Non-Hodgkin’s lymphomas

01Definition and overview

Non-Hodgkin lymphomas (NHL) are clonal cancers of lymphocytes that grow as solid tumours in lymph nodes or other tissues; some also circulate in the blood. They are everything that is not Hodgkin lymphoma: dozens of diseases, each matching a stage of normal B-, T- or NK-cell development. The WHO 5th edition (2022) and the International Consensus Classification (ICC, 2022) name them by cell of origin, appearance, immunophenotype and genetics; their names and a few definitions differ, but nearly all the diseases are the same.

Hairy cell leukaemia, a rare indolent B-cell cancer of the spleen and marrow, also belongs to this family.

02Etiology and pathophysiology

Causes and risk factors

Most patients have no identifiable cause, but the known ones point to two themes: a weak immune system that cannot control virus-infected B cells, and chronic stimulation that keeps lymphocytes dividing until one goes wrong.

Age, a family history, obesity and some agricultural chemicals add modestly to the risk, and other microbes have been linked with MALT lymphomas of the ocular adnexa (Chlamydia psittaci), skin (Borrelia) and small bowel (Campylobacter jejuni), with links that vary by region.

How lymphomas arise

B cells cut and rejoin their DNA to build antibody genes, and in the germinal centre they mutate them again (somatic hypermutation and class switching). Mistakes in this work can join an oncogene to an immunoglobulin gene, whose strong enhancer then drives it in every daughter cell:

A translocation is rarely enough alone: t(14;18) can be found at low levels in the blood of many healthy people. Further mutations (TP53, the NF-κB and B-cell receptor pathways, genes that hide the cell from T cells) complete the cancer. Put simply, this explains the two behaviours: indolent lymphomas are long-lived cells that fail to die (BCL2) and divide slowly, so they escape chemotherapy, which kills dividing cells; aggressive lymphomas divide fast (MYC) and are killed by it. An indolent lymphoma can later transform into an aggressive one, as follicular lymphoma does into DLBCL.

03Clinical features

Presentation

• Painless lymphadenopathy: widespread and waxing and waning for years in indolent lymphomas, a fast-growing mass in aggressive ones.
• B symptoms (fever above 38 °C, drenching night sweats, loss of more than 10 per cent of weight in 6 months), commoner in aggressive disease.
• Extranodal disease, the presenting site in a fifth to a third, depending on how strictly it is defined: stomach (dyspepsia, bleeding) and bowel (obstruction, perforation, malabsorption), Waldeyer's ring, skin, brain and eye, testis (the commonest testicular tumour in older men), salivary glands, orbit, thyroid, lung, bone and breast.
• Marrow infiltration with cytopenias; lymphoma cells in the blood (mantle cell, small lymphocytic, splenic marginal zone, Sézary syndrome); splenomegaly; a paraprotein; autoimmune haemolysis or thrombocytopenia.

04Diagnosis and management

Diagnosis and staging

The work-up is shared with Hodgkin lymphoma:

• A biopsy, by excision of a node or a core biopsy, with immunohistochemistry; flow cytometry of blood, marrow or fluid where lymphoma cells circulate; FISH for translocations (MYC, BCL2 and BCL6 in large B-cell lymphoma); molecular tests (clonality, TP53).
• PET-CT for the lymphomas that take up FDG (most), CT for the others (small lymphocytic, some marginal zone, mycosis fungoides). A marrow biopsy is needed in some indolent lymphomas, not routinely in DLBCL staged by PET-CT.
• Blood: full count and film, LDH, urate, creatinine, calcium, liver tests, immunoglobulins and electrophoresis; HIV and hepatitis C serology.
• Before rituximab or any anti-CD20 antibody, screen for hepatitis B (HBsAg and anti-HBc): reactivation can cause fatal hepatitis. Positive patients are treated with liver specialists, usually with antiviral prophylaxis.
• Echocardiography before anthracyclines; fertility counselling; brain MRI and CSF (cytology and flow cytometry) in patients at high risk of CNS disease.

The stage follows the Lugano classification (I to IV, as in Hodgkin lymphoma), without the A and B suffixes, which Lugano keeps for Hodgkin lymphoma; limited stage is I and II without bulk. Response is judged by PET-CT on the Deauville scale (1 to 3 is a complete metabolic response).

Treatment in general

• Anti-CD20 antibodies (rituximab, obinutuzumab) kill B cells with complement, antibody-dependent cytotoxicity and direct signals; they are added to chemotherapy for almost every B-cell lymphoma.
• Chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone, every 3 weeks), bendamustine, and intensive or high-dose regimens with an autologous stem cell transplant.
• Radiotherapy to localised disease, often at low doses (about 24 Gy in indolent lymphomas).
• Targeted drugs: BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), lenalidomide, antibody-drug conjugates (polatuzumab vedotin, brentuximab vedotin).
• Immune cell therapies: CAR-T cells (the patient's T cells engineered to kill CD19-positive cells) and bispecific antibodies (glofitamab, epcoritamab, mosunetuzumab, odronextamab), which bind CD20 on the lymphoma and CD3 on T cells. Both can cause cytokine release syndrome (fever, low blood pressure, hypoxia; tocilizumab and steroids) and neurotoxicity (confusion, dysphasia, seizures; steroids). CAR-T also leaves long cytopenias, low immunoglobulins and infections, and since 2024 European regulators warn of T-cell cancers arising after it.

Supportive care: G-CSF when the risk of febrile neutropenia is high; pneumocystis and antiviral prophylaxis with bendamustine, purine analogues and intensive regimens; vaccination before treatment where possible. In the UK, patients treated with bendamustine or a purine analogue such as fludarabine receive irradiated blood for life, and CAR-T recipients from 7 days before cell collection until 3 months after the infusion.

Diffuse large B-cell lymphoma

The pathologist defines the subtype: germinal centre or activated B-cell type (by immunohistochemistry), and MYC, BCL2 and BCL6 rearrangements by FISH. DLBCL/high-grade B-cell lymphoma with MYC and BCL2 rearrangements (the "double hit") does worse. Tumours that only express MYC and BCL2 strongly by immunohistochemistry (double expressors) also do worse but are treated as usual.

The International Prognostic Index (IPI) gives a point each for age over 60, an LDH above normal, ECOG performance status 2 to 4, stage III or IV, and more than one extranodal site:

With R-CHOP, the revised IPI (R-IPI) regroups the same factors: 0 points, 94 per cent alive at 4 years; 1 to 2 points, 79 per cent; 3 to 5 points, 55 per cent.

The CNS-IPI adds kidney or adrenal involvement to the five: with 4 to 6 points, about 1 in 10 patients relapse in the central nervous system within 2 years, and testicular, breast and epidural disease also carry a high risk. These patients have a brain MRI and CSF examination. Intrathecal methotrexate is no longer recommended, and whether high-dose intravenous methotrexate prevents CNS relapse is uncertain.

First-line treatment in European recommendations (2025):

In the POLARIX trial (IPI 2 to 5), pola-R-CHP raised progression-free survival at 2 years from 70 to 77 per cent without changing overall survival; it is licensed in the EU for untreated DLBCL. Radiotherapy is kept for a single site still PET-positive at the end. Particular forms: primary mediastinal large B-cell lymphoma (young women, a bulky anterior mediastinal mass; R-CHOP every 2 weeks or DA-EPOCH-R, without radiotherapy if PET-negative); testicular lymphoma (R-CHOP, radiotherapy to the other testis and CNS prophylaxis); and primary CNS lymphoma (a biopsy, then high-dose methotrexate-based chemotherapy with rituximab, consolidated by a thiotepa-based autologous transplant in fit patients).

About 30 to 40 per cent of patients relapse or are refractory. A biopsy confirms it, and the timing decides the treatment:

1. 1

   Refractory, or relapse within 12 months

   For fit patients, CAR-T cells: axicabtagene ciloleucel or lisocabtagene maraleucel, both licensed in the EU for this second line. In the ZUMA-7 trial, event-free survival at 2 years was 41 against 16 per cent with salvage chemotherapy and transplant.
2. 2

   Later relapse

   For fit patients, salvage chemotherapy (R-DHAP, R-ICE, R-GDP) and, if the lymphoma responds, high-dose BEAM with an autologous stem cell transplant; about 4 in 10 patients treated this way stay in long-term remission.
3. 3

   Not fit for intensive treatment

   Glofitamab with gemcitabine and oxaliplatin (licensed in the EU for those not fit for a transplant), polatuzumab vedotin with bendamustine and rituximab, or tafasitamab with lenalidomide.
4. 4

   Third line and beyond

   CAR-T cells if not yet given; bispecific antibodies (glofitamab, epcoritamab, odronextamab), which give complete remissions in about 4 in 10; loncastuximab tesirine; an allogeneic transplant for a few.

Follicular lymphoma

Grading by the number of large cells is optional in the WHO 5th edition; the old grade 3B, whose follicles are made only of large cells (centroblasts), is now follicular large B-cell lymphoma and is treated like DLBCL; the ICC keeps the grades, grade 3B included. The FLIPI gives a point each for age over 60, stage III or IV, haemoglobin below 120 g/L, a raised LDH and more than four nodal areas.

• Stage I to II: involved-site radiotherapy, 24 Gy, which keeps about half free of disease for 10 years or more.
• Advanced, low burden, no symptoms: watch and wait, since early treatment does not lengthen survival. Treatment starts with any of the GELF criteria: a mass of 7 cm or more, three nodal sites each of 3 cm or more, B symptoms, a large spleen, compression of an organ, an effusion, cytopenias or many lymphoma cells in the blood. Rituximab alone suits a low burden that needs treating.
• High burden: rituximab or obinutuzumab with bendamustine or CHOP, then the antibody every 2 months for 2 years. Maintenance (PRIMA) and obinutuzumab instead of rituximab (GALLIUM) lengthened progression-free survival but not overall survival; obinutuzumab caused more toxicity. In the UK, obinutuzumab is used first line when the FLIPI is 2 or more.
• About 1 in 5 progress within 24 months of chemoimmunotherapy (POD24), a sign of high risk. A rapidly growing node, a rising LDH, new B symptoms or hypercalcaemia suggest transformation to DLBCL (about 2 per cent a year), which needs a biopsy of the most active site and DLBCL treatment.
• Relapse: re-biopsy, then options include lenalidomide with rituximab (alone or with tafasitamab or epcoritamab), bispecific antibodies after two lines (mosunetuzumab, epcoritamab, odronextamab), zanubrutinib with obinutuzumab, CAR-T cells, and an autologous transplant for early chemosensitive relapse.

Marginal zone lymphomas

• Gastric MALT lymphoma with Helicobacter pylori: eradication therapy for every patient, whatever the stage, and on its own first in localised disease. In a pooled analysis of early-stage cases, it brought remission in 77.5 per cent, but in only about 1 in 5 of those with t(11;18); remission can take 12 months or more, and is followed with endoscopy and biopsies. Relapse runs at about 2 per cent a year.
• Persisting or Helicobacter-negative localised MALT lymphoma: low-dose radiotherapy (about 24 Gy); advanced disease: rituximab with or without chemotherapy. Surgery is rarely needed.
• Splenic marginal zone lymphoma: antiviral treatment if hepatitis C is present; otherwise rituximab, or splenectomy.
• Zanubrutinib is licensed in the EU for marginal zone lymphoma after anti-CD20 therapy.

Mantle cell lymphoma

The cells are CD5-positive, CD23-negative and cyclin D1-positive, usually SOX11-positive. The MIPI combines age, performance status, LDH and white count; a Ki-67 of 30 per cent or more, blastoid or pleomorphic cells and TP53 mutation mark high risk and poor response to chemotherapy. Leukaemic non-nodal mantle cell lymphoma (SOX11-negative, in blood, marrow and spleen) is often indolent and can be watched.

• Fit, up to about 65: R-CHOP alternating with R-DHAP, with ibrutinib added and continued for 2 years. In the TRIANGLE trial, adding ibrutinib raised failure-free survival at 3 years from 72 to 88 per cent, and ibrutinib without a transplant (86 per cent) did at least as well as the transplant without ibrutinib, which questions the place of the transplant. The regimen without a transplant is licensed in the EU.
• Older or unfit: bendamustine with rituximab, with acalabrutinib added (licensed in the EU), or R-CHOP followed by rituximab maintenance.
• Relapse: a BTK inhibitor if not yet used; pirtobrutinib, a non-covalent BTK inhibitor, or CAR-T cells (brexucabtagene autoleucel, lisocabtagene maraleucel) after a covalent one; lenalidomide. Zanubrutinib, used for mantle cell lymphoma in the USA, is not licensed for it in the EU.

Burkitt lymphoma

Medium-sized cells with nearly all dividing (Ki-67 near 100 per cent) and macrophages full of debris give a "starry sky"; the cells are CD10- and BCL6-positive and BCL2-negative or weak, with a MYC translocation, t(8;14) in about 8 in 10. The WHO 5th edition recommends dividing it by EBV status (positive or negative) rather than into the old endemic, sporadic and immunodeficiency types: endemic Burkitt lymphoma of children in malarial equatorial Africa, with jaw and orbit tumours, is almost always EBV-positive; sporadic cases, mostly abdominal, usually are not.

Burkitt lymphoma grows within days, so work-up and treatment are urgent, with tumour lysis prevention before the first dose. That means intravenous fluids, rasburicase (or allopurinol, if G6PD deficient), and potassium, phosphate, calcium, urate and creatinine checked several times a day in the first days. Treatment is intensive and given with curative intent whatever the HIV status: R-CODOX-M alternating with R-IVAC, or the gentler DA-EPOCH-R, used in older or lower-risk patients and, since a randomised trial in 2023, also an option in high-risk disease without CNS involvement. CNS prophylaxis is intrathecal, and R-CODOX-M/R-IVAC adds high-dose methotrexate and cytarabine.

T-cell and NK-cell lymphomas

05Epidemiology

• GLOBOCAN estimates 562,793 new cases of NHL worldwide in 2024, the tenth commonest cancer, and 234,903 deaths; in Europe, about 128,800 new cases and 48,600 deaths.
• Incidence rises steeply with age, and most patients are over 60; men are affected slightly more often (mantle cell lymphoma about 3 to 1).
• Incidence roughly tripled in high-income countries in the second half of the 20th century, partly from HIV and better diagnosis, and has since levelled off in many.
• B-cell lymphomas make up most cases in Europe. T- and NK-cell lymphomas are commoner in East Asia; adult T-cell leukaemia/lymphoma clusters where HTLV-1 is common, and follicular lymphoma is less common in Asia than in Europe.
• In equatorial Africa, endemic Burkitt lymphoma is the commonest cancer of children. Childhood NHL elsewhere is mostly aggressive (Burkitt, lymphoblastic, anaplastic large cell and large B-cell lymphoma) and is treated in paediatric protocols.

06Prognosis

• DLBCL: R-CHOP or pola-R-CHP cures about 6 in 10 overall, from more than 9 in 10 at an R-IPI of 0 to about half at 3 or more. Patients free of events at 2 years then live about as long as their peers. Of relapsed or refractory patients, about 4 in 10 have lasting remissions after CAR-T cells; double-hit and CNS disease do badly.
• Follicular lymphoma: median survival is now well beyond 10 years. Progression within 24 months (POD24) cut 5-year survival to 50 per cent, against 90 per cent in the rest; after transformation, median survival was about 4 years in the rituximab era.
• Marginal zone lymphomas: most patients are alive 10 years after diagnosis, and gastric MALT lymphoma that responds to eradication rarely threatens life.
• Mantle cell lymphoma: survival varies widely, from many years in non-nodal or low-risk disease to short survival in TP53-mutated or blastoid disease; BTK inhibitors in first line have lengthened remissions.
• Burkitt lymphoma: about 9 in 10 low-risk patients and more than 6 in 10 high-risk or HIV-positive patients are cured if full treatment is given; patients in remission at 2 years are usually cured, and relapse is rarely salvaged.
• T-cell lymphomas: most have a poor outcome with chemotherapy and relapse is common, ALK-positive anaplastic large cell lymphoma and early mycosis fungoides being the exceptions.

Follow-up is clinical, without routine surveillance scans. It covers relapse and transformation, and the late effects: heart failure after anthracyclines, second cancers, low immunoglobulins and infections after anti-CD20 antibodies and CAR-T cells, neuropathy, and the effects of radiotherapy.