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Non-Hodgkin Lymphomas


Peter Martin

, MD, Weill Cornell Medicine;

John P. Leonard

, MD, Weill Cornell Medicine

Reviewed/Revised May 2022 | Modified Sep 2022
Topic Resources

Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the spleen, the liver, and the gastrointestinal tract. Presenting symptoms usually include peripheral lymphadenopathy. However, some patients present without lymphadenopathy but with abnormal lymphocytes in circulation. Disease is likely to be disseminated at the time of presentation, and diagnosis is usually based on lymph node or bone marrow biopsy or both. Management strategies may include watch and wait, chemotherapy, targeted drugs (eg, kinase inhibitors), and immunotherapies (eg, monoclonal antibodies, chimeric antigen receptor T cells); occasionally, radiation therapy is added. With few exceptions, stem cell transplantation is usually reserved for patients with aggressive lymphomas after incomplete remission or relapse.

Non-Hodgkin lymphoma is more common than Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Hodgkin Lymphoma . It is the 6th most common cancer in the US and represents 4% of all new cancers in the US each year and 3% of all cancer deaths. Over 80,000 new cases are diagnosed annually in all age groups and there are about 20,000 deaths. Non-Hodgkin lymphoma is not one disease but rather a category of lymphocyte cancers with a number of subgroups largely divided into aggressive and indolent types. Incidence increases with age (median age, 67 years).

Etiology of Non-Hodgkin Lymphomas

The cause of non-Hodgkin lymphoma is unknown, although, as with the leukemias Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more , substantial evidence suggests a viral cause (eg, human T-cell leukemia-lymphoma virus, Epstein-Barr virus Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more Infectious Mononucleosis , hepatitis B virus Hepatitis B, Chronic Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more , hepatitis C virus Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more , HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Human Immunodeficiency Virus (HIV) Infection , human herpesvirus 8 Overview of Herpesvirus Infections Eight types of herpesviruses infect humans (see table ). After initial infection, all herpesviruses remain latent within specific host cells and may subsequently reactivate. Clinical syndromes... read more ) in some cases. Helicobacter pylori infection also increases lymphoma risk.

Patients at increased risk of non-Hodgkin lymphoma include those with

Non-Hodgkin lymphoma is the 2nd most common cancer in HIV-infected patients Non-Hodgkin lymphoma AIDS-defining cancers in patients infected with HIV are Kaposi sarcoma Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of central nervous system read more , and some AIDS patients present with lymphoma. Indeed, patients with non-Hodgkin lymphoma should generally be screened for HIV and hepatitis viruses.

Genetic factors appear to play a role. Recent evidence shows that certain single nucleotide polymorphisms increase the risk of lymphoma. Also, patients with a first-degree relative with Hodgkin or non-Hodgkin lymphoma have an increased risk of non-Hodgkin lymphoma.

Pathophysiology of Non-Hodgkin Lymphomas

Most (80 to 85%) non-Hodgkin lymphomas arise from B lymphocytes; the remainder arise from T lymphocytes or natural killer cells. The stage of lymphocyte differentiation at which the oncogenic event occurs determines the disease presentation and outcome.

Most lymphomas are nodal with variable involvement of the bone marrow and peripheral blood. A leukemia-like picture with peripheral lymphocytosis and bone marrow involvement may be present in up to 50% of children and about 20% of adults with some types of non-Hodgkin lymphoma.

Hypogammaglobulinemia caused by a progressive decrease in immunoglobulin production is present in 15% of patients at diagnosis. Hypogammaglobulinemia increases the risk of serious bacterial infection, and patients may require IV immune globulin to replace deficient immunoglobulins.

Pearls & Pitfalls

  • There is considerable overlap between non-Hodgkin lymphoma and leukemia; both may have peripheral lymphocytosis and bone marrow involvement.

Classification of Non-Hodgkin Lymphomas

Pathologic classification of non-Hodgkin lymphoma continues to evolve, reflecting new insights into the cells of origin and the biologic bases of these heterogeneous diseases. The 2016 WHO classification is valuable because it incorporates immunophenotype, genotype, and cytogenetics, but numerous other systems exist (eg, Lyon classification).

Non-Hodgkin lymphomas are commonly also categorized as indolent or aggressive:

  • Indolent: Slowly progressive and responsive to therapy but not typically curable with standard approaches

  • Aggressive: Rapidly progressive but responsive to chemotherapy and often curable

In children, non-Hodgkin lymphoma is almost always aggressive. Follicular and other indolent lymphomas are unusual. The treatment of these aggressive lymphomas (Burkitt Burkitt Lymphoma Burkitt lymphoma is an aggressive B-cell non-Hodgkin lymphoma occurring in children and adults. Endemic (African), sporadic (non-African), and immunodeficiency-related forms exist. (See also... read more Burkitt Lymphoma , diffuse large B cell, and lymphoblastic lymphoma) presents special concerns, including gastrointestinal tract involvement (particularly in the terminal ileum); meningeal spread (requiring cerebrospinal fluid prophylaxis or treatment); and other sanctuary sites of involvement (eg, testes, brain). In addition, with these potentially curable lymphomas, treatment of adverse effects as well as outcome must be considered, including late risks of secondary cancer, cardiorespiratory sequelae, fertility preservation, and developmental consequences.

Symptoms and Signs of Non-Hodgkin Lymphomas

Most patients present with

  • Asymptomatic peripheral lymphadenopathy

Enlarged lymph nodes can be rubbery and discrete and later coalesce into masses. Affected nodes are usually not painful, unlike the tender nodes that often occur with viral infections. Nodal involvement is localized in some patients, but most patients have several areas affected. The initial physical examination should carefully look for nodes in the cervical, axillary, inguinal, and femoral regions.

In some patients, enlarged mediastinal and retroperitoneal nodes press on nearby structures, leading to symptoms. The most important of these are

  • Compression of the superior vena cava (SVC): Shortness of breath and facial edema (SVC syndrome Regional spread Regional spread )

  • Compression of the external biliary tree: Jaundice

  • Compression of the ureters: Hydronephrosis

  • Bowel obstruction: Vomiting and obstipation

  • Interference with lymph drainage: Chylous pleural or peritoneal fluid or lymphedema of a lower extremity

The skin is involved in some non-Hodgkin lymphomas. B-cell non-Hodgkin lymphoma can affect the scalp (follicular non-Hodgkin lymphoma) or the legs (large cell non-Hodgkin lymphoma), typically causing slightly raised, erythematous nodules. In cutaneous T-cell non-Hodgkin lymphoma, skin lesions can be diffuse, nonpalpable erythema or discrete papules, plaques, or tumors.

Systemic symptoms (eg, fatigue Fatigue Fatigue is difficulty initiating and sustaining activity due to a lack of energy and accompanied by a desire to rest. Fatigue is normal after physical exertion, prolonged stress, and sleep deprivation... read more , fevers, night sweats, weight loss Involuntary Weight Loss Involuntary weight loss generally develops over weeks or months. It can be a sign of a significant physical or mental disorder and is associated with an increased risk for mortality. The causative... read more ) can be the first manifestations in some patients, most commonly in aggressive lymphomas. These patients may not have noticed lymphadenopathy or not have external, palpable disease; these patients require CT or positron emission tomography (PET) imaging to discover the lesion(s).

Anemia is initially present in some patients and eventually develops in many. It may be caused by bleeding due to gastrointestinal lymphoma, with or without low platelet levels; hemolysis due to hypersplenism or Coombs’-positive hemolytic anemia; bone marrow infiltration due to lymphoma; or bone marrow suppression due to chemotherapy or radiation therapy.

Manifestations of some specific lymphomas

Adult T-cell leukemia-lymphoma, which is associated with human T-lymphotropic virus 1 (HTLV-1), has a fulminating clinical course with skin infiltrates, lymphadenopathy, hepatosplenomegaly, and leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more . The leukemic cells are malignant T cells, many with convoluted nuclei. Hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more often develops, related to humoral factors rather than to direct bone invasion.

Anaplastic large cell lymphoma may cause rapidly progressive skin lesions, adenopathy, and visceral lesions. This disease may be mistaken for Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Hodgkin Lymphoma or metastatic undifferentiated carcinoma.

Diagnosis of Non-Hodgkin Lymphomas

  • Lymph node biopsy

  • Often unilateral bone marrow aspiration and biopsy

  • FDG-PET/CT of chest, abdomen, and pelvis for staging

  • MRI of brain and/or spinal cord if neurologic symptoms are present

As with Hodgkin lymphoma, non-Hodgkin lymphoma is usually suspected in patients with

  • Painless lymphadenopathy

  • Adenopathy detected on a chest x-ray or CT done for other reasons

Diagnostic tests

Enlarged lymph nodes are biopsied. If a node is palpable, no imaging is required initially, although CT or ultrasonography may be needed to properly plan subsequent tests.

If the lesion is easily palpable, an open biopsy is preferred. If the lesion is in the lung or abdomen, a core needle biopsy (18- to 20-gauge needle) done using CT or ultrasound guidance can often obtain an adequate specimen for diagnosis. A fine needle biopsy (percutaneous or bronchoscopic) frequently will not produce adequate tissue, especially for initial diagnosis; core biopsy is preferred if deemed safe.

Biopsies should be reviewed by a pathologist with expertise in lymphoma diagnosis so that the lymphoma can be correctly classified. If this review is not available locally, the slides should be sent to a reference laboratory with hematopathology expertise. The proper classification of non-Hodgkin lymphoma is critical for treatment planning. Non-Hodgkin lymphomas are potentially curable, but without a precise diagnosis, optimal therapy may not be chosen.

Histologic criteria on biopsy include destruction of normal lymph node architecture and invasion of the capsule and adjacent fat by characteristic neoplastic cells. Immunophenotyping studies to determine the cell of origin are of great value in identifying specific subtypes and helping define prognosis and management; these studies also can be done on peripheral cells if they are present, but typically these stains are applied to formalin-fixed, paraffin-embedded tissue. Demonstration of the leukocyte common antigen CD45 by immunoperoxidase rules out metastatic cancer, which is often in the differential diagnosis of “undifferentiated” cancers. The test for leukocyte common antigen, most surface marker studies, and gene rearrangement (to document B-cell or T-cell clonality) can be done on fixed tissues. Cytogenetics and flow cytometry require fresh tissue.

Staging tests

Once the diagnosis of lymphoma is made, staging tests are done.

A combined fluorodeoxyglucose (FDG)-PET/CT scan of the chest, abdomen, and pelvis is recommended. PET/CT provides accurate location of lesions, their size (from CT) and tumor metabolism (from FDG-PET). If combined FDG-PET/CT is not available, a contrast-enhanced CT scan of the chest, abdomen, and pelvis is done.

Unilateral bone marrow aspiration and biopsy is often done in patients with non-Hodgkin lymphoma. Bone marrow assessment in low-grade (indolent) non-Hodgkin lymphoma or T-cell non-Hodgkin lymphoma can be limited to cases where findings will change management or are needed to assess cytopenias.

Testing for complications and prognosis

Blood tests typically include complete blood count with white blood cell differential, kidney function and liver tests (including serum creatinine, bilirubin, calcium, aspartate aminotransferase, albumin, alkaline phosphatase, and lactate dehydrogenase), uric acid, beta-2 microglobulin, and vitamin D levels. Serum protein electrophoresis with IgG, IgA, and IgM immunoglobulin levels are also done.

Testing for etiology


After diagnosis, stage is determined to guide therapy. The commonly used Lugano staging system (see table Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma Lugano Staging of Hodgkin Lymphoma and Non-Hodgkin Lymphoma ) incorporates

  • Symptoms

  • Physical examination findings

  • Results of imaging tests, including CT of the chest, abdomen, and pelvis, and functional imaging with FDG-PET

  • Bone marrow biopsy (in selected cases)

Although stage I non-Hodgkin lymphoma does occur, the disease is typically disseminated when first recognized.


Diagnosis reference

  • 1. Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 32(27):3059-3068, 2014.

Prognosis for Non-Hodgkin Lymphomas

Prognosis varies by the type and stage of lymphoma and individual patient factors. In general, patients with peripheral T-cell or natural killer (NK)/T-cell lymphomas typically have a worse prognosis than those with B-cell non-Hodgkin lymphoma. Within each non-Hodgkin lymphoma variant, prognosis is related to differences in tumor cell biology.

The most commonly used prognostic scoring system is the International Prognostic Index (IPI) for diffuse large B-cell lymphoma). However, the IPI score is used only for diffuse large B-cell lymphoma (DLBCL). There are also scoring systems for follicular lymphoma (FLIPI) and mantle cell lymphoma (MIPI). Online calculators are available to estimate prognosis in other types of non-Hodgkin lymphoma as well.

The IPI considers 5 risk factors:

Outcome is worse with an increasing number of risk factors. Patients in the highest risk groups (patients with 4 or 5 risk factors) have a 50% 5-year survival. Patients without any of the risk factors have a very high cure rate. The original IPI score uses the 5 factors as discrete variables (eg, either age over 60 or under 60). A modification, the Diffuse Large B-cell Lymphoma Prognosis (IPI24), which calculates the chance of being disease free at 24 months from diagnosis, includes the above factors as continuous variables and also includes absolute lymphocyte count.

Treatment of Non-Hodgkin Lymphomas

Treatment varies considerably with cell type, which are too numerous to permit detailed discussion. Generalizations can be made regarding limited vs advanced disease and aggressive vs indolent forms. Burkitt lymphoma Burkitt Lymphoma Burkitt lymphoma is an aggressive B-cell non-Hodgkin lymphoma occurring in children and adults. Endemic (African), sporadic (non-African), and immunodeficiency-related forms exist. (See also... read more Burkitt Lymphoma and cutaneous T-cell lymphomas Cutaneous T-cell Lymphomas (CTCL) Mycosis fungoides and Sézary syndrome are uncommon chronic T-cell non-Hodgkin lymphomas primarily affecting the skin and occasionally the lymph nodes. (See also Overview of Lymphoma and Non-Hodgkin... read more Cutaneous T-cell Lymphomas (CTCL) are discussed separately. For patients with indolent lymphomas and no significant signs or symptoms of lymphoma, a "watch and wait" approach (withholding treatment while closely monitoring) can be used.

Limited disease (stages I-II)

For stage I indolent non-Hodgkin lymphoma (uncommon because most patients have stage II o IV when diagnosed), external beam radiation therapy can be the sole initial treatment. Regional radiation therapy may offer long-term control and possibly cure in about 40% of stage I patients. Stage II indolent non-Hodgkin lymphoma is most commonly treated as advanced-stage disease.

Limited-stage aggressive non-Hodgkin lymphomas can be managed with a combination of chemotherapy plus radiation therapy or with chemotherapy alone (plus anti-CD20 monoclonal antibodies for B-cell lymphomas).

Advanced disease (stages II-IV)

Stage II non-Hodgkin lymphoma is managed as advanced stage disease in many circumstances. Most patients with all types of non-Hodgkin lymphoma who have stage II to IV disease are candidates for chemoimmunotherapy. In these cases, radiation therapy may be used to limit the number of cycles of chemoimmunotherapy or provide localized treatment for residual sites of bulk disease.

For indolent lymphomas, treatment varies considerably. Because these lymphomas are highly treatable but not reliably curable, treatment may not be recommended initially for asymptomatic patients, although some patients are given anti-CD20 immunotherapy using rituximab alone. This strategy can delay the need for myelosuppressive chemotherapy, but early immunotherapy alone has not been shown to impact overall survival. Patients with symptoms or bulky disease that puts vital organs at risk are treated with chemoimmunotherapy. In selected cases (eg, chemo-refractory with limited bone marrow involvement), radiolabeled anti-CD20 antibody can be used to target radiation to the tumor cell with potentially fewer effects on nearby normal organs.

In patients with aggressive B-cell lymphomas (eg, diffuse large B cell), the standard drug combination is rituximab plus cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine, and prednisone (R-CHOP). A complete response with disease regression is expected in 80% of cases, with an overall cure rate of about 60%. These results vary significantly by IPI score. Patients who are disease free at 24 months from diagnosis have a life expectancy similar to that of the age- and sex-matched population. This key factor can guide follow-up strategies in this patient population. Patients with lower IPI scores may benefit from adding the antibody-drug conjugate polatuzumab vedotin, a CD79b-directed antibody-drug conjugate to R-CHOP.

The approach in peripheral T-cell non-Hodgkin lymphoma and primary central nervous system lymphoma is different. In these patients, autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more may be offered to initial responders before relapse occurs with the intention of improving the likelihood of cure. In autologous stem cell transplantation, stem cells are obtained from the patient by peripheral blood leukopheresis and are transfused back into the patient after high-dose chemotherapy. Similarly, in some younger patients with mantle cell lymphoma who have responded to initial therapy, autologous stem cell transplantation may be is done to prolong remission.

Lymphoma relapse

Patients with aggressive non-Hodgkin lymphoma not in remission at end of therapy or who relapse are treated with second-line chemotherapy regimens followed by autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more if they are relatively young and in good health. In some patients at very high risk of relapse as well as in those for whom autologous transplant is not feasible or has already failed, stem cells from a matched sibling or unrelated donor (allogeneic transplants) can be effective. In general, the older the patient, the less likely an allogeneic transplantation will be offered because older patients have higher rates of transplantation complications.

Patients with diffuse large B-cell lymphoma (DLBCL) who have persistent lymphoma despite at least 2 prior lines of therapy may be candidates for chimeric antigen receptor (CAR) T cells. CAR T cells are T cells (most commonly autologous T cells) that have been genetically engineered to recognize a tumor antigen (eg, CD19). After infusion, they undergo activation and expansion. About one third of patients achieve a durable response from this therapy.

Patients not eligible for the above therapies, or for whom they have failed, may receive treatment with various therapies, mostly for palliation. These therapies vary widely and are constantly changing as new treatments are developed.

In indolent lymphomas, patients may be managed using a wide variety of strategies depending on

  • Lymphoma-related factors (eg, histopathology, stage, molecular and immunologic characteristics)

  • Patient-related factors (eg, age, comorbidities)

  • The type of and response to prior therapy.

Many of the same drugs used for first-line treatment may be given to patients in relapse. In some cases, the same treatment may be repeated if it was previously effective and well tolerated. High-dose chemotherapy with autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is used occasionally in patients who have high-risk lymphoma biology (including a poor response to chemotherapy), and although cure remains unlikely, remission may be superior to that with secondary palliative therapy alone. Reduced intensity allogeneic transplantation is a potentially curative option in some patients with indolent lymphoma.

The mortality rate of patients undergoing myeloablative transplantation has decreased dramatically to 1 to 2% for most autologous procedures and to 15 to 20% for most allogeneic procedures (depending on age).

Complications of treatment

An immediate complication of most therapies is infection that occurs during periods of neutropenia Neutropenia Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more . Although use of growth factors that stimulate white blood cell production has helped, infection continues to pose a problem.

The gastrointestinal adverse effects of chemotherapy can be largely relieved or prevented by antiemetics and bowel programs.

After successful treatment, patients should be referred to a cancer survivorship clinic for a care plan that can be implemented by the patient's primary care team. This plan is tailored to the patient's comorbidities and risks specific to the treatment they received.

Key Points

  • Non-Hodgkin lymphomas are a group of related cancers involving lymphocytes; they vary significantly in their rate of growth and response to treatment.

  • The disease is usually already disseminated at the time of diagnosis.

  • Molecular and genetic tests are essential for diagnosis and management.

  • Limited indolent disease may be treated with radiation therapy.

  • Treat more advanced disease (indolent or aggressive) with immunotherapy, chemotherapy, hematopoietic stem cell transplantation, or a combination depending on the type and stage of non-Hodgkin lymphoma.

More Information

The following is an English language resource that provides information for clinicians and support and information for patients. THE MANUAL is not responsible for the content of this resource.

Drugs Mentioned In This Article

Drug Name Select Trade
Albuked , Albumarc, Albuminar, Albuminex, AlbuRx , Albutein, Buminate, Flexbumin, Kedbumin, Macrotec, Plasbumin, Plasbumin-20
Calcidol, Calciferol, D3 Vitamin, DECARA, Deltalin, Dialyvite Vitamin D, Dialyvite Vitamin D3, Drisdol, D-Vita, Enfamil D-Vi-Sol, Ergo D, Fiber with Vitamin D3 Gummies Gluten-Free, Happy Sunshine Vitamin D3, MAXIMUM D3, PureMark Naturals Vitamin D, Replesta, Replesta Children's, Super Happy SUNSHINE Vitamin D3, Thera-D 2000, Thera-D 4000, Thera-D Rapid Repletion, THERA-D SPORT, UpSpring Baby Vitamin D, UpSpring Baby Vitamin D3, YumVs, YumVs Kids ZERO, YumVs ZERO
RIABNI, Rituxan, RUXIENCE, truxima
Cyclophosphamide, Cytoxan, Neosar
Adriamycin, Adriamycin PFS, Adriamycin RDF, Rubex
Oncovin, Vincasar PFS
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
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