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