Definition/General
Introduction:
Marginal zone lymphoma (MZL) represents a group of indolent B-cell lymphomas that comprise 5-17% of all non-Hodgkin lymphomas
They are characterized by small to medium-sized B-cells that morphologically and immunophenotypically resemble marginal zone B-cells
These lymphomas show heterogeneous clinical presentations and anatomical sites of involvement
They have indolent clinical course with tendency for localized disease.
Origin:
Originates from post-germinal center B-cells in the marginal zone of lymphoid follicles
These cells have undergone somatic hypermutation but lack ongoing mutation
Shows evidence of antigen selection and activation
Associated with chronic antigenic stimulation in many cases
Infectious agents play important role in pathogenesis
Autoimmune conditions may predispose to development.
Classification:
WHO classification recognizes three main types: Extranodal MALT (mucosa-associated lymphoid tissue)
Nodal marginal zone lymphoma
Splenic marginal zone lymphoma
Each type has distinct clinical features and genetic alterations
Primary cutaneous marginal zone lymphoma is included under MALT type
Grade is not applicable as they are low-grade by definition.
Epidemiology:
Peak incidence in 6th-7th decades
Slight female predominance (M:F = 1:1.2)
MALT lymphoma is most common type (70%)
Geographic variation exists (higher in Mediterranean regions)
H
pylori-associated gastric MALT common in developing countries
Indian population shows increasing incidence with improved diagnosis
Association with autoimmune diseases (Sjögren syndrome, Hashimoto thyroiditis).
Clinical Features
Presentation:
Site-specific symptoms predominate
Gastric MALT: dyspepsia, abdominal pain
Ocular MALT: conjunctival mass, dry eyes
Thyroid MALT: thyroid enlargement
Salivary gland MALT: gland swelling
Nodal MZL: lymphadenopathy
Splenic MZL: splenomegaly, cytopenias
Skin MALT: nodules, plaques.
Symptoms:
B-symptoms uncommon (<10% of cases)
Organ-specific symptoms more common
Gastric symptoms: early satiety, nausea
Ocular symptoms: foreign body sensation
Respiratory symptoms: cough (pulmonary MALT)
Constitutional symptoms rare in early disease
Systemic symptoms suggest transformation or advanced disease
Autoimmune symptoms may be present.
Risk Factors:
Chronic inflammation (most important)
H
pylori infection (gastric MALT)
Autoimmune diseases (Sjögren, Hashimoto)
Hepatitis C virus (splenic MZL)
Borrelia burgdorferi (cutaneous MALT in Europe)
Chlamydia psittaci (ocular MALT)
Age >50 years
Immunosuppression
Previous radiation exposure.
Screening:
No routine screening recommended
H
pylori testing in gastric symptoms
Endoscopic surveillance for gastric MALT after treatment
Imaging studies for staging
Autoimmune markers in relevant clinical settings
CBC and peripheral smear
Serum protein electrophoresis
LDH and β2-microglobulin.
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Gross Description
Appearance:
Variable gross appearance depending on site
Gastric MALT: mucosal thickening, ulceration, polypoid masses
Lymph nodes: enlarged, gray-white, fish-flesh appearance
Spleen: enlarged with white pulp nodules
Thyroid: diffuse enlargement or nodular lesions
Salivary glands: firm enlargement
Conjunctiva: salmon-colored patches.
Characteristics:
Firm consistency in most cases
Gray-white to tan cut surface
Homogeneous appearance without necrosis
Well-circumscribed in some sites
Infiltrative growth in mucosal sites
Preservation of architecture may be seen
Multiple nodules in splenic involvement.
Size Location:
Size varies by location
Gastric lesions: 1-10 cm
Lymph nodes: 1-5 cm typically
Conjunctival lesions: few mm to 2 cm
Splenic involvement: diffuse or nodular
Multiple sites may be involved simultaneously
Bilateral involvement in paired organs
Multifocal disease common in MALT type.
Multifocality:
Multifocal involvement characteristic of MALT lymphoma
Synchronous lesions in same organ
Multiple organ involvement in advanced disease
Gastric and non-gastric MALT may coexist
Transformation to DLBCL may be focal
Disseminated disease more common with nodal and splenic types
Bone marrow involvement varies by subtype.
Microscopic Description
Histological Features:
Small to medium-sized B-cells with irregular nuclei and moderate cytoplasm
Heterogeneous cell population including centrocyte-like cells, monocytoid B-cells, and lymphoplasmacytoid cells
Plasma cell differentiation often present
Reactive germinal centers may be present
Marginal zone expansion around reactive follicles
Infiltration of epithelial structures (lymphoepithelial lesions) in MALT type.
Cellular Characteristics:
Centrocyte-like cells: small to medium-sized with irregular, indented nuclei
Monocytoid B-cells: round nuclei with abundant pale cytoplasm
Lymphoplasmacytoid cells: eccentric nuclei with plasmacytic features
Plasma cells: mature forms with Dutcher bodies
Marginal zone cells: medium-sized with moderate cytoplasm
Large transformed cells scattered throughout
Mitotic activity generally low.
Architectural Patterns:
Marginal zone pattern: expansion around reactive follicles
Interfollicular pattern: infiltration between follicles
Diffuse pattern: complete effacement of architecture
Nodular pattern: discrete nodules of lymphoma cells
Sinusoidal pattern: preferential involvement of sinuses
Lymphoepithelial lesions: invasion of epithelial structures
Follicular colonization: infiltration of germinal centers.
Grading Criteria:
No formal grading system as they are low-grade by definition
Transformation to DLBCL should be assessed
Large cell component >20% suggests transformation
Increased mitotic activity may indicate transformation
Ki-67 proliferation index usually <20%
High-grade transformation changes prognosis and treatment
Histological variants recognized but not graded.
Immunohistochemistry
Positive Markers:
CD20 (positive in all cases)
CD79a (positive)
PAX5 (positive)
BCL2 (usually positive)
CD43 (often positive, unlike other B-cell lymphomas)
CD11c (positive in many cases)
IgM (heavy chain)
Light chain restriction (kappa or lambda)
CD21 (highlights follicular dendritic networks).
Negative Markers:
CD5 (negative, helps exclude CLL/SLL)
CD10 (negative, helps exclude follicular lymphoma)
CD23 (negative, helps exclude CLL/SLL)
BCL6 (negative in marginal zone cells)
Cyclin D1 (negative, excludes mantle cell lymphoma)
CD25 (negative)
Annexin A1 (negative)
CD103 (negative).
Diagnostic Utility:
CD43 positivity is characteristic feature
BCL2 expression without t(14;18)
Absence of CD5, CD10, CD23 helps in differential diagnosis
Light chain restriction confirms B-cell clonality
CD21 staining reveals disrupted follicular dendritic networks
Ki-67 shows low proliferation (<20%)
P53 overexpression rare except in transformation.
Molecular Subtypes:
No molecular subtypes recognized
Site-specific genetic alterations described
MALT1 gene rearrangements in some cases
BCL10 gene alterations
FOXP1 gene alterations
TBL1XR1 gene rearrangements
IGH-MALT1 t(14;18)(q32;q21)
Trisomy 3 and trisomy 18 common.
Molecular/Genetic
Genetic Mutations:
MALT1 gene rearrangements in 20-30% of cases
BCL10 gene alterations less common
FOXP1 gene rearrangements in 10% of cases
TBL1XR1-MALT1 fusion in some cases
MYD88 mutations rare (unlike lymphoplasmacytic lymphoma)
TP53 mutations associated with transformation
TNFAIP3 deletions in some cases.
Molecular Markers:
Clonal immunoglobulin gene rearrangements
Somatic hypermutations present in immunoglobulin genes
Trisomy 3 in 60% of cases
Trisomy 18 in 30% of cases
NF-κB pathway activation
API2-MALT1 fusion t(11;18)(q21;q21)
IGH-MALT1 fusion t(14;18)(q32;q21)
IGH-FOXP1 fusion t(3;14)(p14;q32).
Prognostic Significance:
Indolent clinical course with good overall survival
Site-specific prognosis varies
Gastric MALT with H
pylori: excellent prognosis with antibiotic therapy
Non-gastric MALT: generally good prognosis
Nodal MZL: more aggressive course
Splenic MZL: indolent but may transform
Transformation to DLBCL worsens prognosis (5-10% of cases).
Therapeutic Targets:
H
pylori eradication for gastric MALT (first-line treatment)
Rituximab (anti-CD20) for systemic disease
Radiation therapy for localized extranodal disease
Alkylating agents for advanced disease
Bendamustine-rituximab combination
BTK inhibitors (ibrutinib) showing promise
Immunomodulatory agents under investigation.
Differential Diagnosis
Similar Entities:
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CD5+, CD23+)
Follicular lymphoma (CD10+, BCL6+, t(14;18))
Mantle cell lymphoma (cyclin D1+, CD5+)
Lymphoplasmacytic lymphoma (MYD88 mutation, IgM paraprotein)
Large B-cell lymphoma (large cell morphology, high Ki-67)
Reactive marginal zone hyperplasia (polyclonal).
Distinguishing Features:
MZL: CD43+, CD5-, CD10-, CD23-
CLL/SLL: CD5+, CD23+, CD43+
Follicular lymphoma: CD10+, BCL6+, follicular architecture
Mantle cell lymphoma: cyclin D1+, CD5+, blastoid morphology
Lymphoplasmacytic lymphoma: MYD88 mutation, Dutcher bodies
Reactive hyperplasia: polyclonal, preserved architecture
Immunohistochemistry essential for diagnosis.
Diagnostic Challenges:
Distinguishing reactive marginal zone hyperplasia from neoplastic infiltrate
Limited tissue samples may prevent accurate diagnosis
Transformation to DLBCL may be missed in small biopsies
Mixed populations of cells can be confusing
Site-specific variations in morphology
Immunohistochemistry interpretation requires expertise
Molecular studies may be needed for definitive diagnosis.
Rare Variants:
Plasmacytic differentiation prominent in some cases
Large cell transformation (secondary DLBCL)
Blastoid variant (rare)
Composite lymphomas with other B-cell lymphomas
T-cell rich variant
Sclerotic variant with prominent fibrosis
Intravascular variant (extremely rare).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[Biopsy type] from [anatomical site], measuring [size] cm
Primary Diagnosis
Marginal zone lymphoma, [subtype: extranodal MALT/nodal/splenic] type
WHO Classification
Marginal zone lymphoma (WHO 2016 classification)
Histological Features
Shows [architectural pattern] with small to medium-sized B-cells including centrocyte-like cells and [cellular variants]
Site-Specific Features
[Lymphoepithelial lesions present/absent]; [Other site-specific features]
Cellular Composition
Predominant cell type: [centrocyte-like/monocytoid]; Plasma cell differentiation: [present/absent/prominent]
Immunohistochemistry
CD20+, CD79a+, CD43+, CD5-, CD10-, CD23-, BCL2+, light chain restriction: [kappa/lambda]
Molecular Studies
Clonal B-cell population demonstrated; [Specific genetic alterations if tested]
Staging Information
Clinical stage: [I/II/III/IV]; Site of involvement: [localized/regional/disseminated]
Final Diagnosis
Marginal zone lymphoma, [subtype], WHO 2016