What are the characteristics of Follicular Lymphoma, including lymph node architecture, peripheral blood findings, immunophenotype, and cytogenetics in a 60-year-old adult patient?

Follicular Lymphoma: Comprehensive Characteristics

Follicular lymphoma is characterized by a follicular (nodular) lymph node architecture with neoplastic follicles composed of centrocytes and centroblasts, typically expressing CD10+, CD20+, BCL2+, BCL6+, with the hallmark t(14;18) translocation present in the overwhelming majority of cases. 1

Lymph Node Architecture

The defining architectural feature is a follicular (nodular) growth pattern that effaces the normal lymph node structure, with neoplastic follicles composed of a mixture of centrocytes (small cleaved cells) and centroblasts (large non-cleaved cells). 1

Histologic Grading System

The grading is based on the number of centroblasts per high-power field (HPF): 1

• Grade 1: ≤5 centroblasts/HPF
• Grade 2: 6-15 centroblasts/HPF
• Grade 3A: >15 centroblasts/HPF with centroblasts and intermingled centrocytes
• Grade 3B: >15 centroblasts/HPF with pure sheets of centroblasts

Grade 3B is treated as an aggressive lymphoma (similar to diffuse large B-cell lymphoma), while grades 1,2, and 3A are managed as indolent disease. 1 Any area of diffuse large B-cell lymphoma transformation in a follicular lymphoma of any grade should be diagnosed and treated as diffuse large B-cell lymphoma. 1

A critical pitfall: Core biopsies may miss the heterogeneity of grading, and excisional lymph node biopsy is strongly preferred for accurate diagnosis and grading. 1 Fine needle aspiration is inadequate for reliable diagnosis. 1

Peripheral Blood Findings

Peripheral blood involvement is relatively uncommon in follicular lymphoma at presentation, though circulating lymphoma cells can occasionally be detected. 2, 3

• Cytopenias are relatively common (hemoglobin <12 g/dL is a FLIPI risk factor), but these typically result from bone marrow involvement rather than direct peripheral blood infiltration. 3, 4
• Constitutional B symptoms (fever >38°C, drenching night sweats, >10% weight loss) are uncommon in the absence of transformation. 1, 4
• Complete blood count with differential and platelets is essential for evaluating potential bone marrow involvement and cytopenias. 1, 5

Immunophenotype

The typical immunophenotype is: CD10+, BCL2+, CD20+, BCL6+, with variable CD23+/-, and negative for CD43, CD5, and cyclin D1. 1

Essential Immunohistochemistry Panel

The recommended paraffin section immunohistochemistry panel includes: 1

• CD20 (positive - B-cell marker)
• CD3 (negative - excludes T-cell lymphoma)
• CD10 (typically positive - germinal center marker)
• BCL2 (positive - from t(14;18) translocation)
• BCL6 (positive - germinal center marker)
• Cyclin D1 (negative - excludes mantle cell lymphoma)
• CD21 or CD23 (highlights follicular dendritic cell meshworks)

Flow Cytometry Panel

Cell surface marker analysis should include: 1

• Kappa/lambda (demonstrates monoclonal light chain restriction)
• CD19, CD20 (B-cell markers)
• CD5 (negative in FL, positive in CLL/mantle cell)
• CD23 (variable)
• CD10 (typically positive)

Important caveat: Rare cases of follicular lymphoma may be CD10-negative or BCL2-negative, particularly in young patients with localized disease (pediatric-type follicular lymphoma). 1 BCL2-negative cases in young patients with localized disease should prompt consideration of the distinct pediatric follicular lymphoma entity. 1

Cytogenetics

The hallmark cytogenetic abnormality is the t(14;18)(q32;q21) translocation involving the IgH/BCL2 genes, present in the overwhelming majority of cases (approximately 85-90%). 3, 4

Recommended Genetic Testing

Useful under certain circumstances: 1

• FISH for t(14;18) - detects the BCL2 rearrangement
• Molecular genetic analysis - detects BCL2 rearrangement and immunoglobulin gene rearrangements
• Cytogenetics - identifies t(14;18) and other chromosomal abnormalities

The t(14;18) translocation results in constitutive overexpression of BCL2 protein, which inhibits apoptosis and is detected by immunohistochemistry in virtually all cases. 3, 4

Emerging Prognostic Markers

A clinicogenetic risk score (m7-FLIPI) based on mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11) has been proposed, but these techniques are not yet established in routine clinical practice. 1 Extended gene-expression profiling suggests more favorable outcomes in cases with infiltrating T cells versus non-specific macrophage bystander cells, but this remains investigational. 1

Essential Diagnostic Workup

For a 60-year-old adult patient, the complete diagnostic evaluation should include: 1

• Excisional lymph node biopsy (not core biopsy or FNA)
• Immunohistochemistry panel as outlined above
• Flow cytometry for immunophenotyping
• FISH or cytogenetics for t(14;18)
• CT scan of neck, thorax, abdomen, and pelvis
• Bone marrow biopsy and aspirate (bilateral cores recommended if radioimmunotherapy considered)
• Laboratory tests: CBC with differential, LDH, comprehensive metabolic panel, beta-2 microglobulin, uric acid, hepatitis B and C testing
• FLIPI score calculation using age >60 years, hemoglobin <12 g/dL, elevated LDH, Ann Arbor stage III/IV, and >4 involved nodal areas 1

PET-CT improves staging accuracy for nodal and extranodal sites and should be recommended for routine staging, particularly to confirm localized stage I/II disease before involved-field radiotherapy. 1