Marginal Zone and MALT Lymphoma

• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) — the commonest, arising in stomach, salivary gland, thyroid, lung, ocular adnexa, skin and elsewhere
• Splenic marginal zone lymphoma — massive splenomegaly, circulating villous lymphocytes, and a striking association with hepatitis C
• Nodal marginal zone lymphoma — the least common, behaving like other indolent nodal lymphomas

Chronic antigen stimulation is the engine

• Normal marginal zone B cells respond to antigen at the interface between lymphoid follicles and surrounding tissue. Persistent antigenic drive — microbial or autoantigenic — produces sustained proliferation of a marginal zone B-cell population
• Mucosal sites such as the stomach and thyroid contain no native lymphoid tissue. Chronic inflammation must first acquire organized lymphoid tissue, and lymphoma then arises within it. This is why H. pylori gastritis precedes gastric MALT lymphoma, and why Hashimoto thyroiditis precedes thyroid MALT lymphoma
• Early in its course, the tumour remains dependent on the antigenic stimulus — the biological basis for antigen withdrawal as therapy
• Over time, genetic lesions accumulate that free the tumour from that dependence, and the lymphoma becomes autonomous. At that point antibiotics no longer work

The translocations, and the one that predicts treatment failure

• t(11;18)(q21;q21) creates the API2-MALT1 fusion, constitutively activating NF-κB. It is the most common lesion in gastric and pulmonary MALT lymphoma and — crucially — **predicts failure of H. pylori eradication therapy**, because the tumour no longer needs the antigen
• t(14;18)(q32;q21) involving MALT1 and t(1;14)(p22;q32) involving BCL10 also converge on NF-κB activation. Note that this t(14;18) involves MALT1, not BCL2, and is a different lesion from the follicular lymphoma translocation at the same cytogenetic address
• Inactivating mutations of TNFAIP3 (A20), a negative regulator of NF-κB, occur in translocation-negative cases
• The unifying theme is constitutive NF-κB signalling, replacing the survival signal normally supplied by antigen

Infection-associated — the treatable drivers

• Helicobacter pylori → gastric MALT lymphoma, the commonest MALT lymphoma. Present in the large majority of cases
• Chlamydia psittaci → ocular adnexal MALT lymphoma (conjunctiva, lacrimal gland, orbit), with geographic variation in the strength of the association
• Borrelia burgdorferi → cutaneous MALT lymphoma, particularly in Europe
• Campylobacter jejuni → immunoproliferative small intestinal disease (IPSID), a small bowel MALT lymphoma seen in the Middle East and Mediterranean
• Achromobacter xylosoxidans → pulmonary MALT lymphoma, reported association
• Hepatitis C virus → splenic marginal zone lymphoma and other marginal zone lymphomas, mediated by chronic B-cell stimulation and often with associated cryoglobulinaemia

Autoimmune-associated

• Sjögren syndrome → parotid and other salivary gland MALT lymphoma, with a large relative risk — among the strongest autoimmune-to-lymphoma associations known
• Hashimoto thyroiditis → thyroid MALT lymphoma
• Systemic lupus erythematosus and rheumatoid arthritis confer more modest increases

Other

• Age — median around 60-70
• Slight female predominance in the extranodal form
• Immunosuppression and common variable immunodeficiency

Gastric MALT lymphoma

• Dyspepsia, epigastric pain, nausea, early satiety — indistinguishable from ordinary peptic disease, which is why many are found at endoscopy performed for other reasons
• Occult gastrointestinal bleeding with iron deficiency anaemia
• Endoscopy shows gastritis, erosions, shallow ulcers or thickened folds rather than a discrete mass — the appearance is often unremarkable, and diagnosis depends on the pathologist
• B symptoms are rare; systemic dissemination is uncommon at diagnosis

Other extranodal sites

• Salivary gland: painless parotid swelling in a patient with known Sjögren syndrome
• Thyroid: enlarging goitre or nodule in Hashimoto thyroiditis, sometimes with compressive symptoms
• Ocular adnexa: painless conjunctival "salmon patch", proptosis or lid swelling
• Lung: incidental nodules or consolidation, often asymptomatic
• Skin: solitary or grouped papules and plaques, usually on the trunk or arms

Splenic marginal zone lymphoma

• Massive splenomegaly with abdominal fullness and early satiety
• Cytopenias from hypersplenism, and circulating villous lymphocytes on the blood film
• Frequently no lymphadenopathy — a useful distinguishing feature
• Associated autoimmune haemolytic anaemia, immune thrombocytopenia, cryoglobulinaemia and a small monoclonal paraprotein
• Look for hepatitis C, which may be otherwise silent

Nodal marginal zone lymphoma

• Painless peripheral lymphadenopathy, behaving like other indolent nodal lymphomas

• Tissue biopsy from the involved site. For gastric disease this means multiple endoscopic biopsies from all regions of the stomach, including normal-appearing mucosa, plus biopsies for H. pylori
• Histology: a marginal zone infiltrate of small lymphocytes, monocytoid B cells and plasmacytoid forms, with lymphoepithelial lesions — tumour cells invading and destroying glandular epithelium — a characteristic finding in MALT lymphoma
• Immunophenotype is defined by what it lacks: CD20 positive, but CD5, CD10, CD23 and cyclin D1 all negative. There is no positive marker for marginal zone lymphoma, and the diagnosis is one of exclusion — the pattern rules out CLL/SLL, mantle cell and follicular lymphoma
• FISH for t(11;18) in gastric disease, because a positive result predicts failure of antibiotic therapy and should redirect management from the outset
• ***H. pylori* testing** by histology, rapid urease test, urea breath test or stool antigen. A negative histological result does not exclude infection — confirm with a non-invasive test, since eradication may still benefit some negative patients
• Endoscopic ultrasound to assess depth of gastric wall invasion and perigastric nodes, which predicts response to eradication — disease confined to the mucosa responds best
• Hepatitis C serology in all, particularly with splenic or nodal disease; HIV and hepatitis B before immunotherapy
• Staging: CT of chest, abdomen and pelvis; PET-CT is less reliable in marginal zone lymphoma than in aggressive lymphomas, as these tumours are often not FDG-avid. Bone marrow biopsy, especially in splenic disease
• Exclude transformation to diffuse large B-cell lymphoma where there is a mass lesion, rapid growth or raised LDH — large cell areas within a MALT lymphoma change treatment entirely

Gastric MALT lymphoma — treat the infection first

• ***H. pylori* eradication is first-line therapy** for localized, *H. pylori*-positive disease and produces complete lymphoma remission in roughly 70-80%. This is the only common malignancy in which antibiotics are the primary cancer treatment
• Regression is slow — typically 3 to 12 months, occasionally longer. Follow with serial endoscopy and biopsy rather than treating early for apparent non-response
• Predictors of failure: t(11;18) positivity, invasion beyond the submucosa, nodal involvement, and *H. pylori*-negative disease
• If eradication fails or is inappropriate: involved-site radiotherapy is highly effective for localized disease and generally curative, with modest doses. Rituximab is used where radiotherapy is unsuitable
• Advanced or disseminated disease: rituximab alone, or with chlorambucil or bendamustine
• Surgery has essentially no role

Other extranodal sites

• Localized disease: involved-site radiotherapy is the standard and is highly effective
• Ocular adnexal disease: consider doxycycline where Chlamydia psittaci is implicated, with radiotherapy for non-response
• Cutaneous disease: antibiotics if *Borrelia*-associated; otherwise local radiotherapy or excision
• Asymptomatic disease at any site may be observed, as with other indolent lymphomas

Splenic marginal zone lymphoma

• If hepatitis C positive, treat the hepatitis C. Direct-acting antiviral therapy produces lymphoma regression in a substantial proportion, and is the correct first step before any cytotoxic treatment
• Asymptomatic disease is observed
• Symptomatic disease: rituximab is preferred first-line; splenectomy is effective for symptomatic splenomegaly and cytopenias where rituximab fails or is contraindicated

General

• Screen for hepatitis B before rituximab
• Transformed disease is treated as diffuse large B-cell lymphoma

• Transformation to diffuse large B-cell lymphoma, converting an indolent disease into an aggressive one
• Gastric bleeding, obstruction, or perforation; perforation may occur as bulky gastric disease responds to radiotherapy or chemotherapy
• Persistent or relapsing disease after eradication, requiring prolonged endoscopic surveillance — and the small long-term risk of gastric adenocarcinoma in a stomach with chronic H. pylori damage
• Compressive complications at site-specific locations: airway or oesophageal compression from thyroid disease, proptosis and visual compromise from orbital disease
• Splenic disease: cytopenias from hypersplenism, and post-splenectomy risk of overwhelming infection with encapsulated organisms — vaccinate before splenectomy
• Autoimmune phenomena: haemolytic anaemia, immune thrombocytopenia, cryoglobulinaemic vasculitis with hepatitis C
• Hypogammaglobulinaemia and recurrent infection after repeated anti-CD20 therapy
• Radiotherapy toxicity by site: xerostomia after salivary gland treatment, cataract and dry eye after orbital treatment, hypothyroidism after neck treatment
• Hepatitis B reactivation after rituximab

• **Gastric MALT lymphoma is cured by treating H. pylori in roughly 70-80%** of localized cases — the clearest example in medicine of curing a cancer with antibiotics. Regression takes months, so do not abandon it early
• t(11;18) predicts failure of eradication therapy. The API2-MALT1 fusion activates NF-κB, freeing the tumour from antigen dependence — test for it, and go to radiotherapy instead
• Marginal zone lymphoma is immunophenotypically negative: CD20-positive but CD5, CD10, CD23 and cyclin D1 all negative. It is a diagnosis of exclusion — there is no positive marker
• Lymphoepithelial lesions — tumour cells invading glandular epithelium — are the characteristic histological finding
• Match the organism to the site: H. pylori → stomach; Chlamydia psittaci → ocular adnexa; Borrelia burgdorferi → skin; Campylobacter jejuni → small bowel (IPSID)
• Match the autoimmune disease to the site: Sjögren syndrome → parotid; Hashimoto thyroiditis → thyroid. Sjögren carries one of the highest lymphoma risks of any autoimmune disease
• Splenic marginal zone lymphoma: massive splenomegaly, villous lymphocytes, usually no lymphadenopathy — and check hepatitis C, because treating the virus can treat the lymphoma
• Involved-site radiotherapy is highly effective and often curative for localized extranodal disease that is not antibiotic-responsive
• PET is unreliable here — marginal zone lymphomas are frequently not FDG-avid, so a negative PET does not exclude disease
• The t(14;18) of MALT lymphoma involves MALT1, not BCL2 — a different lesion from the follicular lymphoma translocation at the same address
• Vaccinate against encapsulated organisms before splenectomy in splenic disease
• A mass lesion, rapid growth or a rising LDH means re-biopsy to look for large cell transformation