therapy: It employs a combination of two different classes of anti-retroviral medications. HAART has proven to be very effective in addressing this immunodeficiency disorder caused by a virus

The treatment for Primary CNS Lymphoma is generally undertaken as per the following measures:

• Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells and can be used in patients, for all stages of the tumor
  • There can be severe side effects including fatigue, nausea, hair loss, anemia, high risk of infection, and drug-specific reactions
  • Many lymphomas can be resistant to chemotherapy. It can also damage healthy cells
  • Chemotherapy can be administered as a pill, liquid, shot, or intravenously
  • If cancer has spread to the cerebrospinal fluid, chemotherapy may be given intrathecally

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.

• 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 lymphomas. 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: Steroids, blood transfusions, 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 some cases, bone marrow or stem cell transplants may be considered. This may be performed so that the individuals can undergo more intensive chemotherapy. In this form of treatment, very high doses of chemotherapy drugs are used, which results in a destruction of the bone marrow and stem cells along with the cancer cells. The individual is then usually given donor stem cells, or the individuals own stem cells, which were collected before the treatment
• In order to prevent infections because the immune system is weakened by Burkitt's lymphoma or by its treatment, the patient is kept in an isolated ward and treated with appropriate antibiotics
• Nowadays targeted therapies are being developed that can selectively kill the cancer cells. Many of them are in the stage of clinical trials
• Clinical trials: There may be some newer treatment options, currently on clinical trials, which can be considered for some patients depending on their respective risk factors

If Primary CNS Lymphoma is not fully responsive to treatment, or if the chance of recurrence is high, then bone marrow transplantation or stem cell transplantation can be considered.

• 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
• Stem cell transplantation: This procedure is similar to bone marrow transplantation and 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

Note: 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.

• In order to prevent infections because the immune system is weakened by the lymphoma or by its treatment, the patient is kept in an isolated ward and treated with appropriate antibiotics
• Nowadays, targeted therapies are being developed, that can selectively kill the lymphoma/leukemia cells. Many of them are in the stage of clinical trials
• Clinical trials: There may be some newer treatment options, currently on clinical trials, which can be considered for some patients depending on their respective risk factors

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

How can Primary Central Nervous System Lymphoma be Prevented?

Currently, it is not possible to prevent Primary Central Nervous System Lymphoma. However, controlling certain factors my help lower one’s 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 and other radioactive source
• 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 Primary Central Nervous System Lymphoma? (Outcomes/Resolutions)

• The prognosis of Primary Central Nervous System Lymphoma is poor in immunocompromised patients (those with AIDS)
• In individuals with normal immune function, the prognosis is guarded. In such individuals, the tumor responds to initial radiation therapy and chemotherapy, but after a short period of time, the tumor may stop responding to therapy
• In general, the prognosis depends upon a set of several factors, which include:
  • Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
  • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
  • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
  • The size of the tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
  • Individuals with bulky disease have a poorer prognosis
  • Involvement of vital organs may complicate the condition
  • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
  • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
  • Progression of the condition makes the outcome worse (progressive Primary CNS Lymphoma)
• 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 Primary Central Nervous System Lymphoma:

• Treatment for Primary CNS Lymphoma 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/