Definition/General
Introduction:
Granulomatous lymphadenitis is characterized by the presence of epithelioid cell granulomas within lymph nodes as a response to various infectious, autoimmune, or foreign body stimuli
It represents a chronic inflammatory pattern involving macrophage activation and transformation into epithelioid cells
The condition requires systematic evaluation to determine underlying etiology.
Origin:
Results from chronic inflammatory stimuli requiring sustained macrophage activation
Infectious agents (mycobacteria, fungi, bacteria, parasites)
Autoimmune conditions (sarcoidosis, Crohn disease)
Foreign body reactions (silica, beryllium, talc)
Drug-induced granulomatous reactions
Malignancy-associated granulomas (sarcoid-like reactions)
Idiopathic granulomatous inflammation.
Classification:
Classified by presence of necrosis: Caseating granulomatous lymphadenitis (tuberculosis, histoplasmosis)
Non-caseating granulomatous lymphadenitis (sarcoidosis, berylliosis)
By etiology: Infectious granulomatous lymphadenitis
Non-infectious granulomatous lymphadenitis
Foreign body granulomatous lymphadenitis
Sarcoid-like reactions.
Epidemiology:
Variable epidemiology depending on underlying cause
High prevalence in developing countries (tuberculosis)
Geographic clustering (endemic mycoses)
Occupational associations (pneumoconioses)
Age distribution varies with etiology
Immunocompromised patients at higher risk for infectious causes.
Clinical Features
Presentation:
Chronic, painless lymphadenopathy most common presentation
Progressive enlargement over weeks to months
Firm, non-tender lymph nodes
Regional or generalized involvement depending on cause
Constitutional symptoms variable
Associated organ involvement (lungs, liver, spleen)
Skin manifestations (erythema nodosum, lupus pernio).
Symptoms:
Low-grade fever (infectious causes)
Weight loss and anorexia
Night sweats (tuberculosis)
Cough and dyspnea (pulmonary involvement)
Skin lesions (sarcoidosis, infections)
Eye symptoms (uveitis in sarcoidosis)
Joint symptoms (arthritis, arthralgias).
Risk Factors:
Geographic location (endemic infections)
Occupational exposure (silica, beryllium, organic dusts)
Immunocompromised state (HIV, immunosuppressive therapy)
Travel history (histoplasmosis, coccidioidomycosis)
Family history (sarcoidosis)
Ethnic background (higher sarcoidosis in certain populations)
Drug therapy (TNF-α inhibitors).
Screening:
Detailed history (travel, occupation, exposures)
Physical examination (lymph nodes, skin, chest)
Chest imaging (hilar lymphadenopathy)
Laboratory studies (ACE levels, calcium)
Tuberculin skin test or IGRA
Fungal serology when indicated
Tissue biopsy essential for diagnosis.
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Gross Description
Appearance:
Enlarged lymph nodes with firm consistency
Cut surface shows gray-white nodular areas
Caseous necrosis (tuberculosis) appears as yellow-white, cheese-like material
Non-caseating granulomas show firm, gray-white nodules
Calcification may be present in chronic cases
Fibrosis in healing stages.
Characteristics:
Multinodular appearance with granuloma distribution
Firm to hard consistency
Central necrosis (caseating types)
Surrounding fibrosis in chronic cases
No suppuration typically
Variable pigmentation (fungal infections)
Calcific deposits in healed lesions.
Size Location:
Variable size from 1-10 cm
Hilar lymph nodes (sarcoidosis, silicosis)
Cervical lymph nodes (tuberculosis, atypical mycobacteria)
Mediastinal involvement (occupational lung diseases)
Peripheral lymph nodes (various causes)
Generalized involvement (systemic conditions).
Multifocality:
Multiple lymph node groups commonly involved
Bilateral hilar involvement (sarcoidosis)
Regional spread (infectious causes)
Systemic involvement (sarcoidosis, disseminated infections)
Progressive enlargement over time.
Microscopic Description
Histological Features:
Well-formed epithelioid granulomas with or without central necrosis
Epithelioid cells (activated macrophages) with elongated nuclei and eosinophilic cytoplasm
Multinucleated giant cells (Langhans or foreign body type)
Surrounding lymphocytes and plasma cells
Fibroblasts and fibrosis in chronic cases
Variable architectural preservation.
Cellular Characteristics:
Epithelioid cells with pale, elongated nuclei and abundant cytoplasm
Langhans giant cells with peripheral nuclear arrangement
Foreign body giant cells with randomly distributed nuclei
Caseous necrosis (eosinophilic, structureless material)
Chronic inflammatory cells at periphery
Fibroblasts and collagen deposition.
Architectural Patterns:
Discrete granuloma formation within lymph node parenchyma
Interfollicular location predominant
Confluent granulomas in extensive disease
Architectural effacement variable
Capsular involvement possible
Extranodal extension in severe cases
Zonal arrangement (central necrosis to peripheral fibrosis).
Grading Criteria:
Granuloma maturity (well-formed vs poorly formed)
Presence of necrosis (caseating vs non-caseating)
Giant cell type and number
Degree of fibrosis
Organism identification
Associated inflammatory changes
Extent of involvement.
Immunohistochemistry
Positive Markers:
CD68 positive in epithelioid cells and giant cells
CD163 positive in M2 macrophages
Lysozyme positive in epithelioid cells
S-100 may be positive in some giant cells
Smooth muscle actin may be positive in epithelioid cells
CD3 highlights peripheral T-lymphocytes
CD20 shows B-cells in preserved areas.
Negative Markers:
CD1a and Langerin negative (excludes Langerhans cell histiocytosis)
CD30 negative (excludes lymphoma)
Cytokeratin negative in epithelioid cells
Melanoma markers negative
CD34 negative in epithelioid cells
ALK-1 negative.
Diagnostic Utility:
Limited utility for determining granuloma etiology
CD68 confirmation of histiocytic nature
Organism-specific stains more important (AFB, GMS, PAS)
Polarized light examination for foreign material
Special stains essential for etiologic diagnosis
Culture and molecular methods preferred for organism identification.
Molecular Subtypes:
Etiology-specific classification more relevant than molecular subtypes
Mycobacterial species identification by PCR
Fungal identification by molecular methods
Genetic susceptibility studies (HLA associations)
Drug resistance patterns in mycobacterial infections.
Molecular/Genetic
Genetic Mutations:
Host genetic susceptibility factors important
HLA associations with sarcoidosis
NRAMP1 gene variants (mycobacterial susceptibility)
Cytokine gene polymorphisms
Vitamin D receptor variants
Bacterial resistance mutations (mycobacteria)
No specific host mutations for granuloma formation.
Molecular Markers:
Th1 cytokines (IFN-γ, IL-2, TNF-α)
Macrophage activation markers
Complement activation
Acute phase reactants
Organism-specific nucleic acids
Drug resistance markers
Host immune response markers.
Prognostic Significance:
Variable prognosis depending on underlying cause
Infectious causes: depends on organism and treatment response
Sarcoidosis: often self-limiting but may be chronic
Occupational causes: progressive if exposure continues
Foreign body reactions: generally good prognosis
Malignancy-associated: depends on underlying tumor.
Therapeutic Targets:
Etiology-specific treatment essential
Anti-tuberculosis therapy (mycobacterial infections)
Antifungal therapy (fungal infections)
Corticosteroids (sarcoidosis, autoimmune causes)
Exposure avoidance (occupational causes)
Immunosuppressive therapy (refractory autoimmune cases).
Differential Diagnosis
Similar Entities:
Tuberculosis vs sarcoidosis (classic differential)
Atypical mycobacterial infection
Fungal infections (histoplasmosis, coccidioidomycosis)
Foreign body reactions
Crohn disease
Berylliosis
Malignancy with sarcoid-like reaction.
Distinguishing Features:
Tuberculosis: caseating granulomas, Langhans giants, AFB positive, endemic areas
Sarcoidosis: non-caseating granulomas, bilateral hilar lymphadenopathy, elevated ACE, Schaumann bodies
Histoplasmosis: organisms in giant cells, endemic areas, GMS positive
Foreign body: polarizable material, exposure history
Berylliosis: occupational exposure, beryllium lymphocyte proliferation test.
Diagnostic Challenges:
Overlapping morphology between causes
Negative special stains don't exclude infection
Sparse organisms in some infections
Sarcoid-like reactions in malignancy
Mixed patterns possible
Clinical correlation essential
Multiple diagnostic modalities often required.
Rare Variants:
Epithelioid hemangioendothelioma (vascular tumors with epithelioid cells)
Xanthogranulomatous inflammation
Malakoplakia (Michaelis-Gutmann bodies)
Rheumatoid nodules
Granulomatous slack skin
Orofacial granulomatosis.
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
Granulomatous lymphadenitis, [caseating/non-caseating] pattern
Pattern Classification
Pattern: [caseating/non-caseating], granulomas: [well-formed/poorly formed], necrosis: [present/absent]
Histological Features
Shows [epithelioid granulomas] with [giant cells] and [necrosis pattern/absence of necrosis]
Size and Distribution
Size: [X.X] cm, granulomas: [discrete/confluent], distribution: [interfollicular/diffuse]
Granuloma Characteristics
Granulomas contain [epithelioid cells/Langhans giants/foreign body giants] with [central necrosis/peripheral lymphocytes]
Special Studies
Special stains: AFB [positive/negative], GMS [positive/negative], PAS [positive/negative]
Polarized light: [foreign material present/absent]
Culture: [if performed] [organism identification/negative/pending]
Final Diagnosis
Granulomatous lymphadenitis, [specific etiology when determinable], clinical correlation recommended