Lymphoma

What is Lymphoma?

Lymphomas are a type of cancer that comes from the abnormal growth of certain types of white blood cells known as B-cells, T-cells, and natural killer (NK) cells. These cells are all different types of lymphocytes, or immune cells, that your body produces at various stages of its development.

These cancers, though they can vary significantly, all stem from an overgrowth of these immune cells. They represent about 5% of all cancers. Based on current data, approximately 72% of people diagnosed with lymphoma are estimated to survive. This highlights the importance of early detection and treatment in improving the outcomes for these patients.

What Causes Lymphoma?

Different factors from the environment, infections, and genetics can increase the risk of getting lymphoma, a type of cancer that starts in cells that are part of the body’s immune system.

Firstly, exposure to certain things in your job, like herbicides and pesticides, can make you more likely to develop lymphoma.

Secondly, infections from different organisms can also increase your risk. These include Helicobacter pylori (related to MALT lymphoma), Borrelia burgdorferi, Chlamydia psittaci, Campylobacter jejuni, human T- cell lymphotropic virus (related to adult T- cell leukemia/lymphoma), hepatitis C (related to lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma and marginal zone lymphoma), and human herpesvirus 8 (related to primary effusion lymphoma and Castleman disease). Frequent stimulation of lymphoid tissue (part of your immune system) raises your risk of developing lymphoma, as does a constant infection with viruses like Epstein Barr virus and cytomegalovirus.

Thirdly, immune deficiency diseases like HIV infection, and patients who received transplant, especially those with genetic immune deficiency disorders (like severe combined immunodeficiency and common variable immunodeficiency), are also more prone to the disease.

Certain drugs can also add to the risk. Particularly, drugs that inhibit tumor necrosis factor-alpha have been associated with T- cell lymphoma. Patients who receive chronic immunosuppression after a transplant (either solid organ or bone marrow) see an increased risk of lymphoma.

Autoimmune diseases, which happen when your immune system mistakenly attacks your body, such as, Inflammatory bowel disease (linked with enteropathy-associated lymphoma), rheumatoid arthritis, and Sjögren’s syndrome (related to diffuse large B-cell lymphoma) can also lead to lymphoma.

Lastly, your geographical location can also influence your risk. In particular, the incidence of extranodal NK/T- cell lymphoma, a type of lymphoma, is high in Southern Asia and some parts of Latin America.

Risk Factors and Frequency for Lymphoma

Lymphoma is a kind of cancer that, in the USA between 2009 and 2013, made up approximately 5% of all cancers, with 22 instances occurring for every 100,000 people. Since the 1990s, the rate of lymphoma hasn’t significantly increased or decreased. The average age at which people are diagnosed is 63, and it’s estimated that 72% of individuals with lymphoma survive at least five years after diagnosis.

Lymphomas can be sorted into two types: 10% of cases are Hodgkin lymphoma (HL) and 90% are Non-Hodgkin lymphoma (NHL). Hodgkin lymphoma can be designated as either classical or non-classical. Non-Hodgkin lymphoma can be separated into B-cell, T-cell, and natural killer (NK) cell types. Clinically, lymphoma can also be described as aggressive (high grade) or indolent (low grade).

The World Health Organization (WHO) released a classification of lymphomas in 2016, which includes:

• Mature B-cell neoplasms, such as chronic lymphocytic leukemia/small lymphocytic lymphoma and plasma cell myeloma.
• Mature T and NK neoplasms, such as T-cell prolymphocytic leukemia and adult T-cell leukemia/lymphoma.
• Hodgkin lymphoma, including nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma.
• Posttransplant lymphoproliferative disorders (PTLD), including plasmacytic hyperplasia PTLD and monomorphic PTLD (B- and T-/NK-cell types).

Each of these categories includes many specific types of lymphomas. For instance, mature B-cell neoplasms can include everything from hairy cell leukemia to extraosseous plasmacytoma, while mature T- and NK-cell neoplasms can range from systemic EBV+ T-cell lymphoma of childhood to mycosis fungoides. Hodgkin lymphoma can be either nodular lymphocyte-predominant or it can fall under various types of classical Hodgkin lymphoma.

Signs and Symptoms of Lymphoma

Hodgkin Lymphoma often starts with painless, enlarged superficial lymph nodes. As the disease advances, it tends to spread to other nodes and later to other parts of the body. Most patients present with disease above the diaphragm, and isolated lower body disease is quite rare. It’s common to see enlarged lymph nodes in the neck or above the collarbone, with less common involvement in the axilla (armpit) or chest. Involvement of abdominal organs is rare. However, the disease can spread to other organs like bone, bone marrow, lung, and liver, and in rare cases to the central nervous system.

• Usually start with painless, enlarged superficial lymph nodes
• Can spread to other nodes and later to other parts of the body
• Often seen in the neck or above the collarbone
• Can move to axilla (armpit) or chest
• Involvement of abdominal organs is uncommon
• It can spread to bone, bone marrow, lung, and liver

In about a quarter of the patients, systemic symptoms may appear before lymph node enlargement. These symptoms include fevers, night sweats, and unintentional weight loss. Other symptoms could include severe itching and localized pain following alcohol intake. Rare neurological symptoms have also been reported.

Non-Hodgkin Lymphoma comes in various types, including DLBCL, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, and Burkitt Lymphoma. Each type presents with different symptoms and disease progression, from enlarging lymph nodal mass, malaise and fatigue, to detectable stage 4 disease and involvement of certain sites such as the gastrointestinal tract and various organs.

Testing for Lymphoma

Once the tissue biopsy has confirmed the diagnosis of lymphoma, the next step is to identify where the disease is most active in the body. This is usually done through PET/CT scans which help to measure the activity of the lymphoma, by indicating how much radiolabeled fluorodeoxyglucose (a type of glucose used as a tracer) is absorbed by the body.

This disease activity evaluation, also known as staging, is done before starting any treatment for lymphoma. The staging process involves using the Ann Arbor staging system, which classifies the disease based on symptoms like persistent fever, significant weight loss over six months, or night sweats.

Apart from the PET/CT scans, other tests like blood work are also crucial. These tests include checking the levels of lactate dehydrogenase (an enzyme that plays an important role in energy production), full blood counts with differential (to measure the amount of different types of white cells, red cells and platelets in the blood), comprehensive metabolic panel (to check the levels of various chemicals in the blood), and uric acid.

While there are other scanning methods like CT of the chest, abdomen, and pelvis, whole-body PET/CT imaging is generally the preferred method. We also sometimes do a bone marrow biopsy to help with staging. However, for stage III Diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), we might not do this test because finding out whether it is stage III or stage IV will not change the treatment plan.

In cases where the lymphoma is considered high risk, we might supplement the usual staging process with cerebrospinal fluid testing. There are also tools like CNS-IPI (CNS Internal Prognostic Index) that we use to predict the likelihood of the disease spreading to the central nervous system, especially for aggressive lymphomas like DLBCL.

As for B and T-cells (types of white blood cells that are part of the immune system), their function is determined through the identification of cell-surface receptors or antibodies as appropriate. B-cells mature in the bone marrow and encounter foreign substances for the first time within the lymph node’s germinal center (GC). B-cells can hence be classified into GC (those in the germinal center) or post-GC (those that have encountered a foreign substance and matured).

Some post-GC B-cells eventually develop into plasma cells, which release immunoglobulins (also known as antibodies) that combat these foreign substances. To determine if B-cell lymphomas (a type of cancer) are present, we use a method known as immunohistochemical staining. This technique identifies the presence of light chains (proteins that form part of the antibodies) which indicates whether all the lymphocytes (a type of white blood cell) are expressing either kappa or lambda light chains- a possible sign of cancer. What’s known as light chain restriction points to the presence of a lymphocytic clone – an identical group of lymphocytes potentially pointing to the presence of lymphoma.

Treatment Options for Lymphoma

Hodgkin Lymphoma is typically treated with a combination of chemotherapy and radiotherapy. The majority of cases respond well to these treatments and overall survival is usually high. Different countries have slightly different treatment approaches, with the US typically using a combination of drugs known as ABVD, while Germany often uses BEACOPP. Another treatment used is Stanford V. These all have roughly the same success rates, but BEACOPP carries slightly higher cure rates at the cost of significant side effects.

Supplementary treatments such as radiation are often used, particularly in cases where the disease is extensive or lingering after chemotherapy. The effectiveness of the treatment is evaluated through PET/CT scanning. Emerging strategies are now considering the progression from ABVD to more intensive treatments like BEACOPP only for those who have incomplete responses to ABVD.

After finishing the treatment, patients are evaluated regularly through check-ups and basic lab tests to monitor for any signs of recurrence. Due to the often young age of patients with Hodgkin Lymphoma, these check-ups are particularly important to manage long-term effects of treatment, such as the development of other cancers, and to ensure the disease has not returned.

Diffuse Large B-Cell Lymphoma’s standard treatment is combined chemotherapy, known as R-CHOP. Additionally, radiation therapy can be used for more localized diseases, and milder treatment options are available for patients with poor health status. Amidst the treatment process, continual assessments are done to monitor the effectiveness of treatment and ensure timely modifications can be made.

Follicular Lymphoma, as it is a slow-growing cancer, has a more varied behavior. Some cases can be kept under observation without needing immediate treatment, while others progress and can cause severe symptoms. For patients, therapeutic strategies can start from a less aggressive approach, depending on the disease burden.

In general, different subtypes of lymphoma require different treatment strategies. Early-stage MZL may be treated with radiation therapy or even surgery in the case of splenic MZL. An aggressive disease, such as Mantle Cell Lymphoma, usually requires more intensive treatment. Some patients with highly aggressive diseases, such as Burkitt Lymphoma, require immediate treatment and sometimes even stronger chemotherapy regimens to pre-empt the high proliferation rate of the tumor.

Overall, though the characteristics and course of these diseases vary significantly, most of them can be managed effectively with aggressive and timely treatments that adhere to the specific nature of the disease.

What else can Lymphoma be?

There are several diseases that can present with symptoms similar to other conditions. These include:

• Tuberculosis
• Sarcoidosis
• Behçet disease

What to expect with Lymphoma

The Ann Arbor staging system, which is used to assess both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL), doesn’t always accurately predict how the disease will progress. For this reason, doctors have developed additional tools to better understand and communicate a patient’s prognosis (the likely outcome of the disease).

For example, doctors might use the HL international prognostic score for Hodgkin’s lymphoma, or the international prognostic index (IPI) for diffuse large B-cell lymphoma (DLBCL). In the case of follicular lymphoma, a type of NHL, they may use the follicular lymphoma international prognostic index (FLIPI).

It’s important to know that a low IPI score suggests a better outcome and a high IPI score a worse outcome. This helps doctors plan the most suitable treatment and allows patients to understand their situation more clearly.

Possible Complications When Diagnosed with Lymphoma

Hodgkin Lymphoma Complications:

• Paraneoplastic syndromes: This can include conditions like limbic encephalitis, which is associated with anti-metabotropic glutamate receptor 5 (mGluR5) antibodies. Other conditions can include primary CNS angiitis and cerebellar degeneration related to anti-Tr antibodies, and POEMS syndrome which brings about polyneuropathy, organ enlargement, hormonal imbalances, monoclonal plasma cell disorder, and skin changes.

Non-Hodgkin Lymphoma Complications:

• Transformation of less aggressive lymphomas: Types of lymphoma like follicular lymphoma and marginal zone lymphoma can transform into more aggressive lymphomas like diffuse large B-cell lymphoma.

Chemotherapy Complications:

• Pancytopenias: This is when the body is low on all three types of blood cells.
• Sterility: Difficulty or inability to conceive a child.
• Cardiomyopathy: A condition that makes it harder for your heart to pump blood to the rest of your body. This can be caused by the chemotherapy drug doxorubicin.
• Pneumonitis: Lung inflammation that can be caused by the chemotherapy drug bleomycin.
• Neuropathy: This is nerve damage that could be caused by vincristine and brentuximab vedotin used in chemotherapy.
• Second primary malignancies: Getting a new, unrelated cancer such as acute myeloblastic leukemia or acute lymphoblastic leukemia.

Radiation Therapy Complications:

• Accelerated atherosclerosis: This is when your arteries harden and narrow faster than usual.
• Pericardial fibrosis: Scarring and hardening of the tissue around the heart.
• Second primary cancers: These are new, unrelated cancers in the lung, thyroid, breast or in the soft tissues forming parts of the body.
• Hypothyroidism: This is when your thyroid doesn’t make enough of certain key hormones.

Preventing Lymphoma

Lymphomas, which are a type of cancer that attacks our immune system, account for nearly 5% of all cancer cases. They can occur in people of any age group, both young and old. The usual signs of having lymphoma can include persistent fevers, severe sweats during the night, unintentional weight loss, and swollen lymph nodes, which can be either throughout the body or in only one area. If you notice any of these symptoms, your doctor will likely ask for advice from a specialist in blood disorders, known as a hematologist, as quickly as possible. This is because finding and treating lymphomas early improves the chances of surviving the disease, while also reducing potential further health complications.