The lymphoid system is part of the immune system that protects the body from infection and cancer. It comprises of white blood cells called lymphocytes that reside primarily in lymph nodes that are spread throughout the body, in the spleen, in the thymus, in the tonsils, in the digestive tract, and in the bone marrow. These elements of the lymphoid system are connected by a network of lymph vessels (tubes) and the blood stream.

Typically, lymphomas develop in the lymph nodes or the primary lymphoid organs. However, they can begin in almost any part of the body, and spread similar to other cancers. Non-Hodgkin lymphoma cells can also spread into the cerebrospinal fluid (CSF) that surrounds the brain and the spinal cord or to the bone marrow.

Based on the characteristics and microscopic appearance of the cancer cell, the lymphomas are divided into Hodgkin Lymphoma and non-Hodgkin lymphoma (NHL). The specific type of lymphoma and the extent of its spread will determine the necessary treatment. With current approaches the majority of children with lymphoma are cured from their disease.
Non-Hodgkin lymphomas are classified based on the cell of origin and their appearance under the microscope.

Types of Lymphoma

There are many types of lymphoma but only four common subtypes of lymphoma are encountered in children:

• Burkitt and Burkitt-like lymphoma
• Diffuse large B-cell lymphoma
• Anaplastic large cell lymphoma
• Lymphoblastic lymphoma (of B- or T-cell origin)

Lymphoma Risk Factors

Non-Hodgkin lymphoma may develop in children of all ages and it is more common in boys than girls.
The causes of non-Hodgkin lymphoma are unknown and no risk factors can be identified in most children who are diagnosed with this disease. Certain groups of children are at an increased risk:

• Children whose immune system is weak (inherited or acquired immune deficiency)
• Children with DNA repair defects (i.e. ataxia telangiectasia).

Non-Hodgkin Lymphoma Symptoms

Non-Hodgkin lymphoma may present as painless swelling of lymph nodes (lymphadenopathy). The enlarged lymph nodes are seen in the neck, above the collar bone, under the arms, or in the groin.

Commonly, enlarged lymph nodes may involve internal organs: abdominal mass and cause abdominal pain, constipation, and abdominal distention, a chest (mediastinal) mass can result in cough, difficulty breathing, wheezing, difficulty swallowing, and infrequently bone or bone marrow involvement can cause bone pain. Occasionally non-Hodgkin lymphoma is associated with systemic symptoms including persistent fever (>100.4F or 38C) without an apparent cause, weight loss, and night sweats.

By far the most likely cause of swollen lymph nodes is the normal reaction of the immune system to an infection. However features that are associated with lymphoma include an unusually large or rapidly enlarging lymph node, a lymph node above the collar bone or accompanying systemic symptoms (see below).

Non-Hodgkin lymphoma Diagnoses

If non-Hodgkin lymphoma is suspected, a thorough review of the medical history and detailed physical examination are the initial steps. To establish or rule out the diagnosis of non-Hodgkin lymphoma it is necessary to examine the affected tissue. Unlike other cancers, complete resection of the involved mass is not necessary to cure the disease. Therefore, a limited sampling, or a biopsy, is performed to obtain just enough tissue for analysis. Based on the location of the mass the following diagnostic tests are commonly used to establish the diagnosis. All these procedures are done with the support of the anesthesia and the pain team to minimize pain or discomfort.

• Surgical biopsy. Tissue is removed through a surgical incision.
• Needle biopsy. Tissue is obtained using a specialized needle. This procedure is often done under the guidance of ultrasound or CT imaging.

The tissue sample will be studied by a pathologist under a microscope to look for the cancer cells, and differentiate between the different subtypes of lymphoma. Other confirmatory tests such as immunophenotyping are also performed to establish the diagnosis.

Once the diagnosis of non-Hodgkin lymphoma is established it is important to determine the extent of spread or the stage of the cancer. Accurate staging is crucial to determine the appropriate treatment.

Staging of non-Hodgkin lymphoma (Murphy Staging)

• Stage I: A single tumor (outside a lymph node) or a single lymph node site, with exclusion of the chest or abdomen.
• Stage II: A single tumor (outside a lymph node) with regional involvement,
  • Involvement of two or more lymph node areas on the same side of the diaphragm
  • Two single (outside a lymph node) tumors with or without regional node involvement on the same side of the diaphragm
  • A primary gastrointestinal tract tumor, with or without involvement of nearby nodes, grossly completely removed surgically.
• Stage III: Two single tumors (outside a lymph node) on opposite sides of the diaphragm
  • Involvement of two or more lymph node areas above and below the diaphragm
  • All tumors starting in the chest (mediastinal, pleural, thymic)
  • All extensive tumors starting in the abdomen and cannot be completely removed surgically
  • All lymphomas in areas near the spine or epidural tumors, regardless of other tumor sites
• Stage IV: Any of the above with lymphoma cells involving the brain, cerebrospinal fluid or bone marrow
  • Staging work-up is repeated during therapy and after its completion to assess the response and monitor for disease recurrence.
    • Staging work-up include: 
    • Imaging Including chest X-rays; CT scan, MRI, bone scan, and PET (positron emission tomography) scan are used to generate “pictures” of the internal organs and help determine the extent of the lymphoma. A special dye is commonly injected into the vein and/or swallowed to better delineate internal structures and organs.
    • Blood tests Including a complete blood count (CBC) and blood chemistries are done to look for evidence of disease spread.
    • Bone marrow aspiration and biopsy
    • Bone marrow is removed from the bone (usually the hipbone) by aspiration (suctioning a small amount through a hollow needle) and by biopsy (cutting out a small piece of bone marrow). The marrow is analyzed to determine if Hodgkin lymphoma cells are present.
    • Lumbar puncture (LP) Lymphoma may invade the central nervous system and staging requires the examination of the cerebrospinal fluid (CSF). Fluid is collected by inserting a needle in between the vertebra into the spinal column.
    • Assessment of organ function To allow safe delivery of treatment the function of the lungs, the heart and the kidneys is assessed. Occasionally hearing is tested as well.
      • Based on the results of this evaluation each patient is assigned a stage and patients are grouped into 3 risk groups based on the extent of the disease (stage), the degree of bone marrow or central nervous system involvement. The results of all the tests will be discussed with you at a family meeting, and the appropriate course of therapy will be presented in details.

Risk groups of non-Hodgkin lymphoma

Group A: Stage I and Stage II.
Group B: Patients how are not included in Group A or C
Group C: Any involvement of the brain, cerebrospinal fluid or more than 24% of the bone marrow is occupied by lymphoma 

Non-Hodgkin lymphoma Treatments

The goal of treatment of non-Hodgkin lymphoma is the cure of the disease. Children and adolescents with non-Hodgkin lymphoma should be treated by a team lead by a pediatric oncologist and includes a pediatric radiation oncologist and surgeon.

The details of the therapy are determined based on the subtype of the lymphoma and the stage of the disease. Many children are given the opportunity to enroll on therapy protocols that strive to improve the rate of cure, reduce the risk of long term complications of the therapy, and improve our understanding of non-Hodgkin lymphoma.

Chemotherapy

Chemotherapy is an essential part of therapy for non-Hodgkin lymphoma. It involves the use of a combination of medications that prevent cell growth and kill cancer cells. The medications are given through the vein and/or by mouth during an inpatient hospital stay or in the pediatric oncology outpatient clinic. The appropriate combination depends on the subtype of the lymphoma and the stage of the disease. The treatment of lymphoblastic lymphoma is similar to the treatment of acute lymphoblastic leukemia and includes induction, consolidation, intensification and a two to three years of maintenance period. The treatment of Burkitt, diffuse large B-cell, or anaplastic large cell lymphoma comprises of intensive cycles of chemotherapy over a period of 4-9 months. For all patients, treatment of the central nervous system with injection of chemotherapy into the cerebrospinal fluid is an essential part of therapy.

Monoclonal antibodies are a group of novel agents. These are proteins that recognize and tightly bind specific markers on the surface of the lymphoma cells. Once bound, these antibodies prevent cell proliferation and induce cell death through a variety of mechanisms. Rituximab is an example of such an agent that may be beneficial when combined with chemotherapy for the treatment of mature B-cell lymphomas.

Radiotherapy has a limited role in the treatment of non-Hodgkin lymphoma in children. It involves the delivery of high intensity X-rays that kill cancer cells.

For patients whose lymphoma comes back (relapse) or does not respond adequately to the initial treatment, high dose chemotherapy and hematopoietic stem cell transplantation may offer the best chance of cure. This involves very high doses of chemotherapy with or without radiation followed by infusion of blood forming stem cells from either the patient or a donor.

Although non-Hodgkin lymphoma is a serious disease, 70-95% of newly diagnosed children and adolescents can be cured with current therapy. After completion of therapy long term followup is needed to monitor for disease relapse and long term complications of therapy.