Definition/General
Introduction:
Lymph node reactive hyperplasia is a benign proliferation of lymphoid elements in response to antigenic stimulation
It represents the most common cause of lymphadenopathy accounting for 80-90% of cases
The condition reflects normal immune response to infections, inflammatory conditions, or other antigenic challenges
It maintains normal lymph node architecture with preserved histological compartments.
Origin:
Results from antigenic stimulation of resident lymphoid cells within lymph nodes
The proliferation involves multiple cell types including B-cells, T-cells, plasma cells, and macrophages
The response can be localized to specific lymph node regions or generalized throughout the node
The hyperplastic response aims to enhance immune surveillance and antibody production.
Classification:
Classified based on predominant compartment involved
Follicular hyperplasia (B-cell zones)
Paracortical hyperplasia (T-cell zones)
Mixed pattern hyperplasia (both compartments)
Sinus histiocytosis (medullary sinuses)
Dermatopathic lymphadenopathy (melanin deposition).
Epidemiology:
Most common in children and young adults due to frequent antigenic exposure
Peak incidence in 5-20 years age group
More frequent in immunocompetent individuals
Common in regions with high infectious disease burden
Indian population shows higher prevalence due to endemic infections like tuberculosis and malaria.
Clinical Features
Presentation:
Painless lymphadenopathy (most common presentation)
Tender lymph nodes (acute infections)
Mobile, discrete lymph nodes with smooth surfaces
Size typically 1-3 cm in diameter
Multiple lymph node groups may be involved
Associated with underlying infectious or inflammatory conditions.
Symptoms:
Fever (40-60% of cases)
Malaise and fatigue
Night sweats (less common than malignancy)
Weight loss (minimal, unlike malignancy)
Upper respiratory symptoms (viral infections)
Skin rash (certain viral infections)
No B-symptoms (unlike lymphoma).
Risk Factors:
Recent viral infections (EBV, CMV, HIV)
Bacterial infections (streptococcal, staphylococcal)
Autoimmune disorders (rheumatoid arthritis, SLE)
Drug reactions (phenytoin, allopurinol)
Vaccination (recent immunizations)
Chronic dermatitis (dermatopathic lymphadenopathy).
Screening:
Clinical examination focusing on lymph node characteristics
Assessment of size, consistency, mobility, and tenderness
Evaluation for associated symptoms and signs
Laboratory investigations (CBC, ESR, CRP)
Fine needle aspiration for cytological assessment if indicated.
Master Reactive Hyperplasia Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Enlarged lymph nodes maintaining normal oval shape
Smooth, intact capsule without adhesions to surrounding tissues
Cut surface shows prominent follicles with pale germinal centers
Gray-white to pink coloration
No areas of necrosis or hemorrhage
Preserved corticomedullary differentiation.
Characteristics:
Soft to firm consistency depending on degree of hyperplasia
Homogeneous cut surface without nodularity
Prominent follicular pattern visible grossly
No calcification or fibrosis
Capsular surface smooth without puckering
Normal hilar fat architecture preserved.
Size Location:
Size ranges from 1-4 cm in greatest dimension
Commonly involves cervical lymph nodes (50-60%)
Axillary lymph nodes (20-25%)
Inguinal lymph nodes (15-20%)
Generalized lymphadenopathy in systemic conditions
Multiple lymph node groups may be simultaneously affected.
Multifocality:
Bilateral involvement common in systemic reactions
Regional lymphadenopathy in localized infections
Hierarchical pattern of involvement (drainage pattern)
Symmetric enlargement in generalized conditions
No matting or fixation to surrounding structures.
Microscopic Description
Histological Features:
Preserved lymph node architecture with expanded cortical follicles
Prominent germinal centers with reactive changes
Well-defined mantle zones surrounding follicles
Increased paracortical zone with mixed inflammatory infiltrate
Expanded medullary sinuses containing histiocytes and plasma cells.
Cellular Characteristics:
Germinal centers contain centroblasts and centrocytes
Tingible body macrophages scattered throughout germinal centers
Mitotic activity increased but not atypical
Mixed population of small and medium-sized lymphocytes
Plasma cells present in medullary cords and sinuses.
Architectural Patterns:
Follicular hyperplasia pattern with enlarged reactive follicles
Paracortical hyperplasia with T-cell zone expansion
Mixed pattern combining both follicular and paracortical changes
Sinus histiocytosis with dilated sinuses containing foamy macrophages
Dermatopathic pattern with melanin-laden histiocytes.
Grading Criteria:
Graded based on degree of architectural distortion
Mild hyperplasia: minimal architectural changes
Moderate hyperplasia: prominent follicular or paracortical expansion
Marked hyperplasia: extensive involvement with preserved overall architecture
No grading system for malignant potential as condition is benign.
Immunohistochemistry
Positive Markers:
CD20 highlights B-cell follicles and mantle zones
CD3 demonstrates T-cells in paracortical areas
CD21 outlines follicular dendritic cell networks
BCL-6 positive in germinal center B-cells
Ki-67 shows high proliferation in germinal centers (80-90%)
CD68 highlights tingible body macrophages.
Negative Markers:
BCL-2 negative in germinal center B-cells (important for follicular lymphoma exclusion)
CD10 positive in germinal centers but negative in mantle zones
Cyclin D1 negative (excludes mantle cell lymphoma)
CD5 negative in B-cells (excludes CLL/SLL)
CD30 negative (excludes Hodgkin lymphoma).
Diagnostic Utility:
Immunohistochemistry helps distinguish from lymphoma
BCL-2 negativity in germinal centers excludes follicular lymphoma
CD21 staining demonstrates intact follicular dendritic cell networks
Polyclonal plasma cells (kappa and lambda positive)
Mixed T and B-cell populations maintain normal ratios.
Molecular Subtypes:
No molecular subtypes recognized as condition is reactive
Polyclonal B-cell population demonstrated by flow cytometry
Normal T-cell subset ratios (CD4:CD8 ratio 2:1)
No clonal gene rearrangements detected
Preserved cytogenetic architecture without chromosomal abnormalities.
Molecular/Genetic
Genetic Mutations:
No specific mutations associated with reactive hyperplasia
Polyclonal cell populations without clonal genetic alterations
Normal gene expression profiles reflecting reactive immune response
Absence of oncogene activation or tumor suppressor gene inactivation
Transient genetic changes related to activation and proliferation.
Molecular Markers:
Polyclonal immunoglobulin gene rearrangements
Normal T-cell receptor rearrangements
Elevated cytokine expression (IL-2, IL-4, IL-10)
Increased proliferation markers (Ki-67, PCNA)
Normal apoptosis markers (p53, BCL-2 family)
Activation markers (CD25, CD69) on lymphocytes.
Prognostic Significance:
Excellent prognosis with complete resolution expected
No malignant transformation potential
Response to treatment of underlying condition
Recurrence possible with re-exposure to antigens
No long-term sequelae in most cases
Resolution time varies from weeks to months.
Therapeutic Targets:
Treatment of underlying condition leads to resolution
Anti-inflammatory agents for symptomatic relief
Antibiotics for bacterial infections
Antiviral therapy when indicated
Immunosuppressive agents for autoimmune causes
Observation alone sufficient in many cases.
Differential Diagnosis
Similar Entities:
Follicular lymphoma (BCL-2 positive germinal centers)
Mantle cell lymphoma (cyclin D1 positive)
Marginal zone lymphoma (monocytoid B-cells)
Hodgkin lymphoma (Reed-Sternberg cells)
Infectious mononucleosis (atypical lymphocytes)
Toxoplasma lymphadenitis (epithelioid cell clusters).
Distinguishing Features:
Reactive hyperplasia: BCL-2 negative germinal centers
Reactive hyperplasia: Polyclonal B-cell population
Reactive hyperplasia: Intact FDC networks
Follicular lymphoma: BCL-2 positive germinal centers
Follicular lymphoma: Monoclonal B-cells
Mantle cell lymphoma: Cyclin D1 positive
Hodgkin lymphoma: Reed-Sternberg cells present.
Diagnostic Challenges:
Progressive transformation of germinal centers may mimic lymphoma
Florid follicular hyperplasia can be confused with follicular lymphoma
Paracortical hyperplasia may resemble T-cell lymphoma
Dermatopathic lymphadenopathy requires clinical correlation
Immunohistochemistry essential for accurate diagnosis.
Rare Variants:
Castleman disease-like changes (hyaline-vascular variant)
Kimura disease (eosinophilic infiltrate)
Angioimmunoblastic pattern (aberrant T-cell proliferation)
Plasma cell variant (predominant plasma cell infiltrate)
Histiocytic variant (prominent sinus histiocytosis)
Necrotizing variant (Kikuchi-like changes).
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, [location], measuring [X.X] cm in greatest dimension, weighing [X] grams
Diagnosis
Lymph node reactive hyperplasia, [pattern type]
Pattern Classification
Pattern: [follicular/paracortical/mixed/sinus histiocytosis/dermatopathic]
Histological Features
Shows [preserved/expanded] lymph node architecture with [follicular hyperplasia/paracortical expansion/mixed pattern] and [prominent germinal centers/increased paracortical cellularity/dilated sinuses]
Size and Architecture
Size: [X.X] cm, architecture: [preserved with reactive changes/expanded cortical follicles/prominent paracortical zone]
Cellular Composition
Cellular composition shows [mixed lymphoid population/prominent germinal centers/increased plasma cells/tingible body macrophages]
Special Studies
IHC: CD20 [follicular B-cells], CD3 [paracortical T-cells], BCL-2 [negative in germinal centers], Ki-67 [high in germinal centers]
Flow cytometry: [polyclonal B-cell population/normal T-cell subsets/no aberrant expression]
Molecular: [polyclonal gene rearrangements/no clonal populations detected]
Final Diagnosis
Lymph node reactive hyperplasia, [specific pattern], consistent with benign reactive process