Non-Hodgkin Lymphoma – Causes, Symptoms, Treatment

Non-Hodgkin Lymphoma – Causes, Symptoms, Treatment

Non-Hodgkin lymphoma (NHL) is a neoplasm of the lymphoid tissues, which originates from B cell precursors, mature B cells, T cell precursors, and mature T cells. Non-Hodgkin lymphoma comprises of various subtypes, each with different epidemiologies, etiologies, immunophenotypic, genetic, clinical features, and response to therapy. It can be divided into two groups, ‘indolent’ and ‘aggressive’ based on the prognosis of the disease.

The most common mature B cell neoplasms are Follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, Mantle cell lymphoma, marginal zone lymphoma, primary CNS lymphoma. The most common mature T cell lymphomas are Adult T cell lymphoma, Mycosis fungoides. 

The treatment of NHL varies greatly, depending on tumor stage, grade, and type of lymphoma, and various patient factors (e.g., symptoms, age, performance status).

The natural history of these tumors shows significant variation. Indolent lymphomas present with waxing and waning lymphadenopathy for many years, whereas aggressive lymphomas have specific B symptoms such as weight loss, night sweats, fever and can result in deaths within a few weeks if untreated. Lymphomas that usually have indolent presentations include follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and splenic marginal zone lymphoma. Aggressive lymphomas are diffuse large B cell lymphoma, Burkitt lymphoma, precursor B and T cell lymphoblastic leukemia/lymphoma, and adult T cell leukemia/lymphoma, and certain other peripheral T cell lymphomas.

Up to two-thirds of patients present with peripheral lymphadenopathy. Rashes on the skin, increased hypersensitivity reactions to insect bites, generalized fatigue, pruritus, malaise, fever of unknown origin, ascites, and effusions are less common presenting features. Approximately half of the patients develop the extranodal disease (secondary extranodal disease) during the course of their disease, while between 10 and 35 percent of patients have primary extranodal lymphoma at diagnosis. Primary gastrointestinal (GI) tract lymphoma may present with nausea and vomiting, aversion to food, weight loss, fullness of abdomen, early satiety, visceral obstruction related symptoms. Patients may even present with features of acute perforation and gastrointestinal bleeding, and at times with features of malabsorption syndrome. Primary central nervous system (CNS) lymphoma may present with headache, features of spinal cord compression, lethargy, focal neurologic deficits, seizures, paralysis.

Causes of Non-Hodgkin Lymphoma

Non-Hodgkin lymphomas (NHL) may be associated with various factors, including infections, environmental factors, immunodeficiency states, and chronic inflammation.

Various viruses have been attributed to different types of NHL.

  • Epstein-Barr virus a DNA virus –  is associated with the causation of certain types of NHL, including an endemic variant of Burkitt lymphoma.
  • Human T-cell leukemia virus type 1 (HTLV-1) – causes adult T-cell lymphoma. It induces chronic antigenic stimulation and cytokine dysregulation, resulting in uncontrolled B- or T-cell stimulation and proliferation.
  • Hepatitis C virus (HCV) results in clonal B-cell expansions – Splenic marginal zone lymphoma and diffuse large B cell lymphoma are some subtypes of NHL due to the Hepatitis C virus.
  • Helicobacter pylori infection – is associated with an increased risk of gastric mucosa-associated lymphoid tissue (MALT) lymphomas, a primary gastrointestinal lymphoma.
  • Drugs – like phenytoin, digoxin, TNF antagonist are also associated with Non-Hodgkin lymphoma. Moreover, organic chemicals, pesticides, phenoxy-herbicides, wood preservatives, dust, hair dye, solvents, chemotherapy, and radiation exposure are also associated with the development of NHL.
  • Congenital immunodeficiency states – associated with increased risk of NHL are Wiskott-Aldrich syndrome, severe combined immunodeficiency disease (SCID), and induced immunodeficiency states like immunosuppressant medications. Patients with AIDS (Acquired immunodeficiency syndrome) can have primary CNS lymphoma.
  • The autoimmune disorders – like sjögren syndrome, rheumatoid arthritis, and Hashimoto thyroiditis are associated with an increased risk of NHL. Hashimoto’s thyroiditis is associate with primary thyroid lymphomas. Celiac disease is also associated with an increased risk of non-Hodgkin lymphoma.
  • Some chemicals – like polychlorinated biphenyls (PCBs),[14][15][16] diphenylhydantoin, dioxin, and phenoxy herbicides.
  • Medical treatments – like radiation therapy and chemotherapy
  • Genetic diseases – like Klinefelter syndrome, Chédiak–Higashi syndrome, ataxia-telangiectasia syndrome

Symptoms of Non-Hodgkin Lymphoma

These signs and symptoms may be caused by adult non-Hodgkin lymphoma or by other conditions. Check with your doctor if you have any of the following:

  • Swelling in the lymph nodes in the neck, underarm, groin, or stomach.
  • Fever for no known reason.
  • Drenching night sweats.
  • Feeling very tired.
  • Weight loss for no known reason.
  • Skin rash or itchy skin.
  • Pain in the chest, abdomen, or bones for no known reason.

When fever, drenching night sweats, and weight loss occur together, this group of symptoms is called B symptoms. Other signs and symptoms of adult non-Hodgkin lymphoma may occur and depend on the following:

  • Where the cancer forms in the body.
  • The size of the tumor.
  • How fast the tumor grows.

Diagnosis of Non-Hodgkin Lymphoma


The common histological finding of Non-Hodgkin lymphoma includes follicular pattern and diffuse pattern. Follicular lymphoma shows a follicular pattern where uniform nodularity is seen throughout the lymph node and little variation in size and shape of follicle. The diffuse pattern shows the normal architecture of the lymph node effaced by the infiltration of small lymphocytes. In Burkitt lymphoma, the lymph node is completely effaced with a monomorphic infiltrate of lymphocytes. There are clear spaces interspersed with reactive histiocytes containing phagocytic debris.

Mantle Cell lymphoma can have a histologic pattern of diffuse, nodular, or mantle zone or can be a combination of all. Most cases are composed exclusively of small to medium-sized lymphoid cells, with slightly irregular or “notched” nuclei. On histologic review, tumor cells are usually monomorphous small to medium-sized B lymphocytes with irregular nuclei. The degree of irregularity is usually, but not always, less than that of the centrocytes found in germinal centers and follicular lymphoma.

History and Physical

Patients present with complaints of fever, weight loss, or night sweats, also known as B symptoms. Systemic B symptoms are more common in patients with a high-grade variant of non-Hodgkin lymphoma. More than two-thirds of the patient presents with painless peripheral lymphadenopathy. Waxing and waning episodes of lymphadenopathy, along with other symptoms, can be seen in low-grade lymphoma. Patients have different presentations and vary according to the site involved. Clinical features of the patients according to the subtypes, are:

  • Burkitt Lymphoma – Patients often have rapidly increasing tumor masses. This type of lymphoma may present with tumor lysis syndrome.
  • Endemic (African) – form may have a jaw or facial bone tumors in 50 to 60 percent of cases. The primary involvement of the abdomen is less common. The primary tumor can spread to extranodal sites like the mesentery, ovary, testis, kidney, breast, and meninges.
  • The non-endemic (sporadic) – form involves the abdomen and presents most often with massive ascites, involving the distal ileum, stomach cecum and/or mesentery, bone marrow. Symptoms related to bowel obstruction or gastrointestinal bleeding, often having features of acute appendicitis or intussusception can be seen. Approximately 25 percent of cases have involvement of the jaw or facial bones. If Lymphadenopathy is present, it is usually localized. Bone marrow and CNS involvement is seen in 30 and 15 percent of cases, respectively, at the time of initial presentation, but are more common in the recurrent or treatment-resistant disease. Kidney, testis, ovary, and breast can also be involved.
  • Immunodeficiency-related Burkitt Lymphoma – have a presentation according to the signs or symptoms related to the underlying immunodeficiency (e.g., AIDS, congenital immunodeficiency, acquired immunodeficiency due to hematopoietic or solid organ transplantation). Immunodeficiency-related cases most often involve lymph nodes, bone marrow, and CNS.
  • Mantle cell Lymphoma – Most patients with mantle cell lymphoma have advanced-stage disease at diagnosis (70 percent). Approximately 75 percent of patients initially present with lymphadenopathy, the extranodal disease is the primary presentation in the remaining 25 percent. Common sites of involvement include the lymph nodes, spleen (45 to 60 percent), Waldeyer’s ring, bone marrow (>60 percent), blood (13 to 77 percent), and extranodal sites, such as the gastrointestinal tract, breast, pleura, and orbit. Up to one-third of patients have systemic B symptoms, such as fever, night sweats, and unintentional weight loss, at presentation.
  • Gastrointestinal Lymphoma – Usually presents with nonspecific symptoms such as epigastric pain or discomfort, anorexia, weight loss, nausea and/or vomiting, occult GI bleeding, and/or early satiety.
  • Primary central nervous system (CNS) lymphoma – Patients with primary central nervous system (CNS) lymphoma may present with headache, lethargy, focal neurologic deficits, seizures, paralysis, spinal cord compression, or lymphomatous meningitis. Involved lymphoid sites should be carefully examined. These include Waldeyer’s ring (tonsils, the base of the tongue, nasopharynx), cervical, supraclavicular, axillary, inguinal, femoral, mesenteric, retroperitoneal nodal sites should be examined. The liver and spleen should be examined. A Head and neck examination should be done. Enlargement of preauricular nodes and tonsillar asymmetry suggests nodal and extranodal involvement of the head and neck, including Waldeyer’s ring. Orbital structures like the eyelid, extraocular muscles, lacrimal apparatus, conjunctivae can be involved in the marginal zone, mantle cell lymphoma, and primary central nervous lymphoma (Primary CNS lymphoma). Therefore, these structures should be examined Mediastinal involvement can be seen in primary mediastinal large B cell lymphoma or due to secondary spread. Patients with mediastinal involvement can present with a persistent cough, chest discomfort, or without any clinical symptoms, but patients usually have an abnormal chest X-ray. Superior vena cava syndrome can be part of the clinical presentation.  The involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. Ascites may be present due to lymphatic obstruction, which is usually chylous.
  • Testicular NHL – is the most common malignancy involving the testis in men over age 60. It usually presents as a mass and comprises 1 percent of all NHL, and 2 percent of all extranodal lymphomas.
  • Epidural spinal cord compression (ESCC) – can cause irreversible loss of motor, sensory, and/or autonomic function. NHL is thought to first involve the paraspinal soft tissues and then invade the cord via the vertebral foramen without first causing bony destruction.


Workup in Non-Hodgkin Lymphoma should include the following:

  • Complete blood count – May show anemia, thrombocytopenia, leukopenia, pancytopenia, lymphocytosis, thrombocytosis. These changes in peripheral blood counts can be due to extensive bone marrow infiltration, hypersplenism from splenic involvement, or blood loss from gastrointestinal tract involvement.
  • Complete blood count (CBC) – A procedure in which a sample of blood is drawn and checked for the following: The number of red blood cells, white blood cells, and platelets. The amount of  (the protein that carries oxygen) in the red blood cells. The portion of the sample made up of red blood cells.
  • Serum chemistry tests – Can help rule out tumor lysis syndrome, commonly in rapidly proliferative NHL such as Burkitt or lymphoblastic lymphoma. Lactate dehydrogenase level can also be elevated due to high tumor burden, or extensive infiltration of the liver.
  • Imaging: usually CT scan of neck, chest, abdomen, and pelvis, or PET scan. Dedicated imaging such as MRI of the brain and spinal cord or testicular ultrasound might be needed.
  • Lymph node and/or tissue biopsy – A lymph node should be considered for a biopsy if one or more of the following lymph node characteristics is present: significant enlargement, persistence for more than four to six weeks, progressive increase in size. In general, lymph nodes greater than 2.25 cm (i.e., a node with perpendicular diameters of 1.5 x 1.5 cm) or 2 cm in a single diameter provides the best diagnostic yields. Excisional lymph node biopsy is the gold standard for the diagnosis. Fine Needle Aspiration of the lymph node is avoided.  An excisional biopsy of an intact node allows sufficient tissue for histologic, immunologic, molecular biologic assessment, and classification by hematopathologists. Specific yields of peripheral lymph nodes in patients who are subsequently proven to have NHL are as follows: supraclavicular nodes are 75 to 90 percent, cervical and axillary nodes are 60 to 70 percent, inguinal nodes are 30 to 40 percent.
  • Lumbar puncture – usually reserved in those with a high risk of CNS involvement, i.e., highly aggressive NHL (Burkitt lymphoma, DLBCL, peripheral T cell lymphoma, grade 3b FL, mantle cell lymphoma, precursor T or B lymphoblastic leukemia/lymphoma, human immunodeficiency virus (HIV)-positive NHL), who have epidural, bone marrow, testicular, or paranasal sinus involvement, or at least two extranodal disease sites.  CSF should be sent for both cytology and flow cytometry.
  • Immunophenotypic analysis of lymph node – peripheral blood, and bone marrow. The tumor cells in Burkitt lymphoma express surface immunoglobulin (Ig) of the IgM type and immunoglobulin light chains (kappa more often than lambda), B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center-associated markers (CD10 and BCL6), as well as HLA-DR and CD43Expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor, is dependent on EBV status of the tumors. Essentially all cases of endemic BL are EBV positive and express CD21, whereas the vast majority of non-endemic BL in non-immunosuppressed patients are EBV negative and lack CD21 expression. Mantle cell tumor cells express high levels of surface membrane immunoglobulin M (IgM) and IgD (sIgM±IgD), which is more often of lambda light chain type. They also demonstrate pan-B cell antigens (e.g., CD19, CD20), CD5, and FMC7. Nuclear staining for cyclin D1 (BCL1) is present in >90 percent of cases, including those that are CD5 negative.
  • Blood chemistry studies – A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • LDH test – A procedure in which a blood sample is checked to measure the amount of lactic dehydrogenase. An increased amount of LDH in the blood may be a sign of tissue damage, lymphoma, or other diseases.
  • Hepatitis B and hepatitis C test – A procedure in which a sample of blood is checked to measure the amounts of hepatitis B virus-specific antigens and/or antibodies and the amounts of hepatitis C virus-specific antibodies. These antigens or antibodies are called markers. Different markers or combinations of markers are used to determine whether a patient has a hepatitis B or C infection, has had prior infection or vaccination, or is susceptible to infection. Patients who have been treated for hepatitis B virus in the past need continued monitoring to check if it has reactivated. Knowing whether a person has hepatitis B or C may help plan treatment.
  • HIV test – A test to measure the level of HIV antibodies in a sample of blood. Antibodies are made by the body when it is invaded by a foreign substance. A high level of HIV antibodies may mean the body has been infected with HIV.
  • CT scan (CAT scan) – A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, pelvis, and lymph nodes, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET scan (positron emission tomography scan) – A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Bone marrow aspiration and biopsy – sometimes needed for the staging of the NHL. However, with the widespread use of PET scan, its utility is decreasing.
  • Lymph node biopsy – The removal of all or part of a lymph node. A pathologist views the tissue under a microscope to check for cancer cells. One of the following types of biopsies may be done:
  • Excisional biopsy – The removal of an entire lymph node.
  • Incisional biopsy – The removal of part of a lymph node.
  • Core biopsy – The removal of part of a lymph node using a wide needle.
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      If cancer is found, the following tests may be done to study the cancer cells

      • Immunohistochemistry – A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
      • Cytogenetic analysis – A laboratory test in which the chromosomes of cells in a sample of blood or bone marrow are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
      • Immunophenotyping – A laboratory test that uses antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. This test is used to help diagnose specific types of lymphoma.
      • FISH (fluorescence in situ hybridization) – A laboratory test used to look at and count genes or chromosomes in cells and tissues. Pieces of DNA that contain fluorescent dyes are made in the laboratory and added to a sample of a patient’s cells or tissues. When these dyed pieces of DNA attach to certain genes or areas of chromosomes in the sample, they light up when viewed under a fluorescent microscope. The FISH test is used to help diagnose cancer and help plan treatment.

      The following stages are used for adult non-Hodgkin lymphoma:

      Stage I

      Stage I adult lymphoma. Cancer is found in one or more lymph nodes in a group of lymph nodes or, in rare cases, cancer is found in the Waldeyer’s ring, thymus, or spleen. In stage IE (not shown), cancer has spread to one area outside the lymph system.

      Stage I adult non-Hodgkin lymphoma is divided into stages I and IE.

      In stage I, cancer is found in one of the following places in the lymph system:

      • One or more lymph nodes in a group of lymph nodes.
      • Waldeyer’s ring.
      • Thymus.
      • Spleen.

      In stage IE, cancer is found in one area outside the lymph system.

      Stage II

      Stage II adult non-Hodgkin lymphoma is divided into stages II and IIE.

      • In stage II, cancer is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm.

        Stage II adult lymphoma; drawing shows cancer in two lymph node groups above the diaphragm and below the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.

        Stage II adult lymphoma. Cancer is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm.

      • In stage IIE, cancer has spread from a group of lymph nodes to a nearby area that is outside the lymph system. Cancer may have spread to other lymph node groups on the same side of the diaphragm.

        Stage IIE adult lymphoma; drawing shows cancer that has spread from a group of lymph nodes to a nearby area. Also shown is a lung and the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.

        Stage IIE adult lymphoma. Cancer has spread from a group of lymph nodes to a nearby area that is outside the lymph system. Cancer may have spread to other lymph node groups on the same side of the diaphragm.

      In stage II, the term bulky disease refers to a larger tumor mass. The size of the tumor mass that is referred to as bulky disease varies based on the type of lymphoma.

      Stage III

      Stage III adult lymphoma; drawing shows the right and left sides of the body. The right side of the body shows cancer in a group of lymph nodes above the diaphragm and below the diaphragm. The left side of the body shows cancer in a group of lymph nodes above the diaphragm and cancer in the spleen.

      Stage III adult lymphoma. Cancer is found in groups of lymph nodes both above and below the diaphragm; or in a group of lymph nodes above the diaphragm and in the spleen.

      In stage III adult non-Hodgkin lymphoma,  is found:

      • in groups of lymph nodes both above and below the diaphragm; or
      • in lymph nodes above the diaphragm and in the spleen.

      Stage IV

      Stage IV adult lymphoma. Cancer (a) has spread throughout one or more organs outside the lymph system; or (b) is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm and in one organ that is outside the lymph system and not near the affected lymph nodes; or (c) is found in groups of lymph nodes above the diaphragm and below the diaphragm and in any organ that is outside the lymph system; or (d) is found in the liver, bone marrow, more than one place in the lung, or cerebrospinal fluid (CSF). Cancer has not spread directly into the liver, bone marrow, lung, or CSF from nearby lymph nodes.

      In stage IV adult non-Hodgkin lymphoma, cancer:

      • has spread throughout one or more organs outside the lymph system; or
      • is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm and in one organ that is outside the lymph system and not near the affected lymph nodes; or
      • is found in groups of lymph nodes both above and below the diaphragm and in any organ that is outside the lymph system; or
      • is found in the liver, bone marrow, more than one place in the lung, or cerebrospinal fluid (CSF). The cancer has not spread directly into the liver, bone marrow, lung, or CSF from nearby lymph nodes.

      Treatment of Non-Hodgkin Lymphoma

      Treatment of Non-Hodgkin lymphoma is based on the type, stage, histopathological features, and symptoms. The most common treatment includes chemotherapy, radiotherapy, immunotherapy, stem cell transplant, and in rare cases, surgery. Chemoimmunotherapy, i.e., rituximab, in combination with chemotherapy, is most commonly used. Radiation is the main treatment for early-stage (I, II). Stage II with bulky disease, stage III, and IV are treated with chemotherapy along with immunotherapy, targeted therapy, and in some cases, radiation therapy. Treatment according to the type of the lymphoma are listed below:

      Nine types of standard treatment are used:

      Radiation therapy

      Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing.

      External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Sometimes total-body irradiation is given before a stem cell transplant.

      Proton beam radiation therapy is a type of high-energy, external radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This type of treatment can lower the amount of radiation damage to healthy tissue near a tumor, such as the heart or breast.

      External radiation therapy is used to treat adult non-Hodgkin lymphoma, and may also be used as palliative therapy to relieve symptoms and improve quality of life.

      For a pregnant woman with non-Hodgkin lymphoma, radiation therapy should be given after delivery, if possible, to avoid any risk to the unborn baby. If treatment is needed right away, the woman may decide to continue the pregnancy and receive radiation therapy. A lead shield is used to cover the pregnant woman’s abdomen to help protect the unborn baby from radiation as much as possible.


      Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using two or more anticancer drugs. Steroid drugs may be added, to lessen inflammation and lower the body’s immune response.

      Systemic combination chemotherapy is used for the treatment of adult non-Hodgkin lymphoma.

      Intrathecal chemotherapy may also be used in the treatment of lymphoma that first forms in the testicles or sinuses (hollow areas) around the nose, diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and some aggressive T-cell lymphomas. It is given to lessen the chance that lymphoma cells will spread to the brain and spinal cord. This is called CNS prophylaxis.

      Intrathecal chemotherapy; drawing shows the cerebrospinal fluid (CSF) in the brain and spinal cord, and an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). Top section shows a syringe and needle injecting anticancer drugs into the Ommaya reservoir. Bottom section shows a syringe and needle injecting anticancer drugs directly into the cerebrospinal fluid in the lower part of the spinal column.

      Intrathecal chemotherapy. Anticancer drugs are injected into the intrathecal space, which is the space that holds the cerebrospinal fluid (CSF, shown in blue). There are two different ways to do this. One way, shown in the top part of the figure, is to inject the drugs into an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). The other way, shown in the bottom part of the figure, is to inject the drugs directly into the CSF in the lower part of the spinal column, after a small area on the lower back is numbed.

      When a pregnant woman is treated with chemotherapy for non-Hodgkin lymphoma, the unborn baby cannot be protected from being exposed to chemotherapy. Some chemotherapy regimens may cause birth defects if given in the first trimester.


      Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. Immunomodulators and CAR T-cell therapy are types of immunotherapy.

      • Immunomodulators: Lenalidomide is an immunomodulator used to treat adult non-Hodgkin lymphoma.
      • CAR T-cell therapy: The patient’s T cells (a type of immune system cell) are changed so they will attack certain proteins on the surface of cancer cells. T cells are taken from the patient and special receptors are added to their surface in the laboratory. The changed cells are called chimeric antigen receptor (CAR) T cells. The CAR T cells are grown in the laboratory and given to the patient by infusion. The CAR T cells multiply in the patient’s blood and attack cancer cells. CAR T-cell therapy (such as axicabtagene ciloleucel or tisagenlecleucel) is used to treat large B-cell lymphoma that has not responded to treatment. CAR T-cell therapy is being studied to treat mantle cell lymphoma that has relapsed or not responded to treatment.

      CAR T-cell therapy. A type of treatment in which a patient’s T cells (a type of immune cell) are changed in the laboratory so they will bind to cancer cells and kill them. Blood from a vein in the patient’s arm flows through a tube to an apheresis machine (not shown), which removes the white blood cells, including the T cells, and sends the rest of the blood back to the patient. Then, the gene for a special receptor called a chimeric antigen receptor (CAR) is inserted into the T cells in the laboratory. Millions of the CAR T cells are grown in the laboratory and then given to the patient by infusion. The CAR T cells are able to bind to an antigen on the cancer cells and kill them.

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      Targeted therapy

      Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapy may cause less harm to normal cells than chemotherapy or radiation therapy do. Monoclonal antibody therapy, proteasome inhibitor therapy, and kinase inhibitor therapy are types of targeted therapy used to treat adult non-Hodgkin lymphoma.

      • Monoclonal antibody therapy: This treatment uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies are given by infusion.

        Types of monoclonal antibodies include:

        • Rituximab, used to treat many types of non-Hodgkin lymphoma.
        • Obinutuzumab, used to treat follicular lymphoma.
        • Mogamulizumab, used to treat certain types of relapsed or refractory T-cell lymphoma.
        • Polatuzumab vedotin, combined with bendamustine and rituximab to treat relapsed or refractory diffuse large B-cell lymphoma.
        • Brentuximab vedotin, which contains a monoclonal antibody that binds to a protein called CD30 that is found on some lymphoma cells. It also contains an anticancer drug that may help kill cancer cells.
        • omab tiuxetan, an example of a radiolabeled monoclonal antibody.
      • Proteasome inhibitor therapy: This treatment blocks the action of proteasomes in cancer cells. Proteasomes remove proteins no longer needed by the cell. When the proteasomes are blocked, the proteins build up in the cell and may cause the cancer cell to die. Bortezomib is used to decrease how much immunoglobulin M is in the blood after cancer treatment for lymphoplasmacytic lymphoma. It is also being studied to treat relapsed mantle cell lymphoma.
      • Kinase inhibitor therapy: This treatment blocks certain proteins, which may help keep lymphoma cells from growing and may kill them. Kinase inhibitor therapies include:

        • Copanlisib, idelalisib, and duvelisib, which block P13K proteins and may help keep lymphoma cells from growing. They are used to treat follicular non-Hodgkin lymphomas that have relapsed (come back) or have not gotten better after treatment with at least two other therapies.
        • Ibrutinib and acalabrutinib, types of Bruton tyrosine kinase inhibitor therapy. They are used to treat lymphoplasmacytic lymphoma and mantle cell lymphoma.


      If the blood becomes thick with extra antibody proteins and affects circulation, plasmapheresis is done to remove extra plasma and antibody proteins from the blood. In this procedure, blood is removed from the patient and sent through a machine that separates the plasma (the liquid part of the blood) from the blood cells. The patient’s plasma contains the unneeded antibodies and is not returned to the patient. The normal blood cells are returned to the bloodstream along with donated plasma or a plasma replacement. Plasmapheresis does not keep new antibodies from forming.

      Watchful waiting

      Watchful waiting is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change.

      Antibiotic therapy

      Antibiotic therapy is a treatment that uses drugs to treat infections and cancer caused by bacteria and other microorganisms..


      Surgery may be used to remove the lymphoma in certain patients with indolent or aggressive non-Hodgkin lymphoma.

      The type of surgery used depends on where the lymphoma formed in the body:

      • Local excision for certain patients with mucosa-associated lymphoid tissue (MALT) lymphoma, PTLD, and small bowel T-cell lymphoma.
      • Splenectomy for patients with marginal zone lymphoma of the spleen.

      Patients who have a heart, lung, liver, kidney, or pancreas transplant usually need to take drugs to suppress their immune system for the rest of their lives. Long-term immunosuppression after an organ transplant can cause a certain type of non-Hodgkin lymphoma called post-transplant lymphoproliferative disorder (PLTD).

      Small bowel surgery is often needed to diagnose celiac disease in adults who develop a type of T-cell lymphoma.

      Stem cell transplant

      Stem cell transplant is a method of giving high doses of chemotherapy and/or total-body irradiation and then replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient (autologous transplant) or a donor (allogeneic transplant) and are frozen and stored. After the chemotherapy and/or radiation therapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

      Stem cell transplant.

      • (Step 1): Blood is taken from a vein in the arm of the donor. The patient or another person may be the donor. The blood flows through a machine that removes the stem cells. Then the blood is returned to the donor through a vein in the other arm.
      • (Step 2): The patient receives chemotherapy to kill blood-forming cells. The patient may receive radiation therapy (not shown).
      • (Step 3): The patient receives stem cells through a catheter placed into a blood vessel in the chest.

      New types of treatment are being tested in clinical trials.

      This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied.

      Vaccine therapy

      Vaccine therapy is a cancer treatment that uses a substance or group of substances to stimulate the immune system to find the tumor and kill it.

      Patients may want to think about taking part in a clinical trial.

      For some patients, taking part in a  may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the .

      Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

      Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

      Patients can enter clinical trials before, during, or after starting their cancer treatment.

      Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

      Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the website.

      Follow-up tests may be needed.

      Some of the tests that were done to diagnose cancer or to find out the stage of cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change or stop treatment may be based on the results of these tests.

      Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

      Treatment of Indolent Non-Hodgkin Lymphoma

      Treatment of indolent stage I and indolent, contiguous stage II adult non-Hodgkin lymphoma may include the following:

      • Radiation therapy.
      • Monoclonal antibody therapy (rituximab) and/or chemotherapy.
      • Watchful waiting.

      If the tumor is too large to be treated with radiation therapy, the treatment options for indolent, noncontiguous stage II, III, or IV adult non-Hodgkin lymphoma will be used.

      Treatment of indolent, noncontiguous stage II, III, or IV adult non-Hodgkin lymphoma may include the following:

      • Watchful waiting for patients who do not have signs or symptoms.
      • Monoclonal antibody therapy (rituximab) with or without chemotherapy.
      • Maintenance therapy with rituximab.
      • Monoclonal antibody therapy (obinutuzumab).
      • PI3K inhibitor therapy (copanlisib, idelalisib, or duvelisib).
      • Lenalidomide and rituximab.
      • Radiolabeled monoclonal antibody therapy.
      • A clinical trial of high-dose chemotherapy with or without total-body irradiation or radiolabeled monoclonal antibody therapy, followed by autologous or allogeneic stem cell transplant.
      • A clinical trial of chemotherapy with or without vaccine therapy.
      • A clinical trial of new types of monoclonal antibodies.
      • A clinical trial of radiation therapy that includes nearby lymph nodes, for patients who have stage III disease.
      • A clinical trial of low-dose radiation therapy, to relieve symptoms and improve quality of life.

      Other treatments for indolent non-Hodgkin lymphoma depend on the type of non-Hodgkin lymphoma. Treatment may include the following:

      • For follicular lymphoma, treatment may be within a clinical trial of new monoclonal antibody therapy, new chemotherapy regimen, or a stem cell transplant.
      • For follicular lymphoma that has relapsed (come back) or has not gotten better after treatment, therapy may include a PI3K inhibitor (copanlisib, idelalisib, or duvelisib).
      • For lymphoplasmacytic lymphoma, Bruton tyrosine kinase inhibitor therapy and/or plasmapheresis or proteasome inhibitor therapy (if needed to make the blood thinner) is used. Other treatments that are like those used for follicular lymphoma may also be given.
      • For gastric mucosa-associated lymphoid tissue (MALT) lymphoma, antibiotic therapy to treat Helicobacter pylori infection is given first. For tumors that do not respond to antibiotic therapy, treatment is radiation therapy, surgery, or rituximab with or without chemotherapy.
      • For extragastric MALT lymphoma of the eye and Mediterranean abdominal lymphoma, antibiotic therapy is used to treat infection.
      • For splenic marginal zone lymphoma, rituximab with or without chemotherapy and B-cell receptor therapy is used as initial treatment. If the tumor does not respond to treatment, a splenectomy may be done.

      Treatment of Aggressive Non-Hodgkin Lymphoma

      For information about the treatments listed below, see the Treatment Option Overview section.

      Treatment of aggressive tage I and aggressive, contiguous stage II adult non-Hodgkin lymphoma may include the following:

      • Monoclonal antibody therapy (rituximab) and combination chemotherapy. Sometimes radiation therapy is given later.
      • A clinical trial of a new regimen of monoclonal antibody therapy and combination chemotherapy.

      Treatment of aggressive, noncontiguous stage II, III, or IV adult non-Hodgkin lymphoma may include the following:

      • Monoclonal antibody therapy (rituximab) with combination chemotherapy.
      • Combination chemotherapy.
      • A clinical trial of monoclonal antibody therapy with combination chemotherapy followed by radiation therapy.

      Other treatments depend on the type of aggressive non-Hodgkin lymphoma. Treatment may include the following:

      • For extranodal NK-/T-cell lymphoma, radiation therapy that may be given before, during, or after chemotherapy and CNS prophylaxis.
      • For mantle cell lymphoma, monoclonal antibody therapy with combination chemotherapy, followed by stem cell transplant. Monoclonal antibody therapy may be given afterwards as maintenance therapy (treatment that is given after initial therapy to help keep cancer from coming back).
      • For posttransplantation lymphoproliferative disorder, treatment with immunosuppressive drugs may be stopped. If this does not work or cannot be done, monoclonal antibody therapy alone or with chemotherapy may be given. For cancer that has not spread, surgery to remove the cancer or radiation therapy may be used.
      • For plasmablastic lymphoma, treatments are like those used for lymphoblastic lymphoma or Burkitt lymphoma.

      Treatment of Lymphoblastic Lymphoma

      Treatment of adult lymphoblastic lymphoma may include the following:

      • Combination chemotherapy and CNS prophylaxis. Sometimes radiation therapy is also given to shrink a large tumor.
      • Targeted therapy with a monoclonal antibody alone (rituximab) or combined with kinase inhibitor therapy (ibrutinib).
      • A clinical trial of stem cell transplant after initial treatment.

      Treatment of Burkitt Lymphoma

      Treatment of adult Burkitt lymphoma may include the following:

      • Combination chemotherapy with or without monoclonal antibody therapy.
      • CNS prophylaxis.

      Treatment of Recurrent Non-Hodgkin Lymphoma

      Treatment of indolent, recurrent adult non-Hodgkin lymphoma may include the following:

      • Chemotherapy with one or more drugs.
      • Monoclonal antibody therapy (rituximab or obinutuzumab).
      • Lenalidomide.
      • Radiolabeled monoclonal antibody therapy.
      • Radiation therapy as palliative therapy to relieve symptoms and improve quality of life.
      • A clinical trial of an autologous or allogeneic stem cell transplant.

      Treatment of aggressive, recurrent adult non-Hodgkin lymphoma may include the following:

      • Chemotherapy with or without stem cell transplant.
      • For certain T-cell lymphomas, monoclonal antibody therapy with mogamulizumab.
      • Monoclonal antibody therapy with or without combination chemotherapy followed by autologous stem cell transplant.
      • Radiation therapy as palliative therapy to relieve symptoms and improve quality of life.
      • Radiolabeled monoclonal antibody therapy.
      • CAR T-cell therapy.
      • For mantle cell lymphoma, treatment may include the following:

        • Bruton tyrosine kinase inhibitor therapy.
        • Lenalidomide.
        • A clinical trial of lenalidomide with monoclonal antibody therapy.
        • A clinical trial comparing lenalidomide to other therapy.
        • A clinical trial of proteasome inhibitor therapy (bortezomib).
      • For diffuse large B-cell lymphoma, treatment may include polatuzumab vedotin, combined with bendamustine and rituximab.
      • A clinical trial of autologous or allogeneic stem cell transplant.

      Treatment of indolent lymphoma that comes back as aggressive lymphoma depends on the type of non-Hodgkin lymphoma and may include radiation therapy as palliative therapy to relieve symptoms and improve quality of life. Treatment of aggressive lymphoma that comes back as indolent lymphoma may include chemotherapy.

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      Treatment of Non-Hodgkin Lymphoma During Pregnancy

      Indolent Non-Hodgkin Lymphoma During Pregnancy

      Women who have indolent (slow-growing) non-Hodgkin lymphoma during pregnancy may be treated with watchful waiting until after they give birth. (See the Treatment Options for Indolent Non-Hodgkin Lymphoma section for more information.)

      Aggressive Non-Hodgkin Lymphoma During Pregnancy

      Treatment of aggressive non-Hodgkin lymphoma during pregnancy may include the following:

      • Treatment given right away based on the type of non-Hodgkin lymphoma to increase the mother’s chance of survival. Treatment may include combination chemotherapy and rituximab.
      • Early delivery of the baby followed by treatment based on the type of non-Hodgkin lymphoma.
      • If in the first trimester of pregnancy, medical oncologists may advise ending the pregnancy so that treatment may begin. Treatment depends on the type of non-Hodgkin lymphoma.

      To Learn More About Adult Non-Hodgkin Lymphoma

      • Non-Hodgkin Lymphoma Home Page
      • Drugs Approved for Non-Hodgkin Lymphoma
      • Targeted Cancer Therapies
      • Immunotherapy to Treat Cancer

      For general cancer information and other resources from the National Cancer Institute, see the following:

      • About Cancer
      • Staging
      • Chemotherapy and You: Support for People With Cancer
      • Radiation Therapy and You: Support for People With Cancer
      • Coping with Cancer
      • Questions to Ask Your Doctor about Cancer
      • For Survivors and Caregivers

      Cell Lymphoma

      • Diffuse Large B cell lymphoma (DLBCL) – In Stage I or II, the R-CHOP regimen is often given for 3 to 6 cycles, with/without radiation therapy to the lymph node that is affected. In stage III or IV, six cycles of R-CHOP is the preferred treatment. Imaging tests such as PET/CT scan is done to evaluate the response of treatment after 2-4 cycles. Intrathecal chemotherapy or high doses of methotrexate intravenously is given to the patients in the presence or at high risk of central nervous system involvement. For “Double-hit” lymphomas, that is with translocations of MYC and BCL2 and/or BCL6 as detected by FISH or standard cytogenetics, DA-EPOCH-R is preferred. Refractory or relapsed DLBCL can be treated salvage regimen followed by bone marrow transplant for eligible patients, or Chimeric antigen receptor T cell (CAR-T) cell therapy. CAR-T therapy is a form of immunotherapy in which the patient’s own T lymphocytes are genetically modified with a gene that encodes a CAR that targets the patient’s cancer. CAR-T therapy has shown effectiveness against refractory CD19-expressing B lymphoid malignancies.
      • Follicular lymphoma – This type of lymphoma has indolent nature, and it shows a good response to treatment, but it is quite difficult to cure. Relapse is usually common after several years. Patients with low burden disease can be observed, and treatment deferred unless symptomatic. The preferred treatment in stage I and stage II in the early stage is radiotherapy. Chemotherapy, along with a monoclonal antibody, is another option. Treatment in stage III, IV, and bulky stage II lymphoma is a monoclonal antibody (rituximab or obinutuzumab) along with chemotherapy. Among the chemotherapy options, bendamustine or a combination regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) are commonly used. After the response to initial treatment, the role of maintenance therapy is conflicting.
      • Mantle cell lymphoma (MCL) – MCL with multiple areas of involvement are commonly treated with aggressive chemotherapy plus rituximab in eligible patients. Intense chemotherapy regimens such as R-Hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, alternately given with high-dose methotrexate plus cytarabine) + rituximab, alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cytarabine, cisplatin),  NORDIC regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine, or RDHAP (Rituximab, dexamethasone, cytarabine, cisplatin). After the response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation is undertaken in eligible patients. This is typically followed by maintenance rituximab for three years.
      • Burkitt lymphoma – This is a very fast-growing lymphoma. Some examples of chemo regimens used for this lymphoma include Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) alternating with high dose methotrexate and cytarabine (ara-C) + rituximab, CODOX-M (cyclophosphamide, vincristine [Oncovin], doxorubicin, and high-dose methotrexate) alternating with IVAC (ifosfamide, etoposide [VP-16], and cytarabine [ara-C]) + rituximab, or Dose adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin) + rituximab. Intrathecal methotrexate is given when there is evidence of involvement of the brain and spinal cord. Tumor lysis syndrome is common in Burkitt lymphoma. Therefore, tumor lysis syndrome prophylaxis and monitoring are required.
      • Primary CNS lymphoma – High dose methotrexate based chemotherapy regimen has been shown to be the most effective treatment. If the patient achieves complete response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation should be considered for eligible patients.

      Cell Lymphoma

      • Anaplastic large cell lymphoma – This is rapidly growing lymphoma and mainly affects lymph nodes. Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone) is preferred. Other regimens include CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), or CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone).
      • Adult T cell leukemia/lymphoma – It is linked to infection with the HTLV-1 virus. There are four subtypes, and treatment varies depending on the subtype. Smoldering and chronic subtypes grow slowly. These often do not require treatment. If treatment is needed, interferon and the antiviral drug zidovudine to treat HTLV-1 infection, or skin-directed therapy if the skin is involved. The acute subtype is treated with either antiviral treatment or chemotherapy (typically the CHOP regimen). If it responds to chemotherapy, consider allogeneic stem cell transplant. Lymphoma subtype is often treated with chemotherapy; antiviral therapy is not helpful for this subtype. It may involve the brain and spinal cord, therefore intrathecal chemotherapy is given.
      • Enteropathy associated T cell lymphoma – This is highly associated with celiac disease. Combination chemotherapy is preferred.  Patients should be evaluated for surgery at the diagnoses, prior to chemotherapy or radiation, because these patients are at high risk of perforation or intestinal blockage (obstruction). A stem cell transplant may be an option if the lymphoma responds to chemotherapy.


      • HIV associated lymphoma – Patients with HIV tend to have more aggressive forms of lymphoma such as diffuse large B-cell lymphoma, primary CNS lymphoma, or Burkitt lymphoma. The use of highly active antiretroviral therapy (HAART) to treat HIV in addition to chemotherapy±immunotherapy is usually employed.
      • Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach – If infection with Helicobacter pylori is present and the lymphoma is confined to the stomach, and peri-gastric lymph nodes, treatment with antibiotics and Histaminic (H2) blockers can eliminate the organism-related antigenic stimulus, and the lymphoma may regress permanently.
      • Mycosis fungoides – This type of T-cell lymphoma of the skin usually has a very indolent course and is best treated with skin-directed treatments, including topical steroids, topical retinoids, skin irradiation, psoralen-associated ultraviolet exposure, topical chemotherapy. If failure with skin-directed therapies can then use systemic biologic therapies.

      Radiation Oncology

      Radiation therapy is recommended in the following situations:

      • Early-stage (stage I or II): Radiation therapy is given alone or in combination with chemotherapy.
      • Advanced and aggressive lymphomas: Usually, chemotherapy is the mainstay of treatment. However, radiation can be employed for palliation purposes, e.g., pain, lymphadenopathy causing urinary/gastrointestinal tract obstruction.

      Radiation therapies are given for several weeks and mostly given five days a week if given for treatment. Palliative radiation is usually shorter.

      Toxicity and Side Effect Management

      Complications following treatment variable depending on the type of chemotherapy used and if radiation or surgery were used as adjunctive measures. Common adverse events of chemotherapy include myelosuppression, neutropenic fever, and immunosuppression. Myelosuppression is treated with transfusions (red cells and platelets) or the administration of colony-stimulating factors (e.g., granulocyte colony-stimulating factor). Neutropenia leads to increase risk of infections from bacteria, viruses, and fungi. Management is dependant on the degree of neutropenia and if febrile. Patients are also susceptible to infections like Varicella and herpes zoster. Post-exposure prophylaxis is given against varicella-zoster infection.

      Multiple chemotherapeutic agents induce nausea and vomiting. Usually, anti-emetic serotonin receptor antagonists and/or benzodiazepines among other agents are used for treatment and prophylaxis.

      Anthracycline can cause cardiotoxicity, especially doxorubicin. Dexrazoxane has shown significant benefits in anthracycline-induced cardiotoxicity. Radiotherapy can also cause heart failure, but the mechanism is different from that of chemotherapy. It causes diffuse fibrosis in the interstitium of the myocardium and progressive fibrosis of pericardial layers, cells in the conduction system, and the cusps or leaflets of the valves. Left ventricular ejection fraction is usually preserved.

      Vincristine can cause neurotoxicity.

      Long-term fatigue is a common symptom present in two-thirds of survivors of NHL. Fatigue usually improves in the year after treatment completion, but a significant number of patients continue to experience fatigue for months or years after treatment.

      The risk of developing a second malignancy is increased in long-term survivors of NHL. The risk of developing a second malignancy differs depending upon the subtype of NHL and the treatment received. The risk of developing the myelodysplastic syndrome and acute myeloid leukemia is high. The risk of developing lung cancer and cutaneous melanoma was increased among survivors of follicular lymphoma. Depending on the area of radiation, patients can develop squamous cell carcinoma of the head and neck and breast cancer.

      Radiation to the neck and mediastinum can result in hypothyroidism. Patients undergoing hematopoietic cell transplantation with total body irradiation (TBI) conditioning were documented to suffer from the growth hormone deficiency, hypogonadism, insulin resistance, and dyslipidemia.

      NHL survivors are at risk for developing endocrine abnormalities such as gonadal dysfunction and hypothyroidism. Cytotoxic agents and radiation therapy can produce gonadal dysfunction in both males and females. Fertility preservation should be offered to all. Options include freezing (cryopreservation) of embryos, oocytes, and spermatozoa.

      Cranial irradiation, a history of intrathecal chemotherapy, older age at the time of treatment, and hematopoietic cell transplantation can lead to neurologic and psychiatric complications like post-traumatic stress disorder and disorder. Patients treated with an anti-CD20 monoclonal antibody (rituximab) are at risk for the development of progressive multifocal leukoencephalopathy (PML). All patients at increased risk should undergo screening for neurocognitive impairment so that appropriate occupational therapy and social services referrals may be made.


      The Lugano classification is the current staging used for patients with NHL. The Lugano classification is based on the Ann Arbor staging system, which was originally developed for Hodgkin lymphoma in 1974 and modified in 1988. This staging system is based on the number of tumor sites (nodal and extranodal) and their location.

      • Stage I refer to NHL that involves a single lymph node region (stage I) or a single extra lymphatic organ or site (stage IE) without nodal involvement. A single lymph node region can involve one node or a group of adjacent nodes.
      •  Stage II refers to two or more involved lymph node regions on the same side of the diaphragm (stage II) or with localized involvement of an extra lymphatic organ or site (stage IIE).
      •  Stage III refers to lymph node involvement on both sides of the diaphragm (stage III).
      •  Stage IV refers to the widespread involvement of one or more extra lymphatic organs like liver, bone marrow, lung, with or without associated lymph node involvement.

      The subscript “E” is used if the limited extranodal extension is noted; the more extensive extranodal disease is categorized as stage IV. Spleen involvement is considered nodal, rather than extranodal.


      Life-threatening emergent complications of NHL should be considered during the initial workup and evaluation. Early recognition and prompt therapy are critical for these situations, which may interfere with and delay treatment of the underlying NHL. These can include:

      • Febrile neutropenia
      • Hyperuricemia and tumor lysis syndrome – Presents with fatigue, nausea, vomiting, decreased urination, numbness, and tingling of legs and joint pain. Laboratory findings include an increase in uric acid, potassium, creatinine, phosphate, and a decrease in calcium level. This can be prevented with vigorous hydration and allopurinol.
      • Spinal cord or brain compression
      • Focal compression depending on the location and type of NHL – airway obstruction (mediastinal lymphoma), intestinal obstruction and intussusception, ureteral obstruction
      • Superior or inferior vena cava obstruction
      • Hyperleukocytosis
      • Adult T-cell leukemia-lymphoma can cause hypercalcemia
      • Pericardial tamponade
      • Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia can cause hyperviscosity syndrome
      • Hepatic dysfunction 
      • Venous thromboembolic disease 
      • Autoimmune hemolytic anemia and thrombocytopenia – can be observed with small lymphocytic lymphoma


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