How to assess cyclin D1 and t(11;14) translocation in mantle cell lymphoma?

Assessment of Cyclin D1 and t(11;14) in Mantle Cell Lymphoma

Cyclin D1 should be assessed primarily by immunohistochemistry on tissue biopsy specimens, with FISH for t(11;14) performed on bone marrow or peripheral blood as a complementary diagnostic test. 1

Primary Diagnostic Approach

Immunohistochemistry for Cyclin D1

• Perform cyclin D1 immunohistochemistry on formalin-fixed, paraffin-embedded tissue from lymph node biopsy or bone marrow biopsy. 1
• Look for strong, diffuse nuclear staining in the majority of tumor cells, which is the typical pattern in cyclin D1-positive MCL. 2
• Cyclin D1 IHC is robust with currently available reagents and yields reliable staining in routine diagnostic settings. 1
• Compare tumor cell staining intensity to internal controls (endothelial cells and fibroblasts) to confirm overexpression. 3

FISH for t(11;14)

• Perform FISH analysis using a dual-color, dual-fusion probe strategy to detect t(11;14)(q13;q32) translocation. 1
• FISH can be performed on bone marrow aspirate, peripheral blood specimens, or tissue sections. 1
• The test detects juxtaposition of the CCND1 locus at 11q13 with the IgH locus at 14q32. 1
• FISH is particularly useful in leukemic cases where bone marrow aspirate is the primary specimen. 1

When Each Test is Most Useful

Use IHC as First-Line Test When:

• Adequate tissue biopsy (lymph node or bone marrow core) is available. 1
• Rapid diagnosis is needed, as IHC provides faster turnaround than FISH. 4
• The morphology and immunophenotype (CD5+, CD20+, CD23-) strongly suggest MCL. 1

Use FISH as Confirmatory or Primary Test When:

• Cyclin D1 IHC is equivocal or technically suboptimal. 1
• Only leukemic manifestation is present with bone marrow aspirate available. 1
• Cyclin D1 IHC is negative but clinical suspicion for MCL remains high. 5
• Molecular confirmation is required for definitive diagnosis. 1

Critical Diagnostic Pitfalls

Cyclin D1-Negative MCL

• Approximately 5% of MCL cases are cyclin D1-negative and t(11;14)-negative. 1
• In these rare cases, perform SOX11 immunohistochemistry, which is positive in almost all MCL cases regardless of cyclin D1 status. 1, 6
• These cyclin D1-negative variants may show overexpression of cyclin D2 or cyclin D3 instead, though IHC for these is not diagnostically helpful. 1
• CCND2 gene rearrangements occur in 55% of cyclin D1-negative cases. 1, 6

False-Negative FISH Results

• A normal FISH signal pattern for t(11;14) does not exclude MCL if morphology and immunophenotype are suggestive. 5
• Always perform cyclin D1 IHC when FISH is negative but clinical suspicion persists, as rare cases may have cryptic translocations not detected by standard FISH probes. 5

MCL In Situ

• Cyclin D1-positive B-cells restricted to mantle zones in otherwise reactive lymph nodes represent MCL in situ, not overt MCL. 1, 6
• This finding has uncertain malignant potential and very indolent behavior—do not diagnose as MCL. 1
• Exclude overt MCL through thorough staging (additional node biopsies, peripheral blood flow cytometry, CT imaging) before concluding MCL in situ. 1

Recommended Combined Testing Strategy

The optimal diagnostic algorithm combines both methods for maximum sensitivity and specificity: 1

1. Obtain adequate tissue biopsy (lymph node preferred; bone marrow core acceptable if lymphadenopathy absent). 1
2. Perform cyclin D1 IHC first on tissue sections as the primary screening test. 1
3. Simultaneously order FISH for t(11;14) on bone marrow aspirate or tissue. 1
4. If both cyclin D1 and FISH are positive, diagnosis of MCL is confirmed. 7, 8
5. If cyclin D1 is positive but FISH is negative, MCL diagnosis is still supported (rare cryptic translocations exist). 5
6. If both are negative but suspicion remains high, perform SOX11 IHC to detect cyclin D1-negative MCL. 1

Combined Detection Rates

• Cyclin D1 IHC detects 72-95% of MCL cases. 2, 3, 8
• FISH for t(11;14) detects 65-70% of MCL cases. 7, 8
• Combined detection of cyclin D1 and/or t(11;14) achieves 80.5% sensitivity. 8

Additional Required Testing

Mandatory Concurrent Tests

• Include Ki-67 in the IHC panel to assess proliferation rate, the most established biological risk factor in MCL. 1
• Perform flow cytometry for immunophenotype: CD5+, CD19/20+, CD23-/+, CD10- is typical. 1
• Consider CD200 evaluation to help differentiate from chronic lymphocytic leukemia (MCL is typically CD200-negative). 1, 9

Quality Control Considerations

• Ensure beta-actin or other housekeeping gene is detected when performing PCR-based methods to confirm DNA quality. 8
• Use standardized methods for Ki-67 quantification due to inter-pathologist variability. 1
• Interpret cyclin D1 staining as exclusively nuclear; cytoplasmic staining is non-specific. 2, 3