Definition/General
Introduction:
Lymph node follicular hyperplasia is a reactive B-cell proliferative response characterized by expansion and prominence of germinal centers within lymphoid follicles
It represents the most common pattern of reactive lymphadenopathy in response to antigenic stimulation
The condition demonstrates active B-cell immune response with enhanced antibody production and memory cell formation.
Origin:
Results from B-cell activation following antigenic challenge
Viral infections (EBV, CMV, HIV) commonly trigger follicular hyperplasia
Bacterial infections and autoimmune conditions also stimulate response
Vaccination and drug reactions may cause similar changes
Germinal center reaction involves B-cell proliferation, somatic hypermutation, and class switching
T-helper cell interaction essential for sustained response.
Classification:
Classified by pattern and extent: Simple follicular hyperplasia (enlarged reactive germinal centers)
Florid follicular hyperplasia (marked enlargement with architectural distortion)
Progressive transformation of germinal centers (PTGC)
Interfollicular plasma cell hyperplasia
Atypical follicular hyperplasia
Age-related patterns: pediatric vs adult responses.
Epidemiology:
Most common reactive lymph node pattern across all age groups
Higher frequency in children and young adults due to frequent antigenic exposure
No gender predilection
Seasonal variation following viral epidemics
Geographic variation based on endemic infections
Immunocompetent individuals show typical patterns
Associated with vaccination programs.
Clinical Features
Presentation:
Painless lymphadenopathy (most common presentation)
Regional lymph node enlargement following drainage patterns
Bilateral involvement common in systemic antigenic exposure
Mobile, discrete lymph nodes with smooth surfaces
Size typically 1-4 cm
Multiple lymph node groups may be involved
Associated with underlying infectious or inflammatory conditions.
Symptoms:
Constitutional symptoms variable depending on underlying cause
Fever if associated with acute infection
Malaise and fatigue common
Upper respiratory symptoms (viral infections)
Sore throat (streptococcal infections)
Skin rash (viral exanthems, drug reactions)
No significant weight loss (distinguishes from malignancy).
Risk Factors:
Recent viral infection (EBV, CMV, adenovirus)
Bacterial infections (streptococcal, staphylococcal)
Autoimmune conditions (rheumatoid arthritis, SLE)
Drug reactions (phenytoin, allopurinol)
Recent vaccination
Young age (frequent antigenic exposure)
Immunocompetent state (appropriate immune response).
Screening:
Clinical examination for lymphadenopathy characteristics
Complete blood count (atypical lymphocytes, reactive changes)
Viral serology (EBV, CMV) when indicated
Autoimmune markers if suspected
Imaging studies for extent assessment
Fine needle aspiration may suggest reactive changes
Excisional biopsy for definitive diagnosis.
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Gross Description
Appearance:
Enlarged lymph nodes with smooth, intact capsule
Cut surface shows prominent white nodules (enlarged follicles) against gray background
Soft to firm consistency
Discrete follicular pattern visible grossly
No necrosis or hemorrhage typically
Preserved corticomedullary differentiation
Capsule not thickened significantly.
Characteristics:
Multinodular appearance with prominent follicular pattern
White to gray-white cut surface coloration
Homogeneous texture without areas of softening
No calcification or fibrosis
Vascular prominence minimal
Multiple lymph nodes may show similar changes
Size proportional to degree of stimulation.
Size Location:
Variable size from 1-4 cm typically
Cervical lymph nodes most commonly affected (head/neck infections)
Axillary lymph nodes (upper extremity drainage)
Inguinal lymph nodes (lower extremity, pelvic drainage)
Mediastinal involvement (systemic conditions)
Generalized lymphadenopathy in systemic antigenic exposure.
Multifocality:
Multiple lymph nodes in drainage region commonly affected
Bilateral involvement in systemic conditions
Regional pattern following lymphatic drainage
Symmetric involvement in generalized conditions
Progressive resolution with removal of antigenic stimulus
Hierarchical involvement pattern typical.
Microscopic Description
Histological Features:
Enlarged, reactive germinal centers with increased cellularity and mitotic activity
Well-defined mantle zones surrounding germinal centers
Preserved follicular architecture without effacement
Tingible body macrophages prominent in germinal centers
Mixed cell population (centroblasts, centrocytes)
Reactive paracortical changes
Normal sinusoidal pattern.
Cellular Characteristics:
Centroblasts (large cells with vesicular nuclei, prominent nucleoli)
Centrocytes (smaller cells with irregular, cleaved nuclei)
Tingible body macrophages with phagocytosed apoptotic debris
Increased mitotic activity without atypia
Mixed small and large lymphocytes
Plasma cells in interfollicular areas
Immunoblasts scattered.
Architectural Patterns:
Follicular hyperplasia pattern with enlarged germinal centers
Preserved mantle zones and interfollicular areas
Well-demarcated follicles without coalescence
Polar distribution (dark and light zones in germinal centers)
Intact follicular dendritic cell networks
Paracortical reactive changes
Normal sinus architecture.
Grading Criteria:
No standard grading system for follicular hyperplasia
Degree of enlargement (mild, moderate, marked)
Germinal center activity (mitotic rate, tingible body macrophages)
Architectural preservation vs distortion
Mantle zone integrity
Associated paracortical changes
Resolution potential with removal of stimulus.
Immunohistochemistry
Positive Markers:
CD20 positive in B-cells (follicles and mantle zones)
CD3 shows T-cells in paracortical areas
BCL-6 positive in germinal center B-cells
CD10 positive in germinal centers
Ki-67 high in germinal centers (70-90%)
CD21 and CD23 highlight follicular dendritic cell networks
IgD positive in mantle zone B-cells.
Negative Markers:
BCL-2 negative in germinal center B-cells (critical for follicular lymphoma exclusion)
Cyclin D1 negative (excludes mantle cell lymphoma)
CD5 negative in B-cells (excludes CLL/SLL)
CD30 negative (excludes lymphoma)
CD138 negative in germinal centers
TdT negative (excludes precursor B-cell neoplasms).
Diagnostic Utility:
BCL-2 negativity in germinal centers essential for distinguishing from follicular lymphoma
CD21/CD23 staining demonstrates intact follicular dendritic cell networks
Ki-67 shows appropriate proliferation pattern
Light chain staining demonstrates polyclonal B-cell population
CD10/BCL-6 confirm germinal center phenotype
Flow cytometry shows polyclonal population.
Molecular Subtypes:
No molecular subtypes for reactive follicular hyperplasia
Polyclonal B-cell population by flow cytometry and molecular studies
No clonal immunoglobulin gene rearrangements
Normal karyotype without chromosomal translocations
Cytokine expression profile shows reactive pattern
No BCL-2 or MYC translocations.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations in reactive follicular hyperplasia
Somatic hypermutation occurs normally in germinal center B-cells
Class switch recombination active
Normal chromosomal complement
No oncogene activation or tumor suppressor inactivation
Transient genetic changes related to B-cell activation
Normal DNA repair mechanisms.
Molecular Markers:
Polyclonal immunoglobulin gene rearrangements
Active transcription factors (PAX5, BCL-6, IRF4)
Cytokine expression (IL-4, IL-21, CXCL13)
Chemokine receptors (CXCR5, CCR7)
Activation markers (CD69, CD25)
Proliferation markers (Ki-67, PCNA)
Apoptosis markers (BCL-6, FAS).
Prognostic Significance:
Excellent prognosis with complete resolution expected
Self-limiting condition in most cases
Resolution time varies from weeks to months
No malignant transformation risk
Recurrence possible with re-exposure to antigens
Chronic stimulation may lead to architectural distortion
Long-term follow-up unnecessary in typical cases.
Therapeutic Targets:
Treatment of underlying condition leads to resolution
Supportive care for symptomatic relief
Anti-inflammatory agents for discomfort
Antibiotics for bacterial infections
Antiviral therapy rarely needed
Immunosuppressive agents for autoimmune causes
Observation appropriate for typical cases.
Differential Diagnosis
Similar Entities:
Follicular lymphoma (BCL-2 positive germinal centers)
Mantle cell lymphoma (cyclin D1 positive)
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Marginal zone lymphoma
Progressive transformation of germinal centers
Castleman disease (hyaline-vascular variant)
Infectious mononucleosis.
Distinguishing Features:
Follicular hyperplasia: BCL-2 negative germinal centers, polyclonal B-cells, intact FDC networks, appropriate Ki-67 pattern
Follicular lymphoma: BCL-2 positive germinal centers, monoclonal B-cells, t(14;18)
Mantle cell lymphoma: cyclin D1 positive, CD5+ B-cells, t(11;14)
CLL/SLL: CD5+ CD23+ B-cells, prolymphocytes
PTGC: large, irregular follicles with mantle cell infiltration.
Diagnostic Challenges:
Florid follicular hyperplasia may architecturally mimic lymphoma
Atypical hyperplasia may show irregular features
Progressive transformation of germinal centers requires recognition
Composite patterns may be present
Age-related changes affect interpretation
Immunohistochemistry essential for accurate diagnosis.
Rare Variants:
Progressive transformation of germinal centers (PTGC)
Florid follicular hyperplasia with marked architectural distortion
Hyalinized follicular hyperplasia
Atypical follicular hyperplasia
Interfollicular plasma cell hyperplasia
Age-related follicular hyperplasia
Drug-induced follicular hyperplasia.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Lymph node biopsy from [anatomical location], measuring [X.X] cm in greatest dimension
Diagnosis
Lymph node follicular hyperplasia, reactive pattern
Pattern Classification
Pattern: [simple/florid follicular hyperplasia], degree: [mild/moderate/marked]
Histological Features
Shows [enlarged reactive germinal centers] with [tingible body macrophages] and [preserved mantle zones]
Size and Architecture
Size: [X.X] cm, follicles: [enlarged/prominent], architecture: [preserved/mildly distorted]
Germinal Center Features
Germinal centers show [mixed centroblasts and centrocytes/tingible body macrophages/high mitotic activity] without atypia
Special Studies
IHC: CD20 [B-cells], BCL-2 [negative in germinal centers], CD21 [intact FDC networks], Ki-67 [high in germinal centers]
Flow cytometry: [if performed] polyclonal B-cell population, no aberrant expression
Molecular: [if performed] polyclonal immunoglobulin gene rearrangements
Final Diagnosis
Lymph node follicular hyperplasia, reactive B-cell proliferation, benign condition