How do you differentiate between Diffuse Large B-Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL) pleomorphic variant?

Differentiating DLBCL from Mantle Cell Lymphoma Pleomorphic Variant

The key to distinguishing pleomorphic MCL from DLBCL is Cyclin D1 and SOX11 immunostaining, but be aware that up to 40% of pleomorphic MCL can be cyclin D1-negative, making SOX11 the most reliable discriminator since it is consistently positive in MCL and negative in DLBCL.

Diagnostic Algorithm

Initial Immunohistochemical Panel

The ESMO guidelines recommend a comprehensive immunohistochemical panel including CD20, CD79a, BCL6, CD10, MYC, BCL2, Ki67, IRF4, CyclinD1, CD5 and CD23 to distinguish DLBCL from blastic/pleomorphic mantle cell lymphoma 1.

Critical markers for differentiation:

• Cyclin D1: Traditionally positive in MCL, but 40% of pleomorphic MCL can be cyclin D1-negative 2
• SOX11: The most reliable discriminator - positive in 89% of MCL (including pleomorphic variants) but consistently negative in cyclin D1-positive DLBCL 3, 2
• CD5: Usually positive in classic MCL but can be negative in pleomorphic variants 4

Step-by-Step Approach

Step 1: Morphologic Assessment

• Pleomorphic MCL shows large cells with marked nuclear pleomorphism, mimicking DLBCL morphologically 2
• Both can show sheet-like growth patterns 1

Step 2: First-Line Immunophenotyping

For CD5-positive, large cell lymphomas 1:

• If Cyclin D1-positive → Blastoid/pleomorphic MCL 1
• If Cyclin D1-negative → Check SOX11, BCL6, and Ki67 to differentiate CD5+ DLBCL from cyclin D1-negative pleomorphic MCL 1

For CD5-negative, large cell lymphomas 1:

• If Cyclin D1-positive → Pleomorphic MCL 1
• If Cyclin D1-negative → Check SOX11 to identify rare CD5/cyclin D1 double-negative pleomorphic MCL 4

Step 3: SOX11 Testing (Critical)

• SOX11-positive → Pleomorphic MCL, even if cyclin D1-negative 4, 3, 2
• SOX11-negative → DLBCL, even if cyclin D1-positive 5, 3

Additional Distinguishing Features

Immunophenotypic patterns:

• Pleomorphic MCL 4, 2:

  • SOX11: Positive (key feature)
  • CD23: Typically negative or dim/partial
  • BCL6: Variable, can be positive
  • Ki67: Often 60-90% 1
  • CD10: Usually negative

• DLBCL 1:

  • SOX11: Negative
  • CD23: Variable
  • BCL6: Frequently positive
  • Ki67: Variable
  • CD10: Positive in germinal center type

Molecular/Cytogenetic Confirmation

When diagnosis remains uncertain 1:

• FISH for CCND1 (IGH-CCND1) translocation: Present in cyclin D1-positive MCL, absent in cyclin D1-positive DLBCL 5, 3
• FISH for CCND2/CCND3: May be present in cyclin D1-negative pleomorphic MCL 4, 2
• BCL6 rearrangement: Can coexist with IGH-CCND1 in rare cyclin D1-positive DLBCL 5
• Genome-wide copy number profiling: Pleomorphic MCL shows similar patterns to classic MCL, with frequent PIK3CA and CCDC50 gains in cyclin D1-negative cases 2

Common Diagnostic Pitfalls

Critical caveat: Approximately 1.5% of DLBCL can aberrantly express cyclin D1 without CCND1 rearrangement, typically showing a non-germinal center phenotype (CD5-/CD10-/BCL6+/MUM1+) and SOX11 negativity 3. These cases require SOX11 testing and FISH to avoid misdiagnosis.

Second major pitfall: Up to 40% of pleomorphic MCL are cyclin D1-negative, making them easily misclassified as DLBCL 2. These cases are SOX11-positive and may have CCND2 translocations or secondary genetic alterations (PIK3CA/CCDC50 gains) 4, 2.

Third pitfall: Rare CD5/cyclin D1 double-negative pleomorphic MCL exists and can only be identified by SOX11 positivity and molecular confirmation 4.

Clinical Implications

The distinction is critical for treatment decisions and prognosis, as pleomorphic MCL has a median survival of only 11 months and requires MCL-specific therapy rather than DLBCL regimens 2. The genome-wide copy number profile of pleomorphic MCL is similar to classic MCL, confirming it as a true MCL variant rather than a DLBCL subtype 2.