All About Non-Hodgkin Lymphoma

Carolyn Vachani RN, MSN, AOCN
Updated by: Karen Arnold-Korzeniowski, BSN RN
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 22, 2016

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

The lymph system is essentially the "housekeeping system" of the body. It is a network of vessels (tubes), which connect the lymph nodes. These nodes can vary in size, but are normally up to about 2 centimeters in width. They contain cells that clear bacteria and other foreign debris 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. From the lymph node, the debris may pass through several more nodes in the system before being dumped into the bloodstream to ultimately 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) are important in fighting infection and mount what is called the "immune response." B cells produce proteins called antibodies, which move through the bloodstream and attack a specific target as directed by the B cell. They start their lives in the bone marrow and then develop fully in the lymph nodes. T cells are developed in the thymus gland and directly attack the cells identified as foreign by the B cells. In addition, both of these cells are able to remember bacteria from previous infections, and thus respond quicker to future infections.

What are the non-Hodgkin's lymphomas?

Non-Hodgkin lymphomas (NHLs) 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). In 2001, the World Health Organization developed a comprehensive classification system for the 30+ different types of NHLs, which are then further divided according to the cell type involved (either B cell or T cell). (See WHO classification at the end of this article) These 30+ types of NHLs are different in their growth rates and aggressiveness, and are often treated differently.

Non-Hodgkin lymphoma makes up about 4% of the cancer diagnoses in the United States with about 71,850 people (both adults and children) diagnosed in 2015. About 95% of these cases are in adults, with the median age of diagnosis being 66. The disease is slightly more common in men than women.

Rates have been increasing 3-4% annually in the U.S. since the 1950's, but incidence varies widely throughout the world. For instance, in the United Kingdom, there are approximately 10 cases for every 100,000 people, whereas in Asia there are only 2 cases for every 100,000 people, compared to approximately 20 per 100,000 in the U.S.

Non-Hodgkin lymphomas should not be confused with Hodgkin's disease, as these are two distinct diseases. Although Hodgkin's disease also occurs in the lymph system, providers are able to differentiate between the two because of the presence of Reed-Sternberg cells in Hodgkin's tumors. (Read about Hodgkin's disease in adults or in children).

Am I at risk for non-Hodgkin lymphoma?

The actual cause of NHLs is still unknown in most cases, but there are some factors known to increase a person's risk. These factors are related to the immune system, and cause either a chronic decrease or chronic increase in immune response. Certain viruses and bacteria increase the risk of certain types of NHLs, possibly because they cause a long-term increase in immune response. For instance, MALT lymphoma is associated with Helicobacter pylori infection, the same bacteria that causes stomach ulcers. Epstein-Barr (EBV) virus is associated with 30% of Burkitt's lymphoma cases in the U.S., but 95% of 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 increased risk of NHLs. This includes infection with the human immunodeficiency virus (HIV), organ or bone marrow transplant (requiring immune suppression medications), rheumatoid arthritis, and 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, meaning 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. Permanent hair-darkening dyes have also been the subject of many studies, but the majority of these studies did not find an increased risk in hair dye users.

Rates are much higher among persons over the age of 65 (68 for every 100,000 people). NHL occurs more often in whites than in blacks, and it is more common among men than women.

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 available?

Unfortunately, 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 and symptoms of NHL?

Oftentimes, the first sign of NHL is the swelling of lymph nodes, but this symptom is easily ignored because the enlargement in many cases is painless. Only about 20% of patients have systemic symptoms (symptoms throughout the body). When they do occur, symptoms include: persistent fever, drenching night sweats, or weight loss. These are sometimes referred to as "B symptoms". Other symptoms may include fatigue, itchy skin, and alcohol intolerance.

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?

When a patient presents with signs or symptoms of NHL, the physician will perform a complete medical health history and a physical exam. A biopsy of the enlarged lymph node is necessary to determine if lymphoma is present, and if so, of what type. This can be done by inserting a needle into the 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 determine if the lymphoma has spread, where it has spread to, and other prognostic information. These tests may include further blood tests (complete blood count, sedimentation rate, LDH, albumin and beta-2 microglobulin), chest x-ray, CT scan or MRI of the chest, abdomen and pelvis, PET scan, and bone marrow biopsy.

How is NHL staged?

Staging is then done based on the Ann Arbor Staging Classification:

  • Stage I indicates that the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I will often not have obvious, outward symptoms.
  • Stage II indicates that the cancer is located in two separate lymph node regions, and that both areas are on the same side of the diaphragm (the muscle located at the bottom of the lungs) - that is, both are above the diaphragm or both are below the diaphragm.
  • Stage III indicates that the cancer involves lymph nodes or organs on both sides of the diaphragm.
  • Stage IV : Any of the following means that the disease is stage IV
  • Cancer has spread to multiple spots of an organ (or multiple organs) outside the lymph system. Cancer cells may or may not be found in the lymph nodes near these organs.
  • Cancer has spread to only one organ outside the lymph system, but lymph nodes far away from that organ are involved.
  • Bone marrow involvement

These letters can be added to all stages: (ex: stage IIA, stage IIIB)

A : No symptoms

B : Presence of "B symptoms" (fever, night sweats, weight loss > 10% of body weight)

E: is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue.

X : is used if the largest tumor is >10 cm large (also called "bulky disease"), or whether the lymph node mass in the center of the chest (mediastinum) is wider than 1/3 of the chest on a chest X-ray.

(Note: Cutaneous T-cell Lymphoma, mycosis fungoides is staged differently)

In addition to staging, the subtype of NHL must be taken into consideration. Some types are classified as aggressive because they grow more quickly and require immediate treatment. The good news is that chemotherapy works by attacking fast-growing cells, so aggressive lymphomas are more sensitive to treatment. Although these lymphomas are aggressive, a percentage of them can be cured by chemotherapy. Indolent lymphomas are those that are considered slow- growing. In some cases, indolent lymphomas may not be treated immediately but rather followed with a "watch and wait" methodology. These lymphomas may respond to treatment, but they often return, requiring more treatment. Although these patients may remain well for many years with little or no therapy, indolent lymphomas are generally not curable, i.e. they do not "go away" permanently or completely.

How is NHL treated?

Treatment is determined by the type of NHL, but in general, chemotherapy is the most commonly used treatment. Other therapies include immunotherapy and radioimmunotherapy. Radiation therapy is only able to treat limited areas, and is typically used after chemotherapy, though certain early stage and low grade lymphomas can be treated with radiation alone. Surgery is generally only used to establish a diagnosis; an exception to this is testicular lymphoma, since most suspicious testicular masses require removal of the testicle.


Chemotherapy is a medication that targets quickly-growing and dividing cells, such as cancer cells. It may be taken in a pill form or given through an intravenous (IV) infusion. Chemotherapy is considered a systemic therapy, meaning it travels throughout the body. This is in contrast to radiation therapy, which is a local treatment that targets a limited area. 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 cytoxan, adriamycin (hydroxydoxorubicin), oncovin (vincristine), and prednisone. This combination is given in "cycles" (blocks of time). A cycle may be 21 days, with cytoxan, adriamycin and oncovin being given on day 1, prednisone on days 1-5, followed by 16 days off, and then start over again with the next cycle.

Some other chemotherapies used in NHL therapy include: chlorambucil, methotrexate, etoposide, cytarabine, fludarabine, 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/Biologic Therapy

Immunotherapy (sometimes called biologic therapy) is aimed at using the body's own immune system to attack the cancer cells and includes several different types of agents. Interferon-alpha is one type of immunotherapy that works by targeting certain receptors on the cancer cells, interfering with cell replication and causing the immune system to attack the cells. Interferon alpha is used in follicular and cutaneous T-cell lymphomas.

Monoclonal antibodies are man-made antibodies. They are designed to target a specific marker found on the tumor cell – this marker varies depending on the particular medication and the cancer it is treating. Once the medication is administered, the monoclonal antibody finds and attaches itself to the cancer cell, activating the body's immune system to attack it. This therapy is used alone or in combination with chemotherapy. Rituxan is the most commonly used monoclonal antibody for NHL and targets the CD20 antigen. This means the lymphoma must express the CD20 antigen for this therapy to work. Since monoclonal antibodies target only specific cells, they may cause less toxicity to normal healthy cells than chemotherapy. Rituxan is frequently combined with CHOP chemotherapy, and in such cases, is known as "R-CHOP."

Idelalisib is a type of targeted therapy that works by targeting a protein called phosphoinositide 3-kinase (PI3K) delta, which is important in the activation and proliferation of B cells. PI3K is seen in higher than normal levels in many B-cell cancers. Ibrutinib is a type of targeted therapy that works by interfering with the function of Bruton's tyrosine kinase (BTK), which is found in excess on cancerous B cells. Bortezomib works by inhibiting the 26S proteasome, stopping cancer cells from growing and dividing and is used in the treatment of mantle cell lymphoma.


Radioimmunotherapy combines the technology of 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 thus 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 (Bexxar is no longer on the market).

Bone Marrow and Stem Cell Transplants

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

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. There are clinical trials being studied for the use of targeted therapies, antibiotics, and vaccines for lymphoma. 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 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 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 a patient has been treated for NHL, they need to be closely followed for a recurrence. At first, follow-up visits will be fairly frequent, usually every couple of months. The longer a patient is free of disease, the less often the checkups are needed. The oncologist will tell you when he or she wants 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, financial impact of cancer treatment, employment issues and coping strategies are common emotional and practical issues experienced by breast cancer survivors. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With some 15 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.

This article is meant to give you a better understanding of NHL. Use this knowledge when meeting with your healthcare providers, making treatment decisions, and continuing your search for information.

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.


The World Health Organization Classification of Lymphoid Malignancies

B-Cell Neoplasms

  1. Precursor B-cell neoplasm
  2. Mature (peripheral) B-cell neoplasms
  • Precursor B-lymphoblastic leukemia/lymphoma
  • B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
  • B-cell prolymphocytic leukemia
  • Lymphoplasmacytic lymphoma
  • Splenic marginal zone B-cell lymphoma
  • Nodal marginal zone lymphoma
  • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type
  • Hairy cell leukemia
  • Plasma cell myeloma/plasmacytoma
  • Follicular lymphoma, follicle center
  • Mantle cell lymphoma
  • Diffuse large cell B-cell lymphoma
    • Mediastinal large B-cell lymphoma
    • Intravascular large B-cell lymphoma
    • Primary effusion lymphoma
  • Burkitt's lymphoma/Burkitt's cell leukemia
  • Hairy cell leukemia
  • Plasma cell myeloma
  • Solitary plasmacytoma of bone

B-cell proliferations of uncertain malignant potential

  • Lymphomatoid granulomatosis
  • Post-transplant lymphoproliferative disorder

T-Cell and Natural Killer Cell Neoplasms

  1. Precursor T cell neoplasm
  2. Mature (peripheral) T cell and NK-cell neoplasms
  • Precursor T-lymphoblastic lymphoma/leukemia
  • Blastic NK lymphoma
  • T cell prolymphocytic leukemia
  • T-cell granular lymphocytic leukemia
  • Aggressive NK Cell leukemia
  • Adult T cell lymphoma/leukemia (HTLV1+)
  • Extranodal NK/T-cell lymphoma, nasal type
  • Enteropathy-type T-cell lymphoma
  • Hepatosplenic T-cell lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Mycosis fungoides / Sézary's syndrome
  • Primary Cutaneous Anaplastic large cell lymphoma
  • Peripheral T cell lymphoma, unspecified
  • Angioimmunoblastic T cell lymphoma
  • Anaplastic large cell lymphoma


Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2008). Elsevier, Philadelphia, PA.

The American Cancer Society. Facts and Figures.

Ansell, SM & Armitage, J (2015) Non-Hodgkin's lymphoma: Diagnosis and treatment. Mayo Clinic Proceedings: 90(8): 1152-1163.

Dummer, R. et al. Maintenance therapy in cutaneous T-cell lymphoma: who, when, what?. European Journal of Cancer. 43(16):2321-9, 2007 Nov.

Morgner, A et al. Therapy of gastric mucosa associated lymphoid tissue lymphoma. World Journal of Gastroenterology. 13(26):3554-66, 2007 Jul 14.

NCCN Guidelines v 1.2016 Non –Hodgkin's Lymphomas. Found at:

National Cancer Institute. SEER Stat Facts Sheets: Non-Hodgkin Lymphoma. 2015. Found at:

Pereg, David. Et al. The treatment of Hodgkin's and non-Hodgkin's lymphoma in pregnancy. Haematologica. 92(9):1230-7, 2007 Sep.

Rummel, M et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatments for patients with indolent and mantle-cell lymphomas: an open-label, multicenter, randomized, phase 3 non-inferiority trial. The Lancet. 381(9873):1203-1210. 2013.

Shi, Y et al. Autologous peripheral blood stem cell mobilization following dose-adjusted cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy alone or in combination with rituximab in treating high-risk non-Hodgkin’s lymphoma. Chinese Journal of Cancer. 2015.

Weigert, Oliver. Et al. Current management of mantle cell lymphoma. Drugs. 67(12):1689-702, 2007.


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