marginal zone lymphoma (MZL) (ESMO 2020, BSH 2023) 

Intro

UK incidence: 2.6 per 100,000 (M:F ratio 1.6)

5-15% of all Non-Hodgkin lymphomas

Cell of origin: memory B cells of the marginal zones of secondary lymphoid tissues

Pathophys: Marginal zone B cells have roles in inflammation & autoimmunity —> MZL often occurs in chronic infection or autoimmune disorders

Classification + features

Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT)

  • Usually triggered by chronic antigen stimulation (infection or immune)

  • Particular sites of disease associated with specific triggers

    • Bladder - E.coli

    • Breast - Sjogren’s

    • Dura - IgG4 disease

    • Gastric - H. Pylori (and other helicobacter species, e.g. heilmannii)

    • Gallbladder - Gallstones

    • Liver - Viral Hepatitis, H. pylori, AI hepatitis/PBC/Sjogren’s, Liver cancer, Ascariasis

    • Lung - Achromobactor, HIV, Hep C, Smoking, Sjogren’s, CVID

    • Ocular - Chlamydia psittaci, Hep C, IgG4 disease

    • Salivary glands - Sjogren’s, Hep C, IgG4 disease

    • Skin - borrelia, tattoos, vaccines, IgG4 disease

    • Small intestine - campylobacter

    • Thymus - Sjogren’s, Rheumatoid arthritis, scleroderma

    • Thyroid - Hashimoto thyroiditis, IgG4 disease

Splenic Marginal Zone Lymphoma (SMZL)

  • Spleen involvement +/- bone marrow / blood / liver / hilar splenic lymph nodes

  • Specific morphology - villous lymphocytes

  • 20% have autoimmune presentations - AIHA, ITP, Cold agglutinins, Acquired Von Willebrand, C1 esterase deficiency

Nodal Marginal Zone Lymphoma (NMZL)

  • Shares similarities with other MZL’s, ?Probably derived from an occult site of extranodal MZL

  • Small IgM paraproteins may be present

  • (Paediatric NMZL is distinct condition, much better prognosis than in adults)

Clonal B-Cell Lymphocytosis of marginal zone origin (CBL-MZ)

  • Analogous to monoclonal B lymphocytosis (MBL - a pre-cancer clonal population with a CLL immunophenotype)

  • In contrast to MBL there is no lymphocyte count cut-off

  • Requires no clinical evidence of MZL

  • 15-20% progress to MZL (usually splenic) at 5 years follow-up

  • Associated with del7q and NOTCH2 mutations

Investigation / work-up

History + Examination

Bloods

  • FBC, film, paraprotein, LDH, B2 microglobulin, DAT, Protein electrophoresis, Hep C, cryoglobulins, Hep B, HIV

Imaging

  • CT / PET-CT staging

  • Consider PET-CT for early stage prior to radiotherapy, or suspected high grade transform.

  • MRI for certain sites, e.g. orbits, salivary glands

Morphology / Histology

  • Core tissue biopsy

  • +/- Bone marrow biopsy - for Splenic MZL or in presence of cytopenias

Immunophenotyping / Immunohistochemistry

  • No disease defining immunophenotype, important to rule out other LPD’s that form the differential diagnosis

  • Typical immunophenotype:

    • CD20+, CD21+, BCL2+, BCL6+, Light chain restricted

    • CD5-, CD23-, CD10-, Cyclin D1-, SOX11-

Cytogenetics

  • Splenic MZL: Del 7q, Del 17p

  • Nodal MZL: Trisomy 3, Trisomy 18, 2p+, 6p+, 1p-, 6q-

  • Extranodal MZL:

    • Presence of t(11;18)/BIRC3::MALT1 indicates lesser likelihood of responding to pathogen eradication

    • t(14;18)/IGH::MALT1

    • t(1;14)/IGH::BCL10

    • t(3;14)/IGH::FOXP1

    • Trisomy 3, Trisomy 18

Molecular

  • MYD88 mutation usually not present

    • If present, can be difficult to differentiate from LPL/Waldenstroms

  • Splenic MZL: NOTCH2, TP53, IGHV. MYD88

  • Nodal MZL: KMT2D, PTPRD, NOTCH2, KLF2

  • Extranodal MZL molecular findings: TNFAIP3, FAS

Staging

Lugano, Ann Arbor & Paris staging systems have all been used (see guideline)

In Gastric EMZL, multiple site OGD biopsies can be taken to “map” the tumour but this is not essential if high quality photos and description of macroscopic lesions are recorded.

prognosis

MALT-IPI (Extranodal)

  • Age >70, Anna Arbor Stage III/IV, Raised LDH. Reflects 5-year EFS

HPLL (Splenic)

  • Hb, Plt, LDH, extrahilar LN

Management

Localised Gastric MALT

  • Triple therapy H.pylori eradication for all patients, as 30% CR achieved even in H.pylori negative cases (due to false negative cases and other helicobacter species)

  • Assess response with stool antigen or urea breath test >6 weeks after eradication

  • Approx. 62% CR at one year following eradication

  • Repeat OGD 3-6 months after eradication to assess response (GELA scoring system)

  • For those not responding to Abx:

    • 24Gy ISRT of whole stomach —> CR of 95-100%

  • 5-yr OS 90%, 10-yr OS 75-80% for treated gastric MALT

  • 2% recurrence per year, small increased risk of gastric carcinoma —> OGD surveillance every 12-18 months is recommended

  • Systemic therapies discussed in relapsed/refractory section below

Localised Non-Gastric MALT

  • Eradication may still be applicable, e.g. chlamydia for ocular disease (see top of page)

  • If no response, 24Gy ISRT —> Response rate >90%, most patients cured

  • Retrospective studies found RT superior to surgery or immunochemotherapy

Splenic

  • Ideally watchful waiting in first instance (30% untreated at 10 years)

  • Hep C eradication if required

  • Rituximab monotherapy - 10-yr PFS >60%

    • weekly x6 then 2-monthly for one year - 10-yr PFS 64%, 10-yr OS 85%

    • weekly x4 is alternative

  • Splenectomy is alternative - 5-yr PFS 50-60%, 5-yr OS 70-80%

  • Radiotherapy for those not fit for SACT or surgery

  • R-Chemo if no response - good response but 25% serious adverse events

Nodal MZL and Advanced stage MALT

  • Incurable. Watchful waiting appropriate for asymptomatic patients

  • Consider palliative 4Gy radiotherapy to symptomatic sites

  • Consider systemic therapy in symptomatic, advanced stage disease:

    • Rituximab mono, R-Chlorambucil, R-Benda, R-CVP

    • Consider maintenance Rituximab after R-CVP

    • Follow the principles of treatment for follicular lymphoma

relapsed/refractory MZL

Similar principles to management of relapsed follicular lymphoma

  • Watchful waiting of asymptomatic relapse

  • Radiotherapy for localised relapse

  • R-Chlorambucil, R-Benda, R-CVP —> high rates of adverse effects

Not yet available in UK (as of 2023)

  • BTKi’s (e.g. Zanubrutinib in MAGNOLIA 2021) (under review by NICE as of 2023)

  • Lenalidomide-Rituximab (R2)

  • Tafasitamab (anti-CD19) being trialled in combination with R2

  • CAR-T has shown some effect but longer-term outcomes awaited

high grade transformation

Cumulative incidence of approx. 5% at 10 years

Usually to diffuse large B cell lymphoma

Follow management principles of transformed follicular lymphoma