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Non-Hodgkin's lymphoma

Medical Professionals

Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Non-Hodgkin's lymphoma article more useful, or one of our other health articles.

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What is non-Hodgkin's lymphoma?

Non-Hodgkin's lymphomas (NHLs) are an heterogeneous group of lymphoproliferative malignancies with differing patterns of behaviour and responses to treatment. There is a much greater predilection to disseminate to extranodal sites than in Hodgkin's lymphoma. The prognosis depends on the histological type, stage and treatment. They can be divided into two prognostic groups:1

  • Low-grade: relatively good prognosis, with median survival as long as 10 years. However, they are usually not curable in advanced clinical trials.

  • High-grade: shorter natural history but a significant number of these patients can be cured with intensive combination chemotherapy regimens.

Classification of non-Hodgkin's lymphomas

The World Health Organization (WHO) Classification is an update of the Revised European American Lymphoma (REAL) Classification. The Classification includes:1

  • Precursor B-cell neoplasms: precursor B-lymphoblastic lymphoma.

  • Mature (peripheral) B-cell neoplasms:

    • High-grade:

      • Diffuse large B-cell lymphoma (DLBCL); 30-58% of all NHLs.2

      • Mediastinal large B cell.

      • Primary central nervous system lymphomas (PCNSLs).

      • Primary effusion lymphoma.

      • Burkitt's lymphoma.

      • Mantle cell lymphoma.

    • Low-grade:

      • Follicular lymphoma; 20-25% of all NHL.

      • Mucosa-associated lymphoid tissue (MALT) lymphoma.

      • Waldenström's macroglobulinaemia.

  • Precursor T-cell neoplasms: precursor T-lymphoblastic lymphoma.

  • Mature (peripheral) T-cell neoplasms:

    • High-grade:

      • Enteropathy-type T-cell lymphoma.

      • Peripheral T-cell lymphoma.3

      • Subcutaneous paniculitis-like.

      • Systemic anaplastic.

      • Angio-immunoblastic.

    • Low-grade:

      • Mycosis fungoides and cutaneous T-cell lymphomas.

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How common is non-Hodgkin's lymphoma? (Epidemiology)

  • Non-Hodgkin's lymphoma is more than five times as common as Hodgkin's disease.

  • White people have a higher risk of developing non-Hodgkin's lymphoma than black and Asian people.1

  • The median age at presentation is older than 50 years, except for patients with high-grade lymphoblastic and small noncleaved lymphomas, which are the most common types of NHL observed in children and young adults. Low-grade lymphomas are very rare in children.1

  • The two most common types of NHL are DLBCL and follicular lymphomas.

  • The overall annual incidence of DLBCL in Europe is 3.8/100,000 but the incidence increases with age and varies considerably across Europe.2

  • About 2,200 people are diagnosed with follicular lymphoma every year in the UK.4

  • Primary cutaneous lymphomas are the second most common group of extranodal non-Hodgkin's lymphomas with an estimated annual incidence of 1/100,000 in Western countries.5

  • Extranodal marginal zone lymphomas of MALT type represent about 7% of all types of non-Hodgkin's lymphomas in the Western world.6

Risk factors for non-Hodgkin's lymphoma

  • Chromosomal translocations and molecular rearrangements.

  • Some viruses are implicated, including:

    • Epstein-Barr virus: associated with Burkitt's lymphoma, Hodgkin's disease, lymphomas in immunocompromised patients (eg, from HIV infection, organ transplantation) and sinonasal lymphoma.

    • Human T-cell leukaemia virus type 1 (HTLV-1) causes a latent infection via reverse transcription in activated T-helper cells.

    • Hepatitis C is associated with certain subtypes.

    • Kaposi's sarcoma-associated herpesvirus is associated with lymphomas in patients with HIV infection.

  • Environmental factors: eg, pesticides, herbicides, solvents, organic chemicals, wood preservatives, dusts, hair dye, chemotherapy and radiation exposure.

  • Congenital and acquired immunodeficiency states.

  • Autoimmune disorders: eg, Sjögren's syndrome and Hashimoto's thyroiditis, promote the development of MALT and predispose patients to subsequent lymphoid malignancies.

  • Helicobacter pylori infection is associated with the development of primary gastrointestinal lymphomas, especially gastric MALT lymphomas.1

Non-Hodgkin's lymphoma symptoms

  • Low-grade lymphomas:

    • Painless, slowly progressive peripheral lymphadenopathy is the most common clinical presentation. Spontaneous regression of enlarged lymph nodes may occur.

    • Primary extranodal involvement and systemic symptoms (fatigue, weakness, fever, night sweats, weight loss) are not common at presentation but are common in patients with advanced or end-stage disease.

    • Bone marrow is frequently involved and may be associated with cytopenia.

    • Splenomegaly.

    • Hepatomegaly.

  • Intermediate- and high-grade lymphomas:

    • Most patients present with rapidly growing and bulky lymphadenopathy.

    • Systemic symptoms and extranodal involvement (especially the gastrointestinal tract, skin, bone marrow, sinuses, genitourinary tract, thyroid, and central nervous system (CNS)) are more common.

    • Hepatomegaly, splenomegaly.

    • Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy obstructing the ureters may occur.

    • Primary CNS lymphomas: account for 1% of all intracranial neoplasms and are more commonly observed in patients with immunodeficiency - eg, Wiskott-Aldrich syndrome, transplantation or HIV infection.

    • Testicular mass.

    • Skin lesions: associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large-cell lymphoma and angio-immunoblastic lymphoma.

    • Lymphoblastic lymphoma: high-grade lymphoma, which often manifests with a mediastinal mass, superior vena cava syndrome and meningeal disease with cranial nerve palsies.

    • Burkitt's lymphoma: often presents with a large abdominal mass and symptoms of bowel obstruction.

Editor's note

Dr Krishna Vakharia, 16th October 2023

Suspected cancer: recognition and referral7

The National Institute for Health and Care Excellence (NICE) has recommended that an adult person should receive a diagnosis or ruling out of cancer within 28 days of being referred urgently by their GP for suspected cancer.

Continue reading below

Differential diagnosis

See also the separate Generalised Lymphadenopathy and Splenomegaly and Hypersplenism articles.


  • FBC: anaemia (marrow failure or autoimmune haemolytic anaemia), thrombocytopenia and neutropenia. Thrombocytosis and lymphocytosis may also occur.

  • Renal function and electrolytes: obstructive nephropathy, hypercalcaemia.

  • LFTs.

  • Serology: HIV, HTLV-1, hepatitis C.

  • Cytogenetics and immunochemistry play a significant role in the diagnosis of Burkitt's lymphoma.8

  • CXR: mediastinal adenopathy, pleural or pericardial effusions and parenchymal involvement.

  • Biopsy: fine-needle aspiration samples should not normally be used as the sole tissue for diagnosis. Fresh tissue should be submitted to laboratories where a diagnosis of lymphoma is suspected.9 Lymph node excision or adequate core biopsy is required for the diagnosis of follicular lymphoma - histology enables an assessment of the tumour grade and the exclusion of transformation to a more aggressive histological subtype.10

  • CT scan of the neck, chest, abdomen and pelvis: to detect enlarged lymph nodes, hepatosplenomegaly. This is the most widely used investigation for initial staging and assessment of treatment response.

  • Bone scans.

  • Other scans used include gallium scan and whole body positron emission tomography (PET) using radioisotope fluorodeoxyglucose (18F) (FDG-PET) scan.

  • MRI of the brain and spinal cord: if there is suspected primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma or vertebral body involvement by lymphoma.

  • Ultrasound of the scrotum.

  • Endoscopy and barium studies for gastrointestinal lesions.

  • Bone marrow aspirate and biopsy; a bone marrow trephine biopsy should always be carried out if a diagnosis of lymphoma is suspected or has been made on another tissue.11

  • Lumbar puncture.


The Ann Arbor staging system is the most commonly used staging system for patients with NHL.1

  • Stage I: involves a single lymph node region (I) or localised involvement of a single extralymphatic organ or site (IE).

  • Stage II: two or more lymph node regions on the same side of the diaphragm (II) or localised involvement of a single associated extralymphatic organ in addition to criteria for stage II (IIE).

  • Stage III: lymph node regions on both sides of the diaphragm (III) that also may be accompanied by localised involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE).

  • Stage IV: disseminated or multifocal involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant node involvement.

Subscript letters represent involvement of extralymphatic organs: L - lung, H - liver, P - pleura, O - bone, M - bone marrow, D - skin. E is used when extranodal lymphoid malignancies arise in tissues that are separate from but near to the major lymphatic system aggregates.

Stages I-IV can be followed by A or B designations:

  • A - no systemic signs and symptoms.

  • B - any of the following signs and symptoms: unexplained loss of more than 10% of body weight in the preceding six months before diagnosis, unexplained fever with temperature above 38°C, and drenching night sweats.

Non-Hodgkin's lymphoma treatment and management

  • Treatment options vary because of the heterogeneous nature of NHLs. Options include watchful waiting, single-agent or multi-agent chemotherapy and regional or extended radiotherapy.

  • The role of surgery in treatment is limited but may be useful in certain situations - eg, localised disease, complications (eg, gastrointestinal obstruction or perforation) or orchidectomy as part of the initial management of testicular lymphoma.

  • Vaccinations: polyvalent pneumococcal vaccine and influenza vaccine should be given to all patients with NHL.12

  • Meningococcal group C conjugate vaccine and Haemophilus influenzae type b (Hib) vaccine are also recommended, especially for patients receiving treatment and those with asplenia or splenic dysfunction.

  • Any patient with severe neutropenia should be given antibiotic prophylaxis with chemotherapy.

  • Recombinant human granulocyte colony-stimulating factor (rhG-CSF) stimulates the production of neutrophils and may reduce the duration of chemotherapy-induced neutropenia and thereby reduce the incidence of associated sepsis.

Diffuse large B-cell non-Hodgkin's lymphoma2

  • Rituximab is recommended for use in combination with a regimen of cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin®), and prednisolone (CHOP) for first-line treatment.

  • Fewer cycles of treatment with rituximab and CHOP with additional regional radiotherapy are an alternative.

  • High-dose chemotherapy with stem cell transplantation remains experimental in first-line therapy.

  • Concurrent CNS prophylaxis with intrathecal methotrexate or cytarabine has been recommended for patients at risk of CNS involvement (defined as lymphoma involvement in the bone marrow, testis, nasal or paranasal sinuses, orbits, bone or peripheral blood).13

Editor's note

Dr Krishna Vakharia, 23rd March 2023

Polatuzumab vedotin in combination for untreated diffuse large B-cell lymphoma14

NICE has recommended polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisolone (R‑CHP) for untreated diffuse large B-cell lymphoma (DLBCL) in adults if their International Prognostic Index (IPI) score is between 2 to 5.

This combination has been shown to increase the time before their cancer gets worse compared to those who have R-CHOP alone.

Dr Krishna Vakharia, 27th June 2023

Axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy


NICE has made available the use of axicabtagene ciloleucel within the Cancer Drugs Fund as an option for treating diffuse large B‑cell lymphoma in adults when an autologous stem cell transplant is suitable if it has relapsed within 12 months after first-line chemoimmunotherapy or is refractory to first-line chemoimmunotherapy.

As the trial is still ongoing, NICE has allowed access to this medication via the Cancer Drugs Fund which allows the ability to gather data whilst offering patients alternative and a quicker route to newer medications. Current evidence shows that when an autologous stem cell transplant is suitable, axicabtagene ciloleucel increases how long people live compared with standard care but it is uncertain how long for as the trial is ongoing.

Dr Krishna Vakharia, 30th April 2024

Epcoritamab for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic treatments 16

NICE has recommended epcoritamab as an option for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adults after 2 or more systemic treatments. It can only be used if they have had polatuzumab vedotin, or if polatuzumab vedotin is contraindicated or not tolerated. This medicine has not been directly compared to usual treatment protocols but indirect comparisons, though uncertain, indicate that people having epcoritamab live for longer than people having rituximab-based chemoimmunotherapy or people having polatuzumab‑BR or axicabtagene ciloleucel.

Mantle cell lymphoma17

  • Mantle cell lymphoma accounts for about 3-10% of all cases of NHL. Mantle cell lymphoma is more common in the over-60s and is three times more common in men than in women.

  • Mantle cell lymphomas are usually responsive to chemotherapy but often relapse after treatment.

  • Treatment options include:

    • Chemotherapy: combinations include rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), fludarabine given in combination with cyclophosphamide and rituximab (FCR). Recently, good results have been achieved with high-dose cytarabine when combined with other chemotherapy regimes.

    • High-dose chemotherapy treatment with stem cell support.

    • Radiotherapy.

    • Bortezomib, lenalidomide, temsirolimus and ibrutinib are being assessed as possible treatments for relapsed or refractory mantle cell lymphoma. Ibrutinib seems to give the best results so far.

    • Allogeneic stem cell transplantation should be considered as consolidation of first-line therapy for all patients deemed fit for intensive therapy. Patients over 60 years of age should be thoroughly assessed for the suitability of this approach.

Follicular lymphoma (FL)

  • Stages I-II: involved site radiotherapy (ISRT) delivering a dose of 24 Gray in 12 daily fractions should be regarded as the standard of care for patients with newly diagnosed stage IA disease.10

  • Observation without ISRT should be considered in people with limited stage FL who have undergone localised excision and where there may be concerns by the clinician or patient about radiotherapy to a particular site.

  • Stages III-IV:

    • Rituximab, in combination with:

      • Cyclophosphamide, vincristine and prednisolone (CVP).

      • Cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP).

      • Mitoxantrone, chlorambucil and prednisolone (MCP).

      • Cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or chlorambucil is recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated people.18

  • Rituximab, in combination with chemotherapy, is recommended as an option for the induction of remission in people with relapsed stage III or IV follicular NHL.19

  • Rituximab monotherapy is recommended as an option for the treatment of people with relapsed or refractory stage III or IV follicular NHL (if there is resistance to, or intolerance of, chemotherapy).19

  • Rituximab maintenance therapy is recommended as an option for the treatment of people with follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.20

  • Autologous stem cell transplantation has no role in first-line therapy for follicular NHL (which has no evidence of histological transformation) outside the setting of a clinical trial.10

Primary CNS diffuse large B-cell lymphoma13

  • If fit for intensive therapy, treatment with high-dose methotrexate, cytarabine, thiotepa, and rituximab should be offered.

  • If unfit for intensive therapy, offer treatment incorporating high-dose methotrexate, rituximab and an orally administered alkylating agent within an established protocol (eg, rituximab, methotrexate, procarbazine).

  • For those patients ineligible for high-dose methotrexate consider one, or a combination, of:

    • Oral chemotherapy (such as temozolomide).

    • Whole-brain radiotherapy +/− orbital radiotherapy if co-existing ocular involvement.

    • Corticosteroids (dexamethasone is typically used).


  • Neutropenia, anaemia, thrombocytopenia (secondary to bone marrow infiltration).

  • Bleeding secondary to thrombocytopenia, disseminated intravascular coagulation or direct vascular invasion by the tumour.

  • Large pericardial effusion or arrhythmias secondary to cardiac metastases.

  • Respiratory problems secondary to pleural effusion and/or parenchymal lesions.

  • Superior vena cava obstruction secondary to a large mediastinal tumour.

  • Spinal cord compression secondary to vertebral metastases.

  • Neurological problems secondary to primary CNS lymphoma or lymphomatous meningitis.

  • Gastrointestinal obstruction, perforation, and bleeding in a patient with gastrointestinal lymphoma (may also be caused by chemotherapy).

  • Pain secondary to tumour invasion.

  • Chemotherapy-related complications - eg, cytopenias, nausea and vomiting, fatigue. Tumour lysis syndrome (commonly occurs after treatment of high-grade bulky lymphomas) may lead to hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia and acute kidney injury.


  • Low-grade NHL types have a relatively good prognosis, with median survival as long as 10 years; however, they are usually not curable when advanced.

  • Intermediate-grade and high-grade lymphomas are more aggressive but are more responsive to chemotherapy.

  • The vast majority of relapses occur in the first two years after therapy.

  • The risk of late relapse is higher in patients with a histology of both low-grade and high-grade disease.

Further reading and references

  1. Adult Non-Hodgkin Lymphoma; National Cancer Institute (US)
  2. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2015)
  3. Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2015)
  4. Follicular lymphoma; Lymphoma Action, 2021
  5. Willemze R, Hodak E, Zinzani PL, et al; Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi149-54. doi: 10.1093/annonc/mdt242. Epub 2013 Jul 17.
  6. Zucca E, Copie-Bergman C, Ricardi U, et al; Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi144-8. doi: 10.1093/annonc/mdt343.
  7. Suspected cancer: recognition and referral; NICE guideline (2015 - last updated October 2023)
  8. Graham BS, Lynch DT; Burkitt Lymphoma
  9. Julien LA, Michel RP; Imprint cytology: Invaluable technique to evaluate fresh specimens received in the pathology department for lymphoma workup. Cancer Cytopathol. 2021 Oct;129(10):759-771. doi: 10.1002/cncy.22442. Epub 2021 May 20.
  10. Guidelines on the investigation and management of follicular lymphoma; British Committee for Standards in Haematology, 2011 (last updated July 2020).
  11. Kwoun WJ, Ahn JY, Park PW, et al; How useful is bone marrow study as an initial investigative tool without lymph node biopsy in malignant lymphoma?: Eleven years of experience at a single institution. J Clin Lab Anal. 2019 May;33(4):e22841. doi: 10.1002/jcla.22841. Epub 2019 Feb 6.
  12. Immunisation against infectious disease - the Green Book (latest edition); UK Health Security Agency.
  13. Kansara R; Central Nervous System Prophylaxis Strategies in Diffuse Large B Cell Lymphoma. Curr Treat Options Oncol. 2018 Sep 10;19(11):52. doi: 10.1007/s11864-018-0569-2.
  14. Polatuzumab vedotin in combination for untreated diffuse large B-cell lymphoma; NICE Technology appraisal guidance, March 2023
  15. Axicabtagene ciloleucel for treating relapsed or refractory diffuse large B-cell lymphoma after first-line chemoimmunotherapy; NICE Technology appraisal guidance, June 2023
  16. Epcoritamab for treating relapsed or refractory diffuse large B-cell lymphoma after 2 or more systemic treatments; NICE Technology appraisal guidance, March 2024
  17. Guideline for the management of mantle cell lymphoma; British Society for Haematology, 2018
  18. Rituximab for the first-line treatment of stage III-IV follicular lymphoma; NICE Technology Appraisal Guidance, January 2012
  19. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma; NICE Technology Appraisal Guidance, February 2008
  20. Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma; NICE Technology Appraisal Guidance, June 2011

Article history

The information on this page is written and peer reviewed by qualified clinicians.

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