What is mantle cell lymphoma?

What is Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare, typically aggressive B-cell malignancy characterized by the chromosomal translocation t(11;14)(q13;q32) leading to cyclin D1 overexpression, representing 5-7% of all lymphomas with a male predominance (3:1 ratio) and median age at diagnosis of 65-70 years. 1

Molecular Pathogenesis

The defining molecular hallmark is the t(11;14)(q13;q32) translocation that juxtaposes the CCND1 gene with the immunoglobulin heavy chain (IgH) locus, resulting in constitutive cyclin D1 overexpression. 1, 2 This can be detected by:

• Fluorescent in situ hybridization (FISH) for t(11;14) 1
• Immunohistochemistry demonstrating cyclin D1 positivity in 98% of cases 3, 4

In approximately 5% of cases that are cyclin D1-negative, cyclin D2 or D3 overexpression substitutes, with CCND2 rearrangements occurring in ~55% of these variants. 1, 2 These cyclin D1-negative cases demonstrate similar clinical behavior and genomic signatures. 2

SOX11 nuclear overexpression is present in almost all MCL cases regardless of cyclin D1 status and helps distinguish MCL from other lymphomas. 1, 2

Clinical Presentation

MCL typically presents as disseminated disease with generalized lymphadenopathy, but extranodal involvement is common, particularly in peripheral blood, bone marrow, and gastrointestinal tract. 1 Key presentation patterns include:

• Nodal disease with systemic lymphadenopathy 1
• Leukemic non-nodal subtype with splenomegaly, peripheral blood lymphocytosis, and minimal nodal disease—this variant often exhibits more indolent features 1
• Gastrointestinal involvement occurs in 15-30% of patients, though prospective endoscopic studies suggest the majority have GI tract involvement when systematically evaluated 1

Histologic Variants and Risk Stratification

Histological patterns include nodular, diffuse, pleomorphic, and blastoid variants, with the latter two associated with particularly aggressive disease. 1

The Ki-67 proliferation index is the most established biological risk factor, with standardized quantification recommended for prognostic purposes. 1

The Mantle Cell International Prognostic Index (MIPI) incorporating age, ECOG performance status, LDH, and leukocyte count stratifies patients into risk groups with distinct survival outcomes. 1, 3 The combined MIPI-c adds Ki-67 to improve prognostication. 1

Diagnostic Workup

Diagnosis requires lymph node biopsy with histological review; core biopsies should only be used when lymph nodes are inaccessible, and fine needle aspiration is inadequate. 1

Essential immunophenotyping shows CD19, CD20, CD22, CD43, CD79a, CD5, and FMC7 positivity with CD23, CD10, CD200, and BCL6 negativity. 1

Mandatory staging includes: 1

• CT neck, chest, abdomen, pelvis (or PET-CT, especially for limited stage disease)
• Bone marrow biopsy with cyclin D1 immunohistochemistry, FISH for t(11;14)
• Complete blood count with differential and flow cytometry if leukemic presentation
• LDH, comprehensive metabolic panel, hepatitis B/C and HIV serology

Lumbar puncture should be performed in high-risk cases with at least two of: blastoid variant, elevated LDH, impaired performance status, or neurological symptoms. 1

Clinical Behavior and Prognosis

MCL follows a heterogeneous clinical course—most cases are aggressive with poor prognosis (median overall survival 4-5 years historically), but a subset exhibits indolent behavior. 1, 3

Indolent MCL is characterized by leukemic non-nodal presentation, SOX11 negativity, and low Ki-67 (<10%), though TP53 mutations can cause aggressive evolution even in these cases. 1

Five-year overall survival rates vary by region, with reported rates of 35.5% in some Chinese cohorts and up to 78% in selected Taiwanese populations. 1

Critical Diagnostic Pitfall

MCL in situ—cyclin D1-positive B-cells restricted to mantle zones in otherwise reactive lymph nodes—should NOT be diagnosed as overt MCL. 1, 2 This entity has uncertain malignant potential, very indolent behavior, and progression to symptomatic MCL is extremely uncommon. 1 Distinguishing MCL in situ from true MCL with mantle zone pattern requires thorough evaluation including additional node biopsies, physical examination, peripheral blood flow cytometry, and cross-sectional imaging. 1