Central Nervous System Lymphoma

Central nervous system lymphoma is a rare and aggressive cancer that develops in the brain, spinal cord, or eyes. Though uncommon, affecting only about 1,500 people each year in the United States, this disease requires prompt diagnosis and specialized treatment to achieve the best possible outcomes.

Table of contents

• What is Central Nervous System Lymphoma?
• Parts of the Body Affected
• Types of CNS Lymphoma
• Who Gets CNS Lymphoma?
• Symptoms
• Causes and Risk Factors
• Diagnosis
• Treatment
• Outlook and Prognosis

What is Central Nervous System Lymphoma?

Central nervous system lymphoma is a rare cancer that develops when white blood cells called lymphocytes grow out of control in the central nervous system. Lymphocytes are normally part of the body’s immune system and help fight infections and diseases^[1].

This cancer is a type of non-Hodgkin lymphoma, which means it starts in the lymphatic system rather than in the lymph nodes of the neck, chest, or abdomen^[1]. Most CNS lymphomas are diffuse large B-cell lymphomas, which develop from B-cells, a specific type of white blood cell^[3].

CNS lymphoma is extremely rare, with only about 1,500 new cases diagnosed each year in the United States^[1]. Despite being rare, it is considered aggressive because it can spread quickly throughout the central nervous system^[1].

• Brain
• Spinal cord
• Cerebrospinal fluid
• Meninges (protective layers covering the brain and spinal cord)
• Eyes (vitreoretinal space)

Parts of the Body Affected

The central nervous system is the part of the body that controls all bodily functions. It includes several key structures that can be affected by this type of lymphoma^[4].

The brain serves as the body’s control center. Tumors in the brain can affect different functions depending on where they are located. The spinal cord runs down the back inside the spinal bones and carries signals between the brain and nerves throughout the body^[4].

The meninges are protective layers of tissue that cover both the brain and spinal cord. These are the same layers that become inflamed when someone has meningitis^[4]. Cerebrospinal fluid is a liquid that surrounds and protects the brain and spinal cord^[4].

Because the eye sits very close to the brain, primary CNS lymphoma can also develop in the eye, in an area called the vitreoretinal space or ocular space^[6].

Types of CNS Lymphoma

There are two main categories of CNS lymphoma, depending on where the cancer first develops^[1].

Primary CNS lymphoma refers to cancer that starts in the central nervous system and is not found anywhere else in the body. This is the most common form when discussing CNS lymphoma^[1]. The disease may develop in the brain, spinal cord, cerebrospinal fluid, or the membranes covering these structures^[5].

Secondary CNS lymphoma describes lymphoma that started somewhere else in the body and later spread to the central nervous system. This happens when systemic lymphoma involves the CNS through different mechanisms, including direct extension from nearby bone marrow or spread through the bloodstream^[3].

Almost all primary CNS lymphomas are B-cell lymphomas, meaning they develop from B-cells. However, in rare cases, the disease can develop from T-cells or other types of lymphocytes^[3].

Who Gets CNS Lymphoma?

Although anyone can develop CNS lymphoma, certain groups of people are at higher risk. Men are more likely to be diagnosed with this cancer than women^[1]. People over the age of 65 are also at increased risk^[1].

Individuals with weakened immune systems have a significantly higher chance of developing CNS lymphoma. The disease increasingly affects people who are immunocompromised, such as those with HIV or AIDS^[3].

The cause of CNS lymphoma is often unknown, but certain factors may increase risk, including infection with Epstein-Barr virus, human immunodeficiency virus (HIV), exposure to certain chemicals such as pesticides or solvents, and a family history of non-Hodgkin lymphoma^[5]. However, having one or more risk factors does not mean a person will definitely develop the disease, and many people diagnosed have never been exposed to any clearly identifiable risk factors^[5].

Symptoms

The symptoms of CNS lymphoma depend on where the tumor is located in the central nervous system. A tumor in the membranes covering the brain and spinal cord may not cause any symptoms, while a tumor near the eyes often causes vision changes. If a tumor grows near the area of the brain that controls movement, weakness or problems with coordination may occur^[1].

Common symptoms include nausea and vomiting, which occur because of increased pressure in the brain^[1]. Weakness can develop in the arms, legs, or face, and sometimes affects only one side of the body, a condition called hemiparesis^[1].

Hearing loss and difficulty swallowing, known as dysphagia, may occur depending on tumor location^[1]. Signs of brain pressure include headaches and confusion^[1].

Vision problems are common and can include blurry vision, seeing double, or seeing floaters^[1]. Changes in mental state may develop, such as trouble speaking, memory loss, or feeling sluggish^[1].

Seizures may occur and can become more frequent over several days or weeks^[1]. Some people experience trouble controlling when they urinate or have bowel movements, conditions known as urinary and fecal incontinence^[1].

The clinical presentation of primary CNS lymphoma is often nonspecific, meaning the symptoms can resemble those of other medical conditions^[11].

Causes and Risk Factors

Like other types of lymphoma, CNS lymphoma develops when cells in lymph tissue start to behave abnormally. They multiply out of control and overtake healthy cells. With CNS lymphoma, the cells that start growing abnormally are usually white blood cells called B-cells^[1].

Researchers are not sure exactly what causes a lymphocyte to transform into a cancer cell. However, they have identified several factors that may increase the risk of developing CNS lymphoma^[1].

Certain conditions associated with having a weakened immune system increase the risk. These include HIV and AIDS, especially when accompanied by an active Epstein-Barr infection^[1]. Immunosuppression-related primary CNS lymphomas are almost always associated with the Epstein-Barr virus^[13].

Genetic conditions that affect the immune system also increase risk. These include Wiskott-Aldrich syndrome, common variable immunodeficiency state, and ataxia-telangiectasia^[1].

People who have undergone organ transplants and take immunosuppressant drugs to prevent rejection are at higher risk. In some cases, patients who develop PCNSL after an organ transplant may need to lower the dose of or stop taking their immunosuppressant medication^[7].

Primary CNS lymphoma may occur in patients who have HIV, AIDS, Epstein-Barr virus, or other disorders of the immune system^[6].

Diagnosis

Healthcare providers use several procedures and tests to diagnose CNS lymphoma. Because the clinical and imaging presentation is often nonspecific, confirmation through tissue examination is required^[11].

A complete medical history and physical examination are the first steps. Providers will perform a neurological exam to check the brain, spinal cord, and nerve function. This exam checks mental status, coordination, ability to walk normally, and how well muscles, senses, and reflexes work^[6]. An eye exam with a dilated pupil may be done to look for signs of a tumor behind the eye^[1].

Imaging tests help visualize the inside of the body. An MRI scan (magnetic resonance imaging), CT scan (computed tomography), or PET scan (positron emission tomography) may be ordered to see where tumors are located and how large they are^[1]. Computed tomography scans may show ring enhancement in 50% of patients with HIV, while uniform enhancement is almost always seen in patients without HIV^[13].

A biopsy is essential for confirming the diagnosis. The diagnosis of CNS lymphoma usually includes a brain biopsy or surgery, performed by a neurosurgeon. The tumor material is then examined by a specialist called a neuropathologist^[12].

Testing of the cerebrospinal fluid may be performed through a procedure called lumbar puncture or spinal tap. This involves removing a small amount of fluid from around the spinal cord to check for cancer cells^[4]. In one study of 282 patients with primary CNS lymphoma, 17% were found to have spread to the meninges by examining the cerebrospinal fluid^[13].

Diagnostic work-up includes an extent of disease evaluation to determine if there is involvement outside of the central nervous system. This could include examination of the eyes and a PET/CT scan of the body to exclude hidden systemic disease^[12].

Treatment

The treatment of CNS lymphoma depends on several factors, including the patient’s age, overall health, immune system status, and whether the lymphoma is in the eye, the CNS, or both^[7]. If left untreated, the disease leads to death within weeks or months^[11].

Treatment often begins with corticosteroids, which are steroid hormones that reduce inflammation and swelling. Drugs like dexamethasone or prednisone are used to destroy lymphoma cells and temporarily reduce swelling in the brain tissue. PCNSL responds very well to corticosteroids^[7].

Chemotherapy is the main treatment for CNS lymphoma. It uses drugs to destroy cancer cells and may be given alone or with other treatments^[7]. If the patient’s general condition permits, treatment should consist of high-dose chemotherapy based on methotrexate combined with rituximab and other drugs that can penetrate the blood-brain barrier^[11].

The most common drug combinations used include high-dose methotrexate with or without rituximab, or combinations that may include cytarabine, thiotepa, ifosfamide, vincristine, procarbazine, and temozolomide^[7]. High-dose methotrexate is an inpatient chemotherapy treatment that requires careful monitoring throughout administration^[12].

Chemotherapy may be given systemically, meaning the drugs travel through the entire body, or as regional chemotherapy directly into the fluid-filled space around the brain and spinal cord, called intrathecal chemotherapy^[7].

Targeted therapy uses drugs to target specific molecules on or inside cancer cells. These drugs stop the growth and spread of cancer cells while limiting harm to normal cells^[7].

Long-term survival can be achieved in patients under age 70 by adding non-myeloablative consolidation chemotherapy or high-dose chemotherapy with autologous stem cell transplantation to the initial treatment^[11]. Autologous stem cell transplant involves collecting the patient’s own stem cells before intensive chemotherapy, then returning them to help the body recover^[7].

Radiation therapy may be used, though its role has evolved. Whole-brain radiation therapy is associated with the risk of severe neurotoxicity and should be reserved for patients who do not qualify for systemic treatment^[11]. Some patients may be considered for low-dose radiation^[12].

For patients with HIV or AIDS-related PCNSL, treatment often includes highly active antiretroviral therapy (HAART), along with corticosteroids and whole-brain radiation therapy. Some may be offered chemotherapy, depending on how well their immune system is working^[7].

Outlook and Prognosis

Primary CNS lymphoma is usually aggressive, but the outlook has improved significantly with modern treatment approaches^[3]. Despite its reputation for aggressiveness and poor prognosis, primary CNS lymphoma often responds well to therapy and has the possibility of curative treatment^[3].

Historical outcomes were dismal, with untreated survival rates as low as 1.5 months and a 5-year survival rate of only 30%. However, PCNSL management is now benefiting from novel chemotherapeutic and immune modulatory treatment approaches^[3].

The 5-year survival rate of all treated patients is 31% according to registry data^[11]. In published clinical trials, the median overall survival generally ranges from 2 to 5 years^[13]. However, a study of 40 patients with low-grade primary CNS lymphoma reported a better long-term outcome, with a median survival of 7 years^[13].

Several factors affect prognosis. Poor prognostic factors include age older than 60 years, HIV positivity, elevated levels of certain substances in the blood or cerebrospinal fluid, involvement of certain areas of the brain, and having disease in both the eye and brain^[13].

About 30% of patients do not respond to initial treatment, and at least 50% experience relapse^[11]. When tumor progression occurs, it is usually confined to the CNS and/or the eye^[13]. In patients who are still in good general condition, relapse can be managed with high-dose chemotherapy and stem cell transplant. Re-treatment with conventional high-dose methotrexate-based chemotherapy is another option if the initial response was long-lasting^[11].

Increasingly, high-dose therapy combined with autologous stem cell transplantation and the development of newer therapeutic strategies offer the possibility of improved outcomes^[3].