Indolent non-Hodgkin lymphoma

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Indolent lymphoma describes tempo, not one disease. Follicular lymphoma usually expresses CD20, CD10 and BCL6 with t(14;18)-related BCL2 dysregulation. Marginal-zone lymphoma may be extranodal MALT, splenic or nodal and can follow chronic antigen stimulation. Lymphoplasmacytic lymphoma commonly produces IgM and becomes Waldenstrom macroglobulinaemia when the paraprotein and marrow criteria are met. Mantle-cell lymphoma can occasionally behave slowly but has distinct cyclin D1 or SOX11 and t(11;14) biology. Treatment must follow the exact pathology.

Obtain excision biopsy where possible. If a deep site requires cores, take multiple large samples and alert pathology to conserve tissue. Report grade, architecture, B-cell phenotype, proliferation and defining genetics. Follicular grade 3B is managed as aggressive lymphoma; grade 3A needs expert context. Stage with PET-CT for FDG-avid follicular disease and CT or subtype-appropriate imaging for MALT. Check FBC, film, renal, liver, calcium, LDH, immunoglobulins, serum electrophoresis, hepatitis B/C and HIV. Marrow biopsy is used when it changes staging or explains cytopenia.

Observation is active care. Advanced low-tumour-burden follicular lymphoma can remain stable for years, and immediate systemic treatment does not improve overall survival simply because stage III or IV is present. Record nodes and spleen, symptoms, FBC and LDH and give rapid-access instructions. Treatment begins for organ threat, symptomatic bulk, clinically important progression, B symptoms, marrow failure, splenic pain or disease-mediated cytopenia. Formal criteria such as GELF structure assessment but do not replace patient function and pace.

Localised follicular lymphoma is potentially curable with involved-site radiotherapy, commonly 24 Gy in 12 fractions. Very low-dose 4 Gy in two fractions provides excellent palliation for selected sites but is less durable and not automatically equivalent when durable local cure is intended. Advanced symptomatic disease uses rituximab or obinutuzumab with bendamustine, CHOP or CVP according to current protocol, fitness and desired tempo. Maintenance anti-CD20 can prolong remission after eligible induction but increases infection and impairs vaccine responses.

Marginal-zone management is site specific. Test gastric MALT for H. pylori with methods that remain reliable after proton-pump inhibitors and antibiotics, and eradicate confirmed infection; some apparently negative cases also receive eradication through the specialist pathway. Repeat endoscopic biopsies because radiological size is not sufficient. Local radiotherapy treats persistent localised disease. Splenic MZL may respond to rituximab, and hepatitis C treatment can regress virus-driven disease. Disseminated symptomatic MZL uses anti-CD20-based systemic treatment.

Transformation is a biological event, not merely faster growth. Use PET-CT to find a discordantly intense or rapidly enlarging site and obtain excision or large cores. A lower-uptake convenient node can miss the aggressive clone. If transformed DLBCL is confirmed, stage and treat through the aggressive lymphoma pathway, considering prior anthracycline and anti-CD20 exposure. An urgent organ emergency may require steroids after diagnostic material is secured. LDH and PET raise probability but cannot prove histology.

At relapse, do not automatically repeat the previous regimen. Re-biopsy when tempo changes or transformation is plausible, document duration of first remission, cumulative marrow, cardiac and infection toxicity and current antigen expression. Options include anti-CD20 combinations, lenalidomide-based therapy, targeted agents for defined subtypes, radiotherapy and cellular treatment after transformation. Infection prevention, immunoglobulin assessment, vaccination timing and skin and second-cancer surveillance become increasingly important with cumulative immune suppression.

Key points

Indolent NHL includes follicular and nodal, splenic and extranodal marginal-zone lymphomas; lymphoplasmacytic lymphoma and some mantle-cell presentations need their own biology-led pathways.
Reference-standard diagnosis is excision biopsy or adequate cores with architecture, flow, immunohistochemistry and genetics; do not label subtype from blood or PET alone.
Advanced stage without symptoms is not a treatment indication: active monitoring is first-line for low-burden asymptomatic follicular lymphoma.
Start therapy for threatened organ function, symptomatic bulky or progressive disease, marrow failure, significant B symptoms, splenic symptoms or disease-mediated cytopenia.
Localised stage I–II follicular lymphoma can be treated with involved-site radiotherapy, commonly 24 Gy; selected observation or systemic treatment follows anatomy and patient priorities.
Advanced symptomatic follicular disease uses anti-CD20-based immunochemotherapy selected from fitness, pace and toxicity, followed by maintenance in eligible responders under current commissioning.
Gastric MALT lymphoma requires H. pylori testing and eradication as first-line when infected, with endoscopic and histological response follow-up.
Rapid discordant growth, new pain, high LDH or severe B symptoms requires PET-CT to choose a biopsy site for transformation; PET cannot replace histology.
Do not use routine surveillance PET after remission; follow symptoms, examination and blood tests and image a new clinical concern.
Screen hepatitis B before anti-CD20 therapy and use antiviral prophylaxis when indicated; avoid live vaccines during meaningful B-cell depletion.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Mature B-cell clones

Most indolent lymphomas arise from mature B cells with acquired survival and differentiation lesions, including BCL2 dysregulation in many follicular lymphomas.

Chronic antigen stimulation

Helicobacter pylori, hepatitis C and autoimmune inflammation drive selected extranodal marginal-zone lymphomas, creating opportunities for cause-directed treatment.

Immune and infectious context

Sjögren syndrome, Hashimoto thyroiditis, HIV and immune suppression alter the risk and anatomical pattern of particular marginal-zone and lymphoplasmacytic diseases.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Slow clonal accumulation
Long-lived malignant lymphocytes accumulate in nodes, marrow, spleen or mucosal tissues, often producing extensive stage with few symptoms.
2
Microenvironment dependence
Follicular helper cells, stromal signals and antigenic stimulation support survival, explaining sensitivity to anti-CD20 therapy and occasional infection eradication.
3
Marrow and immune effects
Infiltration and immune dysregulation cause cytopenia, haemolysis, hypogammaglobulinaemia, recurrent infection and paraprotein-mediated symptoms in selected indolent lymphoma subtypes.
4
Clonal transformation
Additional MYC, TP53 and other lesions can produce aggressive large-cell lymphoma, changing tempo, PET intensity, prognosis and treatment intent.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Slow nodal course

Waxing and waning painless nodes, splenic fullness or incidental deep adenopathy over months suggests indolent tempo but still requires tissue classification.

Treatment indication

Pain, organ compression, progressive bulk, B symptoms, marrow failure or major splenic symptoms matter more than anatomical stage alone.

MALT pattern

Dyspepsia, salivary, thyroid, orbital, pulmonary or cutaneous disease can reflect chronic inflammation-associated extranodal marginal-zone lymphoma.

Transformation signalRed flag

One rapidly enlarging painful site, major LDH rise or new severe B symptoms requires urgent targeted biopsy.

Immune complication

Recurrent sinopulmonary infection, autoimmune haemolysis, neuropathy or paraprotein symptoms may drive treatment despite limited nodal burden.

Red flags requiring action

One node enlarging rapidly, new severe pain, extranodal mass, disproportionate LDH rise or new B symptoms suggests transformation and requires urgent PET-directed biopsy.
Cytopenic bleeding, recurrent infection, haemolysis, massive symptomatic spleen or organ compression can create a treatment indication even without rapid growth.
Headache, visual change, mucosal bleeding or neurological symptoms with an IgM paraprotein suggests hyperviscosity and requires urgent viscosity and plasma-exchange assessment.
Fever during bendamustine, anti-CD20 or maintenance treatment is infection until assessed; lymphocyte depletion can produce prolonged viral and opportunistic risk.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Reference standard: excision biopsyFirst stepReference standard
Why
Preserve architecture and establish exact indolent subtype and grade.
Interpretation and limitations
Integrate morphology, flow, immunohistochemistry and FISH; distinguish follicular, marginal-zone, CLL/SLL and mantle-cell disease before planning treatment.
02
Subtype-appropriate staging imaging
Why
Map burden, establish radiotherapy anatomy and identify transformation targets.
Interpretation and limitations
Use PET-CT for follicular and suspected transformation; use CT, endoscopy or organ imaging where marginal-zone biology is variably FDG avid.
03
Blood, paraprotein and viral baseline
Why
Identify marrow, immune, renal and treatment-safety consequences.
Interpretation and limitations
Check FBC, film, LDH, renal, liver, calcium, immunoglobulins, electrophoresis and hepatitis B/C and HIV; add haemolysis, cryoglobulin or viscosity testing when indicated.
04
H. pylori assessment
Why
Identify a reversible driver of gastric MALT lymphoma.
Interpretation and limitations
Use histology plus another validated test and account for false negatives from proton-pump inhibitors, antibiotics and bleeding; confirm eradication and histological response.
05
PET-directed repeat biopsy
Why
Confirm transformation before aggressive treatment.
Interpretation and limitations
Sample the fastest-growing or most avid accessible site with adequate tissue; necrosis or low-grade tissue elsewhere does not exclude a discordant aggressive clone.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Reactive lymphadenopathy

Infection, autoimmune disease and vaccination cause polyclonal reactive architecture; persistence, progression and excision pathology distinguish a clonal lymphoma.

CLL or small lymphocytic lymphoma

CD5 and CD23 coexpression, blood clonal count and characteristic genetics separate CLL/SLL from follicular and marginal-zone disease.

Mantle-cell lymphoma

Cyclin D1, SOX11 and t(11;14) identify a CD5-positive lymphoma whose usual behaviour and treatment are not reliably indolent.

Aggressive transformation

High-grade morphology in a targeted biopsy, rather than symptoms or PET alone, confirms large-cell transformation requiring curative-intent aggressive therapy.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01New indolent lymphomaClassify before deciding whether to treatFirst stepBiopsy suggests a small B-cell or follicular lymphoma.

1Complete specialist pathology with grade, phenotype and defining genetics and resolve mantle-cell, CLL and lymphoplasmacytic alternatives.
2Stage with subtype-appropriate imaging and assess symptoms, bulk, organ threat, marrow, paraprotein and infection.
3Choose observation, local radiotherapy, cause-directed therapy or systemic treatment from subtype and treatment indication.

02Asymptomatic advanced follicularMonitor without treating stageAdvanced disease has low burden and no organ, marrow or symptom indication.

1Document examination, nodes, spleen, FBC, LDH, symptoms and transformation warning baseline.
2Use interval clinical and laboratory review without routine surveillance PET.
3Start treatment only when symptoms, organ risk, substantial progression or cytopenia creates benefit.

03Gastric MALTRemove the antigenic driver firstBiopsy confirms gastric extranodal marginal-zone lymphoma.

1Test accurately for H. pylori and stage local and disseminated disease.
2Give a complete eradication regimen through current local antimicrobial guidance and confirm eradication.
3Use scheduled endoscopic biopsies; treat persistent, progressive or disseminated disease with radiotherapy or systemic therapy.

04Possible transformationBiopsy the discordant siteGrowth, pain, LDH, B symptoms or PET pattern changes abruptly.

1Stabilise organ compromise and obtain PET-CT to map biological heterogeneity.
2Sample the most avid or fastest-growing accessible lesion before steroids where feasible.
3If aggressive transformation is confirmed, move to curative aggressive lymphoma staging and treatment with prior exposure considered.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

CD20-directed treatment used alone in selected low-burden disease and with chemotherapy for symptomatic follicular and marginal-zone lymphoma.

Rituximab

Give 375 mg/m² IV on day 1 of each protocol cycle, or use the licensed subcutaneous formulation only after at least one tolerated full IV dose; monotherapy schedules and maintenance intervals are indication specific.

Screen hepatitis B and use antiviral prophylaxis when indicated. Premedicate and monitor infusion reaction, infection, late neutropenia, hypogammaglobulinaemia and rare PML; vaccines should be planned before depletion and pregnancy avoided.

Effective first-line systemic immunochemotherapy for selected symptomatic advanced indolent B-cell lymphomas.

Bendamustine with rituximab

A common follicular or marginal-zone regimen gives bendamustine 90 mg/m² IV on days 1 and 2 with rituximab 375 mg/m² day 1 every 28 days for up to six cycles, using exact centre modifications.

Prolonged CD4 lymphopenia and infection can outlast neutropenia; use Pneumocystis, antiviral and irradiated-component policy as indicated. Monitor marrow, renal, liver, skin and infusion toxicity and avoid pregnancy.

Potentially curative treatment for localised follicular or marginal-zone lymphoma and efficient palliation for symptomatic focal disease.

Involved-site radiotherapy

For durable local control use a specialist plan commonly 24 Gy in 12 fractions; for selected palliative sites use 4 Gy in two fractions with retreatment or escalation if control is inadequate.

Choose dose from intent, site and anticipated survival rather than convenience alone. Document salivary, thyroid, ocular, bowel, marrow, fertility and second-cancer exposure and confirm pathology before irradiation.

First-line cause-directed treatment for H. pylori-positive gastric MALT lymphoma and a specialist consideration in some apparently negative localised cases.

H. pylori eradication

Use the current local resistance-informed eradication course at full doses for the recommended duration, with acid suppression and two antibiotics, then confirm eradication after the required antibiotic and proton-pump-inhibitor washout.

Regimen varies with penicillin allergy, previous macrolide or metronidazole exposure and local resistance. Review interactions, renal or hepatic function and pregnancy, and do not infer lymphoma remission from symptom improvement without biopsy follow-up.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Histological transformation

Follicular and other indolent lymphomas can transform to aggressive large B-cell disease with rapid focal progression and shortened survival.

Marrow and immune failure

Progressive infiltration, autoimmune cytopenia and treatment-related lymphocyte depletion cause anaemia, bleeding and recurrent bacterial or opportunistic infection.

Organ and paraprotein injury

Massive spleen, nodal compression, cryoglobulinaemia, neuropathy, renal disease and hyperviscosity can occur in distinctive subtype-specific clinical patterns.

Cumulative treatment harm

Infusion reaction, hepatitis B reactivation, prolonged cytopenia, secondary malignancy and impaired vaccine response accumulate across repeated treatment lines.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During observation review symptoms, node and spleen examination, FBC and LDH at a risk-appropriate interval and bring review forward for transformation warnings.
During systemic treatment monitor counts, renal and liver function, infection, neuropathy, infusion reaction and regimen-specific prophylaxis at every cycle.
After anti-CD20 or bendamustine follow recurrent infection, immunoglobulins, viral reactivation and prolonged lymphopenia and plan non-live vaccination when response can recover.
After gastric eradication confirm organism clearance and perform scheduled endoscopic mapping biopsies until histological remission or an alternative treatment decision.
After remission avoid routine PET surveillance; investigate new rapid growth, B symptoms, LDH rise, cytopenia or organ symptoms with directed imaging and biopsy.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Stage does not mandate therapy

Indolent lymphoma is commonly disseminated at diagnosis. Treating an asymptomatic stage IV label early can add toxicity without extending survival.

Antibiotics can treat lymphoma

Gastric MALT illustrates antigen dependence: eradicating H. pylori can produce durable histological regression without cytotoxic treatment.

Four gray is palliative

Very low-dose radiotherapy is convenient and active, but 24 Gy provides more durable control when local cure or long remission is the intent.

Transformation is spatial

Low-grade and high-grade clones can coexist. Sampling the easiest rather than the most suspicious site can miss the disease driving deterioration.

Immune suppression is prolonged

Bendamustine and anti-CD20 effects persist beyond count recovery, so infection prevention and vaccine planning must extend after the last cycle.

11Common pitfallsFrequent interpretation and management errors.

01
Do not treat advanced anatomical stage alone in asymptomatic low-burden follicular lymphoma.
02
Do not call mantle-cell lymphoma indolent from slow presentation without cyclin D1, SOX11 and t(11;14) classification.
03
Do not diagnose transformation from PET or LDH alone; target adequate tissue from the discordant site.
04
Do not use 4 Gy automatically where durable local cure is intended and 24 Gy is feasible.
05
Do not declare gastric MALT remission after dyspepsia resolves; confirm H. pylori eradication and histological response.
06
Do not give anti-CD20 treatment without hepatitis B assessment and a reactivation-prevention plan.