Overview of Lymphoma

Lymphoma is a cancer that starts in the lymphatic system, a vital part of the immune system responsible for fighting infections and removing waste. It occurs when lymphocytes, a type of white blood cell, grow uncontrollably and form tumors.

There are two main types: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). NHL is the more common type and includes rare subtypes that can affect the central nervous system, such as primary and secondary CNS lymphoma.

Primary CNS lymphoma (PCNSL) begins in the brain, spinal cord, or eyes, while secondary CNS lymphoma (SCNSL) occurs when lymphoma from another part of the body spreads to these areas. Both are aggressive forms of NHL that require timely and specialized treatment. In this article, we’ll explore the types, causes, symptoms, diagnosis, treatments, and outlook for CNS lymphoma to provide a clear understanding of this complex condition.

CNS lymphoma encompasses various subtypes, each with distinct characteristics and implications for treatment and prognosis. The primary classifications include:

Primary CNS Lymphoma (PCNSL) is the most common type of CNS lymphoma, originating within the central nervous system (CNS) without other signs of cancerous conditions elsewhere in the body. Key characteristics of PCNSL include:

• Origin: Develops in the CNS, including the brain, spinal cord, leptomeninges, or eyes.
• Subtype: Most cases are diffuse large B-cell lymphoma (DLBCL).
• Demographics: Typically affects older adults (ages 60–70) and is slightly more common in men.
• Symptoms: Symptoms vary depending on the tumor’s location in the central nervous system. 

Secondary CNS Lymphoma occurs when lymphoma cells from another part of the body metastasize (spread) to the central nervous system. This can happen with various types of systemic lymphomas, including both Hodgkin and non-Hodgkin lymphomas.

Secondary involvement of the CNS is generally associated with a poorer prognosis compared to PCNSL due to the complexity of managing both systemic and CNS disease. Key characteristics of secondary CNS lymphoma include;

• Origin: Spreads from systemic lymphoma to the CNS.
• Subtype: Can involve various lymphoma subtypes, including Hodgkin and non-Hodgkin lymphomas.
• Prognosis: Typically poorer than PCNSL due to the need to manage both systemic and CNS disease.
• Symptoms: Similar to PCNSL but often accompanied by symptoms related to systemic lymphoma.

The causes of primary and secondary CNS lymphomas are not fully understood. However, several risk factors have been identified:

Individuals with compromised immune systems are at a higher risk of developing CNS lymphoma. This includes:

•  HIV/AIDS Patients: The immunosuppression associated with HIV/AIDS significantly increases the risk.
•  Organ Transplant Recipients: Patients undergoing immunosuppressive therapy to prevent organ rejection are more susceptible.
• Congenital Immunodeficiency Syndromes: Genetic conditions that impair immune function can predispose individuals to CNS lymphoma.

Genetic alterations and mutations within lymphocytes, a type of white blood cell, can lead to uncontrolled cell growth, a hallmark of cancer. These mutations can disrupt normal cellular processes, leading to the development of malignant cells.

Chronic inflammatory conditions may create an environment conducive to the development of lymphoma by promoting DNA damage and cellular proliferation. Persistent inflammation can lead to genetic instability and subsequent malignant transformation of lymphocytes.

Exposure to certain chemicals, radiation, or other environmental toxins may increase the risk of developing CNS lymphoma. However, specific associations between environmental factors and CNS lymphoma are not well-established and remain an area of ongoing research

Symptoms of CNS lymphomas are related to the location and size of the tumor and may include:

• Focal neurological deficits
• Altered mental status
• Seizures
• Headaches
• Nausea and vomiting
• Visual disturbances
• Symptoms of increased intracranial pressure

Diagnosing CNS lymphoma involves several steps to ensure an accurate diagnosis and guide treatment:

• Magnetic Resonance Imaging (MRI): MRI is the preferred test for diagnosing CNS lymphoma because it can effectively detect brain tumors. When a contrast dye is used during the MRI, it highlights specific signs of lymphoma, such as evenly bright areas and involvement of critical deep brain regions.
• Computed Tomography (CT) Scan: While less sensitive than MRI, CT scans can detect larger tumors and assess for calcifications or hemorrhage (bleeding).  CT scans are also useful in patients who cannot undergo MRI due to concerns like pacemakers or severe claustrophobia.

Cerebrospinal fluid (CSF) analysis can detect lymphoma cells, increased protein levels, and other findings that support evidence of CNS involvement. However, CSF studies are not perfect, and your care team may need multiple samples to obtain an accurate diagnosis.

Definitive diagnosis of CNS lymphoma often requires a biopsy of the affected tissue. Depending on the tumor’s location, this may involve:

• Neurosurgical Biopsy: Surgical removal of a tissue sample from the brain or spinal cord. This is typically performed using stereotactic techniques to precisely target the lesion.
• Ophthalmic Examination and Biopsy: If eye involvement is suspected, an ocular biopsy may be performed. This involves obtaining tissue from the eye to confirm lymphoma.

Blood tests help assess overall health, immune function, and identify potential markers of lymphoma. These tests may include:

• Complete Blood Count (CBC): Evaluates the levels of different blood cells.
• Liver and Kidney Function Tests: Assess the functionality of vital organs.
• HIV Screening: Particularly in patients with risk factors for immunosuppression.

Advanced tests like flow cytometry, immunohistochemistry, and genetic sequencing provide detailed information about the type of lymphoma. These tests identify specific markers and mutations that help doctors choose the best treatment and predict how the disease will progress.

Neurosurgeons play an essential role in diagnosing and managing primary central nervous system lymphoma (PCNSL). While their primary focus is diagnostic, therapeutic surgical interventions are usually limited because PCNSL responds well to chemotherapy and radiation.

The main neurosurgical procedure for CNS lymphoma is a stereotactic biopsy. This minimally invasive technique uses advanced imaging like MRI or CT to accurately collect tissue samples from the tumor for diagnosis, ensuring minimal disruption to surrounding brain structures.

In some cases, neurosurgeons may place an Ommaya reservoir, or ventricular access device. This device enables repeated delivery of intrathecal chemotherapy (medication administered directly into the brain and spinal cord), which is particularly helpful when the lymphoma involves the innermost tissue layers covering the brain and spinal cord, the leptomeninges.

Although tumor removal surgery is rare due to PCNSL’s diffuse nature, neurosurgeons may intervene for symptom relief in specific cases, such as relieving pressure from a large mass or addressing fluid buildup (e.g., through a ventriculoperitoneal shunt). They work closely with a team of specialists to deliver comprehensive care, combining their expertise with chemotherapy, radiation, and other medical treatments to optimize patient outcomes.

Receiving a diagnosis of CNS lymphoma means you are not alone in your journey. A multidisciplinary team of healthcare professionals will work closely with you to develop a personalized treatment plan tailored to your specific needs and circumstances. Treatment options may include:

• High-dose methotrexate (HD-MTX): This is the primary treatment for PCNSL because it can cross the blood-brain barrier and reach the tumor.
• Combination chemotherapy: Additional drugs like rituximab, cytarabine, and thiotepa are often added to enhance effectiveness.
• Whole-brain radiotherapy (WBRT): This may be used alongside chemotherapy or for patients who cannot tolerate aggressive drug regimens.
• Stem cell transplantation: For recurrent or hard-to-treat cases, autologous stem cell transplantation can be an option.
• SCNSL treatment: Therapy targets both the lymphoma in the CNS and the systemic disease, using systemic chemotherapy that penetrates the CNS, intrathecal chemotherapy (delivered directly into the spinal fluid), and/or radiation focused on the CNS.

These treatment plans are designed to address the unique challenges of CNS lymphomas and offer the best possible outcomes.

High-Dose Methotrexate-Based Chemotherapy

Methotrexate is a cornerstone of CNS lymphoma treatment due to its ability to penetrate the blood-brain barrier effectively. High-dose methotrexate regimens are typically combined with other chemotherapy agents, such as cytarabine, to enhance efficacy.

Key Points:

• Efficacy: Methotrexate is highly effective in targeting CNS lymphoma cells.
• Administration: Typically administered intravenously at high doses.
• Side Effects: Potential for kidney toxicity, mucositis, and myelosuppression, requiring careful monitoring.

Rituximab is a targeted therapy that binds to the CD20 antigen on B-cells, facilitating their destruction. It is often added to chemotherapy regimens to improve treatment outcomes, particularly in B-cell lymphomas like DLBCL.

Rituximab enhances the effectiveness of chemotherapy by targeting specific lymphoma cells. This medication is given intravenously, typically in combination with chemotherapy.

Common side effects can include infusion reactions, increased risk of infections, and potential for immunosuppression, in the setting of an already weak immune system.

Whole Brain Radiation Therapy (WBRT): Whole Brain Radiation Therapy targets the entire brain to eliminate lymphoma cells. While WBRT is effective, its role has diminished due to concerns about long-term neurotoxicity, especially in elderly patients.

Radiation therapy is often reserved for patients who do not respond adequately to chemotherapy or who relapse. Common side effects of radiation therapy treatment for CNS lymphoma include cognitive decline, fatigue, and increased risk of secondary malignancies. In some cases, focal radiation therapy may be considered to minimize toxicity.

High-dose chemotherapy followed by autologous stem cell transplantation can be considered for patients who relapse or do not respond to initial treatments. This approach aims to eradicate lymphoma cells with intensive chemotherapy and then restore the bone marrow using the patient’s own stem cells.

This treatment is typically used in relapsed or refractory CNS lymphoma. The procedure involves taking the patient’s healthy stem cells prior to chemotherapy, administering high-dose chemotherapy, and then reinfusing the stem cells. Risks of autologous stem cell transplantation can include organ toxicity, as well as rejection of the stem cell graft.

Participation in clinical trials offers access to emerging therapies and novel treatment approaches. Clinical trials are essential for advancing the understanding and management of CNS lymphoma and may provide patients with additional treatment options not yet widely available.

More information regarding clinical trials can be found here.

Living with CNS lymphoma involves not only managing the physical aspects of the disease but also addressing emotional and psychological well-being. Here are some strategies to help you navigate this journey:

• Emotional Support: Professional counseling can provide a safe space to express your feelings and develop coping strategies. Connecting with others who are going through similar experiences can offer comfort and practical advice.
• Managing Side Effects: Work closely with your healthcare team to manage side effects and maintain your quality of life. Maintaining a balanced diet, engaging in gentle exercise as advised, and ensuring adequate rest can support your overall well-being.
• Cognitive Rehabilitation: If cognitive impairments occur, cognitive rehabilitation therapies can help improve memory, attention, and problem-solving skills, enhancing your ability to perform daily activities.
• Family and Caregiver Support: Involving family members and caregivers in your treatment plan ensures you have a strong support system. Educating them about CNS lymphoma helps them provide better care and understanding.

The prognosis for CNS lymphoma varies based on several factors, including the patient’s age, overall health, lymphoma subtype, and response to treatment. While CNS lymphoma has historically had a poor prognosis, advancements in chemotherapy and targeted therapies have significantly improved survival rates. Here’s what you need to know:

• Median Survival: With modern treatments, the median survival for PCNSL has increased to approximately 3 to 5 years. Some patients achieve long-term remission, especially those who respond well to initial therapy.
• Five-Year Survival: The five-year survival rate for PCNSL ranges from 30% to 40%, depending on treatment efficacy and individual patient factors. Secondary CNS lymphoma generally has a poorer prognosis due to the complexity of managing both systemic and CNS disease.

Several factors influence the prognosis of CNS lymphoma:

• Age: Younger patients generally have a better prognosis compared to older adults.
• Performance Status: Patients with good functional status and fewer neurological deficits respond better to treatment.
• Response to Initial Therapy: Achieving remission after initial treatment is associated with improved outcomes.
• Lymphoma Subtype: Certain subtypes, like DLBCL, may respond more favorably to treatment compared to others.

CNS lymphoma has a high propensity for relapse, necessitating close monitoring and, in some cases, additional treatment interventions upon recurrence. Factors associated with relapse include incomplete response to initial therapy and the presence of residual disease.

Long-term survivors may experience cognitive impairments, neurological deficits, or other side effects from treatment, impacting their quality of life. Cognitive rehabilitation, physical therapy, and supportive care are essential components of post-treatment management to address these challenges.

Ongoing research aims to develop more effective and less toxic treatments, improve early detection methods, and understand the molecular mechanisms underlying CNS lymphoma. Innovations in immunotherapy, targeted agents, and personalized medicine hold promise for enhancing prognosis and quality of life for patients.

Emerging therapies, such as CAR T-cell therapy and novel small molecule inhibitors, are being investigated for their potential role in treating CNS lymphoma.

Facing CNS lymphoma can be daunting, but you don’t have to go through it alone. Receiving a diagnosis of Central Nervous System (CNS) lymphoma is undoubtedly challenging, but with the right information, support, and treatment, you can navigate this journey with strength and hope.  

Remember, advancements in medical research and treatments continue to improve outcomes for CNS lymphoma patients. You are not alone—reach out to your healthcare team, connect with support networks, and take one step at a time toward recovery and a fulfilling life.

• CNS lymphomas include PCNSL, which starts in the central nervous system, and SCNSL, which spreads from systemic lymphoma to the CNS. Both are aggressive forms of diffuse large B-cell lymphoma (DLBCL) and require specialized care.
• While the exact causes are unknown, risk factors include weakened immune systems (HIV/AIDS, organ transplants), age (over 60), autoimmune diseases, and viral infections like Epstein-Barr virus (EBV).
• Symptoms depend on tumor location and size and may include headaches, seizures, visual changes, nausea, and signs of increased intracranial pressure, such as altered mental status.
• Diagnosis involves MRI, cerebrospinal fluid analysis, and biopsy. Treatment combines high-dose methotrexate-based chemotherapy, additional agents like rituximab, radiotherapy, and sometimes stem cell transplantation for recurrent or refractory cases.
• PCNSL survival has improved with aggressive treatments, extending median survival to 30-60 months for some, while SCNSL prognosis remains more limited. Ongoing research into targeted therapies and immunotherapies offers hope for better outcomes.

• American Cancer Society
• Leukemia and Lymphoma Society
• American Society of Hematology
• Lymphoma Research Foundation
• National Cancer Institute