All About Pediatric Non-Hodgkin Lymphoma

What is lymphoma?

Lymphoma is a type of cancer affecting cells of the lymph system. The lymph system is part of the immune system that is made up of a network of lymph nodes, lymph vessels, and organs, including the thymus, spleen, and bone marrow. Lymphoma can start in any of these tissues. There are two broad categories of lymphoma: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma, which is discussed in a separate article. The cancerous cell in NHL is called a "lymphocyte,” which is a cell that normally is involved in the immune response that protects the body from infection. In NHL, these lymphocytes divide at an abnormally fast rate. This causes enlargement of lymph nodes or other organs in the lymph system and is responsible for the symptoms experienced by children with NHL.

What causes NHL and who is at risk?

Each year about 800 new cases of NHL are diagnosed in children in the United States. Males are affected more often than females. No one knows what causes NHL. As with most childhood cancers, the majority of pediatric cases of NHL occur in patients without risk factors, or "sporadically.”

In come cases, NHL occurs in patients who have a condition or risk factor for developing this cancer. Congenital (meaning you are born with them) and acquired immunodeficiency syndromes can increase the risk of NHL. Congenital immunodeficiencies include Wiskott Aldrich syndrome, ataxia telangiectasia, and X-linked lymphoproliferative syndrome. It can also occur when children need to take medications that suppress certain immune cells, such as after receiving a solid organ transplant (e.g. kidney, liver, heart, lung) to prevent graft rejection, or in the case of viruses such as HIV.

How can NHL be prevented in a child?

Because no one knows exactly what causes NHL, there are no specific steps to prevent developing it.

What screening tests are used?

There are no recommended screening tests for childhood cancer. A child won't be tested for NHL unless they are showing signs or symptoms of the disease.

What are the signs and symptoms of NHL?

Children can have a wide range of symptoms depending on where in the body the lymphoma cells are present. Some common symptoms include:

• Enlarged lymph nodes in the neck, underarm, or groin (usually painless and firm).
• Enlarged spleen or liver. With an enlarged spleen, your child may feel full or have pain in the upper left side of the abdomen or back. An enlarged liver may cause symptoms like jaundice (the skin and whites of eyes appear yellow and urine may be darker in color), feeling full, and fatigue.
• Difficulty breathing or a cough (from an enlarged thymus—an immune organ in the upper chest, or enlarged lymph nodes within the chest).
• Unexplained fevers, unintentional weight loss, or sweating a lot at night.
• Vomiting or belly pain caused by a blockage from enlarged lymph nodes in the intestines.

These symptoms could also be caused by other illnesses. It is important to have your child seen by a provider if they are having any change in how they are feeling.

How is NHL diagnosed?

When a child has symptoms of NHL, a healthcare provider will conduct a history and physical examination. Other tests may include:

• Blood tests to check blood counts, electrolytes & kidney/liver function.
• CT scan of neck, chest, abdomen, and pelvis.
• Positron emission tomography (PET) scan—a type of CT that identifies areas in the body with a high metabolic rate, like cancer.
• Bone marrow biopsy.
• Cerebrospinal fluid sampling by lumbar puncture (spinal tap/LP).

Findings from these tests will determine if a biopsy is needed and in which part of the body the biopsy should be done. A biopsy is the only definitive way to diagnose NHL. If an enlarged lymph node is present, it will be removed and examined under a microscope by a pathologist. If special tests need to be conducted on the biopsy it may take several days or longer to confirm a diagnosis of NHL.

NHL is categorized based on the specific type of lymphocyte that has become cancerous, and its stage of maturation. Each type of NHL responds differently to therapy, and knowing the specific subtype allows for the best treatment. In general, the types of NHL that affect children divide rapidly and are considered aggressive. The following are the major types of NHL seen in pediatric patients:

• Burkitt lymphoma.
• Diffuse large B cell lymphoma (DLBCL).
• Anaplastic large cell lymphoma.
• Lymphoblastic lymphoma (either T- or B-cell).

There are many other types of NHL, but most of these are seen in adults and rarely affect children.

How is NHL staged?

Staging is often used in cancer to help create a treatment plan. Staging takes into account how large a tumor is, how it looks under a microscope and if it has spread. NHL in children is staged using the St. Jude system:

• Stage I: The lymphoma is in one place, either as one tumor or in lymph nodes in one part of the body (not in chest or abdomen).
• Stage II: The lymphoma is in a single tumor and in nearby lymph nodes in one part of the body, or the lymphoma is more than one tumor and/or in more than one set of lymph nodes, all of them being above or below the diaphragm.
• Stage III: The lymphoma started in the chest, or started in the abdomen and can't be removed by surgery, or is next to the spine, or is in tumors/lymph nodes above and below the diaphragm.
• Stage IV: The cancer is in the spinal fluid and/or bone marrow.

What are the treatments for NHL?

Subtype and staging information is critical for making a treatment plan. Often, these tests are done before starting therapy. In some cases, urgent treatment may begin prior to having all the necessary information. An example of this is when the lymphoma is threatening the function of a vital organ or structure such as the heart, airway, spinal cord, or kidneys, or when the rapidly dividing lymphoma cells are causing changes in the electrolyte balances (potassium, calcium, magnesium, etc) in the body. This is uncommon but can happen.

Chemotherapy is a very effective treatment for pediatric NHL. Often, chemotherapy is the only treatment needed. The type of chemotherapy depends on the subtype of NHL and the extent of disease (staging) and varies both in terms of the intensity and duration of treatment. In all cases, combinations of drugs are used to attack the lymphoma in different ways. There are always possible late or long-term effects of treatment. This means that side effects could happen after treatment has ended and later in life. The provider should speak about these possible side effects.

For Burkitt lymphoma and DLBCL, treatment tends to be short (lasting 3-6 months). It is short but intense, often requiring admission to the hospital. Anaplastic large cell lymphoma therapy is somewhat longer (up to 1 year) but the therapy is less intense and can often be given on an outpatient basis. Finally, lymphoblastic lymphomas are treated mostly as outpatients over about 2 years. How often and the types of chemotherapy given really vary depending on the subtype of NHL. Some of the more common medications used (in combination) to treat pediatric NHL are:

• Steroids (prednisone, prednisolone, dexamethasone)
• Cyclophosphamide
• Vincristine
• Doxorubicin
• Methotrexate
• Cytarabine (Ara-c)
• Etoposide
• Rituximab

Chemotherapy is often given directly into a vein (IV) but if lymphoma is present in the cerebrospinal fluid (CSF), chemotherapy may be given directly into the spinal fluid during a lumbar puncture (LP). This is called intrathecal chemotherapy. It is given along with standard chemotherapy, even when lymphoma cells are not seen in the spinal fluid during the initial staging evaluation. Intrathecal chemotherapy is used preventatively to decrease the risk of the lymphoma coming back in the central nervous system.

One of the most important aspects of the treatment process is monitoring the individual patient's response. While we know what medicines work for most children with NHL, currently we cannot predict with complete certainty which lymphomas will respond. During treatment, the oncology team will get imaging tests (mostly CT scans and sometimes PET scans) to see how well the lymphoma is responding. If the response is slow or not complete, changes to the treatment plan may be made.

What if NHL comes back after treatment?

After therapy is over, children who have been treated for NHL are monitored every several months with labs, imaging tests, and physical examinations to determine if the lymphoma is coming back (relapsing). The highest risk for relapse is in the first two years after the end of treatment, but can occur later. Relapsed NHL can be harder to treat and get to remission than initial NHL, and typically involves more intensive therapy—often with different medications than those used at first. If another remission is achieved, many patients will require a bone marrow transplant and radiation. The bone marrow transplant will either use the patient's own cells to help them recover from very high doses of chemotherapy (autologous transplant) or bone marrow cells from another person (allogeneic transplant). The choice of whether to use bone marrow transplant and which type is highly individualized, and depends on the subtype of NHL, the timing of relapse, response to treatment, availability of donors, among many others.

Clinical Trials

There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered, or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Follow-up Care and Survivorship

After treatment for childhood cancer, the patient will be followed closely to monitor for the cancer coming back, to help them heal from ongoing side effects, and to help them to transition to survivorship. Initially they will be seen often and have ongoing tests to monitor their health. As time goes on, these visits and testing will become less frequent. The oncology team will discuss each patient’s individual follow up plan with them.

The treatment used can lead to late effects, meaning side effects that happen after treatment is complete. These can include changes to heart and lung function, slowed growth, bone damage, changes in sexual development, learning difficulties and second cancers. If there are any new health issues it is important that a provider is contacted to work up these new issues.

What can you do to live a healthy life after treatment? There is no supplement or specific food you can eat to assure good health, but there are things you can do to live healthier, prevent other diseases, detect cancers early and work with the social and emotional issues, including insurance, employment, relationships, sexual functioning, and fertility, that a prior cancer diagnosis sometimes brings with it. Your oncology team is there to support you and can help you find support resources.

It is important to have a plan for who will provide follow up care (an oncologist, survivorship doctor or primary care doctor). Talk with the team about developing a survivorship care plan or develop one using the Smart ALACC tool. Your child may benefit from being seen in a survivorship clinic. At a survivorship clinic a provider can review your child's history and provide recommendations. You can contact cancer centers in your area to see if they have a survivor's clinic or search for a clinic on OncoLink's survivorship clinic list.