How can marginal-zone lymphoma be differentiated from small-lymphocytic lymphoma?

Differentiating Marginal Zone Lymphoma (MZL) from Small Lymphocytic Lymphoma (SLL)

The key to distinguishing MZL from SLL lies in immunohistochemistry: MZL is typically CD5-negative and CD23-negative/variable, while SLL is characteristically CD5-positive, CD23-positive, and CD43-positive. 1, 2

Immunophenotypic Approach (Most Critical)

The differential diagnosis relies primarily on a mandatory immunohistochemical panel 1:

MZL Expected Profile:

• CD20: Positive (mandatory)
• CD5: Negative (mandatory - few exceptions may occur)
• CD23: Negative or variable positive (suggested)
• CD10: Negative (mandatory)
• CD43: Typically negative or low expression 3, 4
• Cyclin D1: Negative (mandatory if CD5-positive)
• CD200: Not typically expressed

SLL/CLL Expected Profile:

• CD20: Positive but characteristically LOW expression 2
• CD5: Positive (co-expressed with CD19)
• CD23: Positive 2
• CD43: Positive 2, 3
• CD200: Positive 2
• Surface immunoglobulin: Characteristically LOW 2

Morphologic Features

MZL characteristics 1:

• Small- to medium-sized cells with slightly irregular nuclei
• Inconspicuous nucleoli
• Moderately dispersed chromatin
• Pale cytoplasm (may have monocytoid appearance)
• Dimorphic cytology in splenic MZL 3

SLL characteristics 2:

• Small, mature-appearing lymphocytes
• Narrow border of cytoplasm
• Dense nucleus lacking discernible nucleoli
• Partially aggregated chromatin
• Prolymphocytes may be present but <55%

Flow Cytometry Distinctions

When flow cytometry is available 4:

• CD19 expression intensity: MZL shows significantly brighter CD19 (mean MCF 455.3) compared to SLL/CLL (mean MCF 166.9)
• CD11c: Expressed in 57% of splenic MZL, helpful when positive 4
• CD38: Less commonly expressed in MZL (32%) versus follicular lymphoma (77%) 4

Clinical Context Clues

MZL presentation 1:

• Often extranodal sites (stomach, ocular adnexa, lung, salivary glands)
• May have splenomegaly (splenic MZL)
• Associated with chronic antigenic stimulation (H. pylori, HCV, autoimmune disorders)
• Bone marrow involvement pattern differs

SLL presentation 2:

• Lymphadenopathy and/or splenomegaly
• Peripheral blood lymphocytes <5 × 10⁹/L (if ≥5 × 10⁹/L, it's CLL not SLL)
• Same immunophenotype as CLL

Molecular Testing

When immunophenotyping is equivocal 1:

• MYD88 mutation: Negative in MZL (suggested testing)
• MYD88 mutation: Positive in lymphoplasmacytic lymphoma (helps exclude this mimic)
• MZL rarely harbors MYD88 mutations 1

Common Pitfalls to Avoid

1. CD5-positive MZL: Rare exceptions exist where MZL can be CD5-positive; in these cases, cyclin D1 must be negative to exclude mantle cell lymphoma 1

2. CD23 expression in MZL: Can be variable/positive in some MZL cases, so don't rely on CD23 alone 1

3. MNDA staining: Can show weak nuclear positivity in primary follicles, creating a potential false-positive for MZL 5

4. Marginal zone pattern in other lymphomas: Follicular lymphoma, mantle cell lymphoma, and even SLL can show marginal zone differentiation in the spleen 3

Diagnostic Algorithm

1. Start with mandatory IHC panel: CD20, CD5, CD10, cyclin D1
2. If CD5-negative and CD10-negative: Likely MZL; add CD23, IgD
3. If CD5-positive: Must exclude SLL (check CD23, CD43, CD200) and mantle cell lymphoma (check cyclin D1)
4. Add flow cytometry: Assess CD19 intensity, CD11c (especially if splenic involvement)
5. Consider molecular testing: MYD88 mutation status if diagnosis remains uncertain
6. Correlate with clinical presentation: Site of involvement, presence of chronic antigenic stimulation

The diagnosis must be reviewed by an expert hematopathologist, particularly for nodal MZL where differential diagnosis from other indolent lymphomas is most challenging 1.