Definition/General
Introduction:
Tuberculous lymphadenitis is the most common form of extrapulmonary tuberculosis in India
It accounts for 35-40% of all extrapulmonary TB cases
FNAC is the first-line diagnostic modality for suspected tuberculous lymphadenopathy
It shows characteristic granulomatous inflammation with epithelioid cells and giant cells.
Origin:
Caused by Mycobacterium tuberculosis complex organisms
Primary infection occurs via lymphohematogenous spread from pulmonary foci
Can also result from direct extension from adjacent infected tissues
The organism triggers cell-mediated immunity resulting in granuloma formation
Caseating necrosis is characteristic of TB granulomas.
Classification:
Morphological classification: Epithelioid granulomas with caseous necrosis (most common, 60-70%)
Epithelioid granulomas without caseous necrosis (15-20%)
Necrotizing inflammation only (10-15%)
Acute suppurative inflammation (5-10%)
Each pattern has different diagnostic implications.
Epidemiology:
High prevalence in developing countries, especially India
Peak incidence in 2nd and 3rd decades
Female predominance (60-70%)
Cervical lymph nodes most commonly affected (80-85%)
Associated with HIV co-infection in 15-20% cases
Drug-resistant TB increasing concern.
Clinical Features
Presentation:
Painless lymph node enlargement (most common presentation)
Matted lymph nodes may be present
Cold abscess formation in advanced cases
Sinus tract formation may occur
Constitutional symptoms (fever, weight loss, night sweats) in 60-70% cases
May coexist with pulmonary tuberculosis.
Symptoms:
Low-grade fever (intermittent pattern) in 70-80%
Night sweats in 50-60%
Weight loss and loss of appetite in 60-70%
Fatigue and malaise
Cough if concurrent pulmonary involvement (30-40%)
Chest pain if mediastinal nodes involved.
Risk Factors:
HIV infection (major risk factor)
Immunocompromised states (diabetes, malnutrition)
Close contact with active TB patient
Crowded living conditions
Poor socioeconomic status
Malnutrition
Alcohol abuse
Previous history of tuberculosis.
Screening:
Tuberculin skin test (TST) - may be negative in immunocompromised
Interferon-gamma release assays (IGRA)
Chest X-ray to rule out pulmonary TB
HIV testing mandatory
Sputum examination for AFB
FNAC is the primary diagnostic procedure.
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Gross Description
Appearance:
Lymph nodes are typically enlarged (2-6 cm) and may be matted together
Surface may show adherence to skin
Cut surface reveals yellowish-white caseous material
Areas of necrosis and calcification may be present
Thick capsule with inflammatory adhesions.
Characteristics:
FNAC aspirate appears thick and viscous
Yellowish-white to grayish in color
May contain cheesy caseous material
Blood mixed aspirate common due to vascularity
Aspirate may be scanty in fibrotic/calcified nodes
Purulent material in secondary bacterial infection.
Size Location:
Cervical lymph nodes most commonly involved (80-85%)
Supraclavicular and axillary nodes frequently affected
Mediastinal lymphadenopathy in 15-20% cases
Bilateral involvement possible
Node size varies from 1-8 cm
Matting of nodes characteristic.
Multifocality:
Multiple node involvement common (70-80% cases)
Nodes may be matted and adherent
Regional distribution following lymphatic drainage
Generalized lymphadenopathy in disseminated disease
Cold abscess formation in chronic cases
Sinus tract formation possible.
Microscopic Description
Histological Features:
FNAC shows classical epithelioid cell granulomas
Langhans-type giant cells are characteristic
Caseous necrosis in background (60-70% cases)
Acute inflammatory cells may be present
Chronic inflammatory infiltrate with lymphocytes and plasma cells
Fibroblasts in chronic/healing phase.
Cellular Characteristics:
Epithelioid cells: Large elongated cells with oval vesicular nuclei, abundant eosinophilic cytoplasm
Langhans giant cells: Multiple peripherally arranged nuclei (5-20 nuclei)
Lymphocytes: Small mature lymphocytes surrounding granulomas
Plasma cells and neutrophils may be seen
Caseous necrosis: Amorphous eosinophilic material.
Architectural Patterns:
Well-formed granulomas with epithelioid cells and giant cells
Loose aggregates of epithelioid cells without giant cells
Extensive caseous necrosis with minimal cellular elements
Mixed inflammatory pattern with acute and chronic cells
Suppurative inflammation in secondary bacterial infection.
Grading Criteria:
No formal grading system for tuberculous lymphadenitis
Assessment based on morphological patterns
Grade 1: Epithelioid granulomas with giant cells and caseous necrosis
Grade 2: Epithelioid granulomas without caseous necrosis
Grade 3: Only caseous necrosis without granulomas
Grade 4: Non-specific chronic inflammation.
Immunohistochemistry
Positive Markers:
CD68 positive in epithelioid cells and giant cells
CD3 positive in surrounding T-lymphocytes
CD20 positive in B-lymphocytes (fewer in number)
S-100 positive in dendritic cells
Lysozyme positive in epithelioid cells
CD163 positive in macrophages.
Negative Markers:
Cytokeratin negative (helps exclude carcinoma)
CD30 and CD15 negative (excludes Hodgkin lymphoma)
ALK negative (excludes ALCL)
Melanoma markers negative
CD1a and Langerin negative (excludes Langerhans cell histiocytosis).
Diagnostic Utility:
IHC has limited role in typical cases
Useful to exclude malignancy in atypical presentations
CD68 positivity confirms histiocytic nature of epithelioid cells
Helps differentiate from carcinoma with desmoplastic reaction
T-cell predominance around granulomas supports TB diagnosis.
Molecular Subtypes:
TB lymphadenitis shows Th1-mediated immune response
High levels of interferon-gamma and TNF-alpha
IL-12 and IL-18 elevation
Granuloma formation mediated by T-cell activation
M1 macrophage polarization
Apoptosis and autophagy pathways activated.
Molecular/Genetic
Genetic Mutations:
Host genetic factors influence susceptibility
HLA associations (HLA-DR2, HLA-DQ1)
Vitamin D receptor polymorphisms
TNF-alpha gene polymorphisms
NRAMP1 gene mutations
IL-10 promoter polymorphisms
Mannose-binding lectin deficiency.
Molecular Markers:
Mycobacterial DNA detection by PCR
IS6110 insertion sequence (specific for M
tuberculosis)
16S rRNA amplification
MPB64 antigen detection
Adenosine deaminase (ADA) elevation
Interferon-gamma elevation in lymph node aspirate.
Prognostic Significance:
Good prognosis with appropriate anti-tuberculous therapy
Treatment duration: 6-9 months of anti-TB drugs
Drug resistance may affect outcome
HIV co-infection worsens prognosis
Early diagnosis crucial for prevention of complications
Relapse rate low with complete treatment.
Therapeutic Targets:
Standard anti-TB therapy: Isoniazid, Rifampin, Ethambutol, Pyrazinamide
Drug-resistant TB: Second-line drugs (fluoroquinolones, aminoglycosides)
HIV co-infection: Antiretroviral therapy with TB treatment
Immunomodulation: Corticosteroids in severe cases
Surgical drainage for cold abscesses.
Differential Diagnosis
Similar Entities:
Sarcoidosis (non-caseating granulomas)
Atypical mycobacterial infections
Fungal infections (histoplasmosis, coccidioidomycosis)
Cat scratch disease
Hodgkin lymphoma (granulomatous inflammation)
Kikuchi disease
Foreign body granulomas
Metastatic carcinoma with desmoplastic reaction.
Distinguishing Features:
Sarcoidosis: Non-caseating granulomas, negative AFB, asteroid bodies
Atypical mycobacteria: Acid-fast bacilli with different morphology, different PCR results
Cat scratch disease: Stellate microabscesses, Warthin-Starry stain positive
Hodgkin lymphoma: Reed-Sternberg cells, CD15/CD30 positive
Kikuchi disease: Crescentic histiocytes, absence of neutrophils.
Diagnostic Challenges:
AFB negative cases (60-70% of FNAC cases)
Differentiation from atypical mycobacteria
Non-caseating granulomas in some TB cases
Secondary bacterial infection masking TB features
Sampling error in heterogeneous lesions
HIV co-infection altering morphology.
Rare Variants:
Spindle cell tuberculosis (pseudosarcomatous TB)
Necrotizing tuberculosis without granulomas
Suppurative tuberculosis
Calcific tuberculosis
Sclerotic tuberculosis
Tuberculous lymphadenitis with amyloidosis
Miliary tuberculosis in lymph nodes.
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
Fine needle aspiration cytology of [site] lymph node
Clinical History
Duration of lymphadenopathy: [duration]. Associated symptoms: [symptoms]. HIV status: [status]
Adequacy
Adequate for evaluation - cellular smears with adequate inflammatory cells
Morphological Features
Epithelioid cell granulomas with Langhans-type giant cells. Caseous necrosis present/absent in background. Chronic inflammatory infiltrate with lymphocytes and plasma cells
Special Stains
Ziehl-Neelsen stain for AFB: [Positive/Negative/Scanty]. Auramine-Rhodamine fluorescent stain: [if performed]
Molecular Studies
PCR for Mycobacterium tuberculosis: [if performed]. GeneXpert MTB/RIF: [if performed]
Cytological Diagnosis
Granulomatous lymphadenitis, consistent with tuberculous lymphadenitis
Recommendations
Clinical correlation advised. Anti-tuberculous therapy as per physician discretion. Culture and drug sensitivity testing recommended. Follow-up to monitor response
Comments
The presence of epithelioid granulomas with caseous necrosis is highly suggestive of tuberculosis. Correlation with clinical features, imaging, and molecular studies recommended for confirmation