An Overview of Lymphoma

A group of over 70 blood cancers affecting the lymphatic system

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Lymphoma is a type of cancer that affects the lymphatic system. The lymphatic system is a large network of vessels that carry a clear fluid, called lymph, that helps rid the body of germs, toxins, and other unwanted substances. Also included in the system are lymph nodes, the spleen, thymus gland, bone marrow, and a type of white blood cells known as lymphocytes. Lymphoma can affect any part of the lymphatic system and, in severe cases, spread to organs outside of the system.

There are over 70 different types of lymphoma classified under the two broad categories:

NHL accounts for around 90% of all lymphomas and includes such subtypes as Burkitt lymphoma, chronic lymphocytic leukemia, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, and Waldenstrom macroglobulinemia.

The signs and symptoms of lymphoma are often nonspecific and may include swollen lymph nodes, fever, night sweats, and weight loss. If suspected, lymphoma can be definitively diagnosed with a lymph node biopsy, after which the disease will be categorized and staged to ensure the appropriate treatment.

According to a 2016 study in CA: A Cancer Journal for Clinicians, lymphoma is the fourth most common cancer in the United States—with over 135,000 new diagnoses each year—and the sixth leading cause of cancer deaths.

Symptoms

Lymphoma can cause a wide variety of symptoms depending on which part of the lymphatic system is affected. Oftentimes, the signs and symptoms are so subtle that they can remain unnoticed for years.

The most common symptom—and sometimes the only symptom—is persistently swollen lymph nodes, a condition referred to as chronic lymphadenopathy. The lymph nodes (located in the neck, armpits, chest, and groin) are responsible for filtering excess fluids and toxins from the body.

When lymphocytes become cancerous, they will collect in the lymph nodes and trigger an immune response, causing them to swell and harden.

Lymphadenopathy in people with lymphoma will typically be painless in the early stages. On examination, the lymph nodes will be firm, rubbery, and movable in the surrounding tissues.

Other symptoms of lymphoma may include:

  • Chronic fatigue
  • Loss of appetite
  • Persistent cough
  • Persistent itchiness
  • Easy bruising or bleeding
  • Nausea and vomiting
  • Fever and chills
  • Shortness of breath
  • Weight loss
  • Chest, abdomen, or bone pain
  • Frequent or recurrent infections

The more overt signs and symptoms tend to occur with later-stage disease. Unintended weight loss of greater than 15% and localized symptoms (like chest, abdominal, or bone pain) typically suggest advanced disease.

Causes

Little is known about the causes of lymphoma, but there are certain factors that are known to increase your risk. A number of these are associated with Hodgkin lymphoma, NHL, or both. With that said, it is possible to have no risk factors and still get lymphoma.

Among the six most common risk factors for lymphoma are age, sex, family history, immune dysfunction, infections, and radiation exposure.

Age

Lymphoma can develop in people of any age, including children, but the majority occur in people over 60. With respect to Hodgkin lymphoma specifically, a significant number of cases are diagnosed between 15 and 40, as well.

Sex

Men are slightly more likely to develop lymphoma than women. However, women are more slightly more likely to develop nodular sclerosing Hodgkin's lymphoma (NSHL), the most common and treatable form of Hodgkin's lymphoma.

Family History

Genetics are believed to play a significant role in Hodgkin lymphoma. According to a 2015 study in the journal Blood, there is a two-fold increased risk of lymphoma if your parents have the disease and a six-fold increased risk if a sibling is affected.

By contrast, genetic changes related to NHL are usually acquired rather than being inherited. Acquired gene changes can result from exposure to radiation, chemicals, or infections, but often these changes occur spontaneously and for no apparent reason.

Immune Dysfunction

Immunodeficiency disorders such as HIV can increase your risk of NHL as well as a rare form of Hodgkin lymphoma called lymphocyte-depleted Hodgkin lymphoma (LHDL). Similarly, autoimmune diseases like lupus and Sjögren syndrome are associated with as much as a seven-fold increased risk of NHL.

Even the immunosuppressant drugs used to treat autoimmune diseases or prevent organ transplant rejection are known to increase the risk of NHL, particularly with long-term use.

Infections

A number of common bacterial, viral, and parasitic infections are known to increase the risk of lymphoma. Among them::

  • Epstein-Barr virus (EBV) is closely linked to certain types of NHL, such as Burkitt lymphoma and post-transplant lymphoma, as well as 20% to 25% of all Hodgkin lymphoma cases.
  • Helicobacter pylori (H. pylori), a bacterial infection associated with gastric ulcers, is linked to mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach.
  • Hepatitis C virus (HCV) can increase the risk of certain types of NHL by causing the excessive production of lymphocytes, many of which are malformed and vulnerable to malignancy.
  • Human herpesvirus 8 (HHV8), a virus associated with a rare skin cancer called Kaposi sarcoma in people with HIV, can increase the risk of an equally rare lymphoma known as primary effusion lymphoma (PEL).

Radiation Exposure

People exposed to high levels of radiation, including previous radiation therapy for cancer, are at an increased risk of NHL.

The risk is especially high in people with non-small cell lung cancer in whom radiation may increase the risk of lymphoma by as much as 53%. The risk is further increased when radiation and chemotherapy are combined.

Diagnosis

If lymphoma is suspected, the diagnosis will typically start with a review of your symptoms and medical history, followed by a physical exam to check for swollen lymph nodes or abnormal changes in size or texture of the spleen or liver. A complete blood count (CBC) will also be performed to look for characteristics drops in white blood cells, red blood cells, and platelets.

Additional blood tests may be ordered to rule out other possible causes or to detect infections closely linked to lymphomas, such as HIV and hepatitis C. A chest X-ray may also be ordered to check for lymphadenopathy in the chest.

Other blood tests such as erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and liver functions tests (LFTs), may be performed, although they are generally more useful in staging rather than screening lymphoma.

None of these tests can diagnose lymphoma, but they may provide the evidence needed to move to the next stage of the diagnostic process: the lymph node biopsy.

Lymph Node Biopsy

The lymph node biopsy is the gold standard for the diagnosis of lymphoma. It not only provides definitive evidence of lymphoma but also helps kickstarts the process of classifying and staging the disease.

There are two types of biopsies commonly used to diagnose lymphoma, both of which can be performed on an outpatient basis with local anesthesia:

  • Excisional lymph node biopsy, involving the removal of the entire lymph node.
  • Incisional lymph node biopsy, involving the partial removal of a lymph node or a lymph node tumor

Imaging studies—such as X-ray, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI)—may be performed prior to the biopsy to guide the surgeon to the exact location of the targeted node. Real-time CT scans are especially useful for performing chest node biopsies.

Needle biopsies, such as fine-needle aspiration or core needle biopsy, are less commonly used because they may not obtain enough tissue to render an accurate diagnosis.

The biopsied tissue will be examined under the microscope to detect cellular changes consistent with lymphoma. If lymphoma is diagnosed, additional tests will be used to classify and stage the disease.

Classification

The classification of lymphoma is not always straightforward since there are so many types and subtypes of the disease. Blood tests, positron emission tomography (PET) scans, bone marrow biopsy, and other procedures may be used to help narrow the field.

The systems for classifying lymphoma can vary but are based on similar criteria, namely:

  • Differentiation of Hodgkin or non-Hodgkin lymphoma: Key to differentiation is a type of cell, called a Reed-Sternberg cell, unique to Hodgkin lymphoma only. NHL types and subtypes also require differentiation.
  • Differentiation of T-cells and B-cells: Affected lymphocytes may either be T-cells (derived from the thymus gland) or B-cells (derived from bone marrow). These characteristics can predict if a cell is indolent (slow-growing) or aggressive as well as the treatment options.
  • Areas of involvement: The organs and tissues affected can further aid in the classification of lymphoma. For example, lymphoma is the lining of the stomach is more likely to be MALT lymphoma, while skin lesions are far more likely to occur with NHL than Hodgkin lymphoma in early-stage disease.

Based on these and other factors, lymphoma may be classified as one of 33 types or subtypes under the Revised European American Lymphoma Classification (REAL) system or one of over 70 types and subtypes under the World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Staging

After the initial diagnosis and classification, staging is performed to determine the proper course of the treatment as well as the likely outcome of treatment (referred to as the prognosis). The staging is based on a number of factors, including the number of lymph nodes affected, their location above or below the diaphragm, and whether other organs are involved.

According to the Lugano classification system for lymphoma, revised in 2015, the stages of lymphoma are broken down as follows:

  • Stage 1: Cancer is confined to one lymph node region or one organ of the lymphatic system.
  • Stage 2: Cancer is confined to two or more lymph node regions on the same side of the diaphragm or one lymphatic organ in addition to nearby lymph nodes.
  • Stage 3: Cancerous lymph nodes are found above and below the diaphragm.
  • Stage 4: Cancer has spread to other organs outside of the lymphatic system, such as the liver, lungs, or bone.

Stage 3 and stage 4 lymphomas are still highly treatable and often curable depending on the type and location.

Treatment

Not all lymphomas can be cured. Hodgkin lymphoma tends to be the most treatable, while low-grade NHL (also known as indolent lymphoma) is unlikely to be cured. Even so, incurable lymphomas can often be managed for years and even decades.

Treatment plans are based largely on the type and stage of lymphoma you have as well as your overall health and personal preferences. Not all lymphomas require immediate treatment.

Certain low-grade NHLs, such as follicular lymphoma, may benefit from a watch-and-wait approach (referred to active surveillance). Treatment would only start when symptoms develop or the disease suddenly changes.

When treatment is indicated, the plan may involve one or several of the following:

How and when these treatments are used can vary based on the type of lymphoma you have.

Hodgkin Lymphoma

Hodgkin lymphoma typically is treated with radiation alone as long as the malignancy is localized. Advanced Hodgkin lymphoma will typically require chemotherapy with or without radiation. Most cases in the United States are treated with a combination of drugs called the ABVD regimen. People who relapse after ABVD may still benefit from a stem cell transplant.

Bone marrow transplants are less commonly used today, mainly because it is easier to harvest stem cells from blood rather than from bone marrow. Recovery time is also shorter.

A more aggressive chemotherapeutic approach, called the BEACOPP regimen, is reserved for only the most advanced cases due to high levels of toxicity.

Low-grade NHL

Many low-grade lymphomas remain indolent for many years. If an indolent lymphoma suddenly becomes symptomatic after a period of active surveillance, radiation or chemotherapy may be used to alleviate symptoms, such as painful lymphadenopathy. In most cases, a low-grade NHL cannot be cured.

If chemotherapy is used, some specialists will add the biologic drug Rituxan (rituximab) to help achieve remission. Afterward, Rituxan many used on its own to help sustain remission.

Even though indolent lymphomas are largely incurable, a near-normal life expectancy and high quality of life can often be achieved.

Active surveillance may not be the best option for some people due to high levels of stress. As an alternative, some specialists will use a single dose of Rituxan to keep the malignancy in check while monitoring the status.

High-Grade NHL

High-grade, aggressive NHL can often be cured with aggressive chemotherapy, although a poor response is associated with poorer outcomes. Aggressive combination therapies, such as CHOP and R-CHOP, are known to offer high cure rates, albeit with considerable side effects.

For people who experience a relapse following CHOP or R-CHOP, high-dose chemotherapy followed by a stem cell transplant is a proven approach.

Coping

Living with lymphoma can often be stressful even if you don't have symptoms. Not only can the specter of treatment be scary, but being told that you won't be treated can cause anxiety, sometimes extreme.

It often takes time to sort out your feelings when faced with lymphoma. To make sense of it all, start by educating yourself and those around you. Lymphoma can be a difficult disease to wrap your head around, but the more you understand about what it is and what to expect moving forward, the better able you will be to make informed choices.

Focus on quality resources from certified authorities, including your doctor or websites operated by universities, hospitals, government, or public health organizations.

Emotional

Finding support is key to coping with lymphoma. This not only includes your family, friends, and oncology team but also support groups who fully understand what you are going through. This can be especially important during chemo when words of encouragement, insights, and advice can help you over even the roughest of patches.

In addition to community groups on Facebook, you can be linked to support groups through your oncologist or the American Cancer Society's online resources locator.

If you are unable to cope, ask your doctor for a referral to a psychologist or psychiatrist who can help you come to terms with your diagnosis and start normalizing lymphoma in your daily life.

Physical

Even though there are few things you can do to actively alter the course of lymphoma, keeping yourself healthy and fit can help you better deal with the challenges of living with the disease. This includes maintaining a healthy diet, exercising at least three to four times per week, quitting cigarettes, and losing weight if needed.

If you have HIV, hepatitis, or other chronic diseases, you need to ensure they are treated appropriately to keep your immune system strong and intact. Managing your stress with yoga, meditation, or other mind-body therapies can also help enormously, both physically and emotionally.

Most importantly, you need to stay linked to medical care to ensure you achieve and maintain the best treatment response possible. Even if you have been cured, regular visits to your oncologist can ensure that relapses are identified early before potentially serious complications arise.

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Article Sources

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