All About Non-Hodgkin Lymphoma

Author: Christina Bach, MBE, MSW, LCSW, OSW-C
Content Contributor: Carolyn Vachani RN, MSN, AOCN & Karen Arnold-Korzeniowski, BSN RN 
Last Reviewed:

What is the lymph system, and what are lymph nodes?

The lymph system is the "housekeeping system" of the body. It is a network of vessels (tubes), that connect the lymph nodes. Lymph nodes are made up of cells that clear possible infection-causing germs (bacteria, viruses, etc.)from the body. Lymph is a watery liquid that flows between cells in the body, picking up foreign debris and taking it into the lymph node for filtering. Infection-causing germs may pass through several more nodes in the system before being dumped into the bloodstream to be cleared by the liver. The lymph system flows throughout the body, and also includes the spleen and thymus gland.

What is a lymphocyte?

Lymphocytes are a type of white blood cell. These cells (called B cells and T cells) help fight infection and makeup what is called the "immune response." 

  • B cells start in the bone marrow and fully develop in the lymph nodes. They produce proteins called antibodies. These move through the bloodstream and attack a specific target as directed by the B cell. 
  • T cells develop in the thymus gland. They directly attack the cells identified as foreign by the B cells. 

Both B cells and T cells are able to remember bacteria from previous infections and can respond quickly to future infections.

What are the Non-Hodgkin's lymphomas?

Non-Hodgkin lymphomas (NHL) are a group of cancers that affect the immune system (the very system that is supposed to protect our body against disease). NHLs begin in the lymph nodes and are made up of malignant (cancerous) lymphocytes (either B cells or T cells). There are over 30 different kinds of NHLs.

In 2001, the World Health Organization (WHO) developed a comprehensive classification system for the different types of NHLs. These are further divided according to the cell type involved (either B cell or T cell). These 30+ types of NHLs are different in their growth rates and aggressiveness and are often treated differently. The full, 2016 version of the WHO classification is listed in the appendix. 

Non-Hodgkin lymphoma makes up about 4% of the cancer diagnoses in the United States with about 81,560 people (both adults and children) each year.  NHL is more common in men than women. Rates are much higher among persons over the age of 65. As the population ages, there will likely be an increase in NHL diagnoses.

Non-Hodgkin lymphomas should not be confused with Hodgkin lymphoma. Hodgkin lymphoma also occurs in the lymph system, but providers can tell the difference between the two because of the presence of Reed-Sternberg cells under the microscope in Hodgkin lymphoma. (Read about Hodgkin lymphoma in adults or in children).

What causes NHL and am I at risk?

The cause of NHLs is still unknown in most cases, but there are some factors known to increase your risk. These factors are related to the immune system and immune responses. Certain viruses and bacteria increase the risk of certain types of NHLs, possibly because they cause a long-term increase in immune response. These include:

  • Helicobacter pylori infection, the same bacteria that causes some stomach ulcers, is associated with MALT lymphoma.
  • Epstein-Barr (EBV) virus is associated with some cases of Burkitt's lymphoma, but many Burkitt's cases are in Africa, and nearly all of these cases are associated with EBV. This points to the fact that there are genetic differences in the types of Burkitt's (and probably all NHLs) found in different areas of the world. 
  • Other viruses thought to increase risk include human T-cell leukemia/lymphoma virus 1 (HTLV-1), human herpes virus 8 (HHV-8), and hepatitis C virus.

Suppression of the immune system appears to cause an increased risk of NHL. The immune system can be suppressed by: 

  • Human immunodeficiency virus (HIV) infection.
  • Organ or bone marrow transplant (requiring immune suppression medications).
  • Rheumatoid arthritis.
  • Inherited immune deficiencies. 

The use of pesticides and herbicides was studied by the National Academy of Sciences (NAS) as a risk factor because agricultural workers had higher rates of NHLs. The NAS found a "positive association" between exposure to herbicides and NHL. This means there is an increased risk with herbicide exposure. It is thought that the use of protective equipment (gloves, jumpsuits, and face protection) can decrease this risk.

Changes in your DNA or genes can also cause NHL. Those with a family history of NHL may have an increased risk of lymphoma. Most gene changes happen over a person's lifespan rather than happening at birth. Research is continuing regarding the exact gene changes that can lead to NHL.  

How can I prevent NHL?

Because no one knows exactly what causes NHLs, there are no specific steps anyone can take to prevent it. The factors that increase risk are generally not things that can be avoided, making it difficult to decrease risk in people affected by these viruses, bacteria, and immune suppression.

What screening tests are used for NHL?

At this time, there is no screening test available for NHLs. Because there are so many different types of NHLs, it would be difficult to develop a single effective test that could screen for all types.

What are the signs of NHL?

Often the first sign of NHL is the swelling of one or more lymph nodes. These can occur in the neck, armpit, or groin as well as other parts of the body and may be painless. Other symptoms may include

  • Fever that does not go away.
  • Drenching night sweats.
  • Weight loss.
  • Fatigue.
  • Itchy skin.
  • Cough or chest pain.
  • Abdominal (belly) pain or bloating due to an enlarged spleen or liver.
  • Rash or skin changes.

Fever, drenching night sweats, and a 10% unintentional weight loss over 6 months are often called “B symptoms.” The length of time you have these symptoms may be related to prognosis and staging of the disease.

Because there are so many forms of NHL that can involve all different organs, signs, and symptoms can vary depending on the areas of the body that are affected. For instance, MALT lymphoma affects the stomach lining and can cause nausea, vomiting, and abdominal pain. Cutaneous T-cell lymphoma affects the skin and can cause redness, itching, or raised patches on the skin.

How is NHL diagnosed?

If you have signs or symptoms of NHL, a healthcare provider will perform a complete medical health history and a physical exam. You will have a biopsy of the enlarged lymph node which can tell your provider if lymphoma is present, and if so, what type. This can be done by inserting a needle into the affected lymph node to remove some tissue, but more often the entire node is removed for examination.

Once NHL is found, a series of other tests are done to see if the lymphoma has spread, where it has spread, and other prognostic information. These tests may include: 

  • Blood tests, including complete blood count, sedimentation rate, LDH, albumin, Hepatitis B and C testing, and beta-2 microglobulin
  • Chest x-ray
  • CT scan or MRI of the chest, abdomen, and pelvis.
  • PET scan.
  • Bone marrow biopsy.
  • Echocardiogram or MUGA scan

How is NHL staged?

After your work-up is complete your care team will stage your cancer. Staging is important because it classifies your cancer by how much disease you have and if/where it has spread. Staging helps guide your treatment plan. The following is staging information from the Lugano Modification of Ann Arbor Staging System:



Extranodal (E) Status




  • Stage I

One node or a group of adjacent nodes

Single extranodal lesions without nodal involvement

  • Stage II

Two or more nodal groups on the same side of the diaphragm

Stage I or II by nodal extent with limited contiguous extranodal involvement

  • Stage II bulky 

II as about with “bulky” disease (bulky disease lymph nodes >7.5 cm)





  • Stage III

Nodes on both sides of the diaphragm

Nodes about the diaphragm with spleen involvement


  • Stage IV

Additional non-contiguous extra lymphatic involvement


(Note: Cutaneous T-cell Lymphoma (mycosis fungoides) and breast implant-associated lymphoma are staged differently)

In addition to staging, the subtype of NHL is important in staging/classification and treatment planning. Some types are classified as aggressive because they grow more quickly and need treatment as soon as possible. Chemotherapy works by attacking fast-growing cells, so aggressive lymphomas tend to respond well to treatment. Indolent lymphomas are those that are considered slow-growing. In some cases, indolent lymphomas may not be treated immediately but rather your provider will "watch and wait. These lymphomas may respond to treatment, but they often return, requiring more treatment.

How is NHL treated?

Chemotherapy is the most common treatment. Other therapies include immunotherapy, targeted therapy, and radioimmunotherapy. Radiation therapy is only able to treat limited areas and is often used after chemotherapy, though certain early-stage and low-grade lymphomas can be treated with radiation alone. Surgery is usually. only used to establish a diagnosis. One exception to this is testicular lymphoma, as most suspicious testicular masses require removal of the testicle.


Chemotherapy is a medication that targets quickly growing and dividing cells. It may be taken in a pill form, given through an intravenous (IV) infusion and it can be given directly into your spinal fluid. Chemotherapy is considered a systemic therapy. This means it travels throughout the body. 

Chemotherapy medications can be used alone or in combination with other chemotherapies. This combination of different medications is called a "regimen." The regimen combines medications that work to kill cancer cells in different ways, thereby hopefully maximizing the number of cells killed. These regimens are given names based on the medications used. For instance, CHOP, a common regimen for NHL, is made up of cyclophosphamidedoxorubicinvincristine and prednisone. Another regimen used is CVP which includes cyclophosphamidevincristine, and prednisone.   

There are many different types of chemotherapies used to treat NHL. Some of these include chlorambucilmethotrexateetoposidecytarabinecisplatincarboplatinifosfamidefludarabine, bendamustine, gemcitabine, lenalidomide, and cladribine.

If the lymphoma is affecting the tissues around your brain and spinal cord you may be treated with intrathecal chemotherapy. Intrathecal chemotherapy is chemotherapy that is given directly into the spinal fluid through a procedure called a lumbar puncture. The two chemotherapies commonly given intrathecally are methotrexate and cytarabine.


Immunotherapy is aimed at using the body's own immune system to attack the cancer cells and includes several different types of agents. There are different types of immunotherapy used depending on the specific case of lymphoma being treated and these include:

Targeted Therapy

Targeted therapy is a type of chemotherapy that works by targeting specific genes or proteins that are helping the cancer to grow. They often work by inhibiting the action of a specific enzyme which leads to cancer cell death. They include:


Radiation therapy uses high-energy rays (similar to x-rays) delivered from an external source, to kill cancer cells. Unlike chemotherapy, which goes everywhere in the body, radiation therapy is a local treatment. It is targeted only to small areas. There are two main types of radiation used to treat non-Hodgkin lymphoma: photon (traditional radiation) and proton therapy. Proton therapy is only available at certain centers. You should discuss with your provider which type of radiation therapy is right for you.

Radiation therapy has changed over the years, as concern has grown over the long-term effects having radiation has on important organs, like the heart and lungs. In patients who need radiation, the treatment team will work hard to protect surrounding healthy tissue and organs. 

Advanced radiation techniques and methods, such as IMRT, respiratory gating, breath-holding, and advanced simulation techniques (4D imaging), allow for highly conforming doses. This means the radiation beams are shaped tightly around the tumor and spare surrounding tissue as much as possible. In addition, the area treated has changed over time. Many radiation oncologists now choose to treat just the lymph nodes that were involved and the surrounding areas where tumor had spread (called involved site radiation therapy, ISRT). This has largely replaced treating an entire field surrounding the involved lymph nodes (involved field radiation therapy). In the past, even larger fields were treated, including large areas of healthy tissue (called extended field radiation therapy). 

Although the field of radiation has made great advances, it is not the most commonly used treatment for NHL. It can be used in very early stages, in advanced cases along with chemotherapy, prior to a stem cell transplant or to help manage symptoms being caused by the cancer itself. 


Radioimmunotherapy combines monoclonal antibodies and radiation. Man-made antibodies with a form of radiation (called a radioisotope) attached to them are designed to target the CD20 antigen. The antibody seeks out the tumor cells (by finding the antigen), attaches to them, exposes these cells to the radiation, and kills them along with any nearby cancer cells. Again, since these agents target specific cells, side effects may be less than those typically seen with chemotherapy. Currently, the only available radioimmunotherapy agent is Zevalin.

Bone Marrow and Stem Cell Transplants

Transplants are used for some patients who have NHL and are in remission or relapse during or after treatment. Chemotherapy will be given prior to the transplant and in some cases, patients will also receive radiation. Transplants can be done using a donor's bone marrow or stem cells (allogeneic) or a patient's own bone marrow or stem cells (autologous). Autologous transplants are used to maximize the amount of chemotherapy that a patient can safely receive. The problem with giving large doses of chemotherapy is that this can kill the patient's bone marrow, which would lead to death. However, a patient can tolerate this high dose of chemotherapy if the bone marrow (or stem cells) is replaced soon after the chemotherapy, using cells that have been stored ahead of time. In an allogeneic transplant, this is also true, but in NHL the role of graft-versus-lymphoma effect is the key to its efficacy. This is the ability of the donor's cells and immune system to attack any remaining cancer cells in the recipient.

Clinical Trials

Clinical trials are extremely important in furthering our knowledge of this 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 healthcare 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

Once you have been treated for NHL, you will need to be closely followed for a recurrence. At first, follow-up visits will be fairly frequent, usually every couple of months. The longer you are cancer-free, the less often the checkups are needed. The oncologist will tell you when they want to perform follow-up blood tests, CT scans, or PET scans. Follow-up schedules and the tests ordered will vary depending on the type of NHL. It is very important to attend all of your follow-up appointments and to discuss any new symptoms or side effects you are experiencing with your provider.

Fear of recurrence, the financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by NHL survivors. Your healthcare team can identify resources for support and management of these challenges faced during and after cancer. 

Cancer survivorship is a relatively new focus of oncology care. With nearly 17 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

Leukemia and Lymphoma Society

Provides disease information and support resources.

Lymphoma Research Foundation

Offers education and patient services, information on research, and stories of hope.

American Society of Hematology

The official website of providers who treat blood disorders such as lymphoma.

Aim to bring people together around lymphoma-related issues by providing concise, up-to-date information and a meeting place for lymphoma patients and those who care about them.

Cutaneous Lymphoma Foundation

An independent, non-profit patient advocacy organization dedicated to supporting every person with cutaneous lymphoma by promoting awareness and education, advancing patient care, and facilitating research.


Appendix: The 2016 revision of the World Health Organization classification of lymphoid neoplasms

NHL subtypes

Mature B cell type

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma
  • Splenic marginal zone lymphoma
  • Splenic B-cell lymphoma/leukemia, unclassifiable
    • Splenic diffuse red pulp small B-cell lymphoma
  • Lymphoplasmacytic lymphoma
  • Waldenstrom macroglobulinemia
  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
  • Nodal marginal zone lymphoma
    • Pediatric nodal marginal zone lymphoma
  • Follicular lymphoma
    • In situ follicular neoplasia
    • Duodenal type follicular lymphoma
  • Large B cell lymphoma with IRF4 rearrangement
  • Primary cutaneous follicle center lymphoma
  • Mantle cell lymphoma
    • In situ mantle cell neoplasm 
  • Diffuse large B-cell lymphoma (DLBCL), NOS
    • Germinal center B-cell type
    • Activated B-cell type
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Primary cutaneous DLBCL, leg type
  • DLBCL associated with chronic inflammation
  • Intravascular large B-cell lymphoma
  • ALK+ large B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • Burkitt lymphoma
  • Burkitt-like lymphoma with 11a aberration
  • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
  • High-grade B-cell lymphoma, NOS
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T and NK Neoplasms

  • Systemic EBV+ T cell lymphoma of childhood
  • Adult T-cell leukemia/lymphoma
  • Extranodal NK/T-cell lymphoma, nasal type
  • Enteropathy-associated T-cell lymphoma
  • Monomorphic epitheliotropic intestinal T-cell lymphoma
  • Indolent T-cell lymphoproliferative disorder of the GI tract
  • Hepatosplenic T-cell lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Cutaneous T-cell lymphoma
  • Mycosis fungoides
  • Sezary syndrome
  • Primary cutaneous CD30+ T-cell lymphoproliferative disorders
    • Lymphomatoid papulosis
    • Primary cutaneous anaplastic large cell lymphoma
  • Primary cutaneous γδ T-cell lymphoma
  • Primary cutaneous CD8+ aggressive eipdermotropic cytotoxic T-cell lymphoma
  • Primary cutaneous acral CD8+ T-cell lymphoma
  • Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder
  • Peripheral T-cell lymphoma, NOS
  • Angioimmunoblastic T-cell lymphoma
  • Follicular T-cell lymphoma
  • Nodal peripheral T-cell lymphoma with TFH phenotype
  • Anaplastic large-cell lymphoma, ALK+
  • Anaplastic large-cell lymphoma, ALK-
  • Breast implant-associated anaplastic large cell lymphoma 


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