Definition/General
Introduction:
Lymph node tuberculosis is a chronic granulomatous infection caused by Mycobacterium tuberculosis complex
It represents the most common form of extrapulmonary tuberculosis accounting for 35-40% of cases
The condition is characterized by caseating epithelioid granulomas with chronic inflammatory response
It is endemic in developing countries including India with significant public health implications.
Origin:
Caused by Mycobacterium tuberculosis complex including M
tuberculosis, M
bovis, M
africanum, and M
microti
Airborne transmission through respiratory droplets is primary route
Hematogenous spread from pulmonary focus to lymph nodes
Direct extension from adjacent infected organs
Lymphatic spread following drainage patterns
Primary lymph node infection possible, especially in children
Reactivation of latent infection in immunocompromised states.
Classification:
Classified by anatomical location: Cervical tuberculosis (most common - 60-70%)
Mediastinal tuberculosis
Axillary tuberculosis
Inguinal tuberculosis
Generalized lymphadenopathy
Histological stages: Early inflammatory
Granulomatous
Caseous necrotic
Fibrocaseous
Calcific (healed).
Epidemiology:
High prevalence in developing countries (India: 2.64 million active cases)
Bimodal age distribution: children (5-15 years) and adults (20-40 years)
No gender predilection but slight female predominance in some regions
HIV co-infection increases risk 20-fold
Malnutrition and immunosuppression major risk factors
Social determinants: poverty, overcrowding, poor ventilation.
Clinical Features
Presentation:
Painless, progressive lymphadenopathy (classic presentation)
Cervical lymph nodes most commonly affected (posterior triangle)
Unilateral involvement initially, may become bilateral
Matted lymph nodes in advanced cases
Cold abscess formation (fluctuant, non-tender)
Cutaneous sinus tracts with discharge
Constitutional symptoms (fever, weight loss, night sweats).
Symptoms:
Low-grade fever (60-80% of cases)
Night sweats and weight loss
Anorexia and malaise
Chronic cough (if pulmonary involvement)
Chest pain (mediastinal involvement)
Dysphagia (compression effects)
Hoarseness (recurrent laryngeal nerve involvement)
Superior vena cava syndrome (massive mediastinal lymphadenopathy).
Risk Factors:
HIV infection (20-fold increased risk)
Immunosuppressive therapy (corticosteroids, biologics)
Malnutrition and diabetes mellitus
Chronic kidney disease
Malignancy and chemotherapy
Age extremes (children and elderly)
Household contact with active TB
Overcrowding and poor socioeconomic conditions.
Screening:
Tuberculin skin test (TST) or Interferon-gamma release assays (IGRA)
Chest X-ray to identify pulmonary involvement
Sputum examination (AFB smear and culture)
Fine needle aspiration cytology (FNAC)
Gene Xpert MTB/RIF for rapid diagnosis
HIV testing in all patients
CT imaging for extent assessment.
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Gross Description
Appearance:
Enlarged lymph nodes with thickened, adherent capsule in chronic cases
Cut surface shows yellow-white caseous material (pathognomonic)
Firm to fluctuant consistency depending on stage
Central caseous necrosis surrounded by gray-white tissue
Calcification in healed cases
Matted lymph node masses in advanced disease
Sinus tract formation to skin.
Characteristics:
Multinodular appearance with central necrosis
Cheese-like caseous material (descriptive term "caseous" from cheese-like appearance)
Surrounding fibrosis and sclerosis
Calcific deposits visible as gritty areas
Adherent to surrounding structures
Multiple lymph nodes involved in same region
Variable size from 1-10 cm.
Size Location:
Cervical lymph nodes most common (60-70% of cases)
Posterior cervical triangle preferred site
Mediastinal lymph nodes (25% of cases)
Hilar lymphadenopathy associated with pulmonary TB
Axillary involvement (10-15%)
Inguinal lymph nodes less common
Generalized lymphadenopathy in disseminated disease.
Multifocality:
Regional involvement following lymphatic drainage
Progressive spread to adjacent lymph node groups
Bilateral cervical involvement in advanced cases
Multiple lymph node groups in disseminated TB
Associated pulmonary involvement in 30-50% of cases
Extranodal spread to adjacent structures.
Microscopic Description
Histological Features:
Caseating epithelioid granulomas (pathognomonic feature)
Central caseous necrosis with eosinophilic, structureless material
Epithelioid cells surrounding necrotic center
Langhans giant cells with peripheral nuclei arrangement
Lymphocytes and plasma cells at periphery
Fibroblasts and fibrosis in chronic cases
Variable degree of architectural effacement.
Cellular Characteristics:
Epithelioid cells (activated macrophages) with elongated nuclei and pink cytoplasm
Langhans giant cells with horseshoe-shaped nuclear arrangement
Caseous necrosis appearing as homogeneous, eosinophilic material
Chronic inflammatory cells (lymphocytes, plasma cells)
Fibroblasts and collagen deposition
Rare acid-fast bacilli (AFB) in tissue sections
Calcification in healed lesions.
Architectural Patterns:
Granulomatous inflammation pattern with architectural effacement
Coalescent granulomas with extensive caseous necrosis
Zonal arrangement: central necrosis, epithelioid cells, lymphocytes, fibrosis
Preserved follicular structure in early stages
Complete architectural obliteration in advanced cases
Pericapsular extension with surrounding tissue involvement
Calcification pattern in healed disease.
Grading Criteria:
Stage-based classification: inflammatory, granulomatous, necrotic, fibrocaseous, calcific
Early stage: granulomas without significant necrosis
Intermediate stage: well-formed granulomas with central necrosis
Advanced stage: extensive caseous necrosis with tissue destruction
Healing stage: fibrosis and calcification
Activity assessment based on granuloma morphology and necrosis extent.
Immunohistochemistry
Positive Markers:
CD68 positive in epithelioid cells and giant cells
CD3 highlights peripheral T-lymphocytes
CD20 shows residual B-cells in preserved areas
Lysozyme positive in epithelioid cells
S-100 may be positive in some giant cells
Ki-67 low in granulomatous areas
Smooth muscle actin positive in fibroblasts.
Negative Markers:
CD1a and Langerin negative (excludes Langerhans cell histiocytosis)
CD30 negative (excludes lymphoma)
Cytokeratin negative in epithelioid cells
CD21 and CD23 highlight residual follicular dendritic cells
BCL-2 and BCL-6 negative in granulomas
ALK-1 negative.
Diagnostic Utility:
Acid-fast bacilli (AFB) staining essential for organism identification (Ziehl-Neelsen, Auramine-Rhodamine)
CD68 staining confirms histiocytic nature of epithelioid cells
Immunohistochemistry limited utility for TB diagnosis
PCR-based methods more sensitive than histochemical stains
GeneXpert and molecular diagnostics preferred
Culture remains gold standard.
Molecular Subtypes:
Drug-sensitive tuberculosis (responds to first-line anti-TB drugs)
Multidrug-resistant TB (MDR-TB) (resistant to isoniazid and rifampin)
Extensively drug-resistant TB (XDR-TB) (MDR plus resistance to fluoroquinolones and aminoglycosides)
Totally drug-resistant TB (TDR-TB) (resistant to all tested drugs)
Molecular resistance testing essential for appropriate therapy.
Molecular/Genetic
Genetic Mutations:
Bacterial resistance mutations in genes like rpoB (rifampin), katG (isoniazid), gyrA (fluoroquinolones)
Host genetic susceptibility (HLA associations, cytokine gene polymorphisms)
NRAMP1 gene variants associated with susceptibility
Vitamin D receptor polymorphisms
TNF-α gene variants
IL-10 promoter polymorphisms
No specific chromosomal abnormalities in host tissue.
Molecular Markers:
Mycobacterial DNA detection by PCR (IS6110, 16S rRNA)
GeneXpert MTB/RIF for rapid diagnosis and rifampin resistance
Line probe assays for drug resistance detection
Whole genome sequencing for comprehensive resistance profiling
Interferon-γ and IL-2 in immune response
TNF-α crucial for granuloma formation.
Prognostic Significance:
Excellent prognosis with appropriate anti-TB therapy (cure rate >95%)
Drug-resistant TB has worse prognosis and longer treatment duration
HIV co-infection increases mortality risk
Delayed diagnosis leads to complications
Treatment adherence crucial for cure
Relapse rate low with complete treatment
Latent TB may reactivate with immunosuppression.
Therapeutic Targets:
First-line anti-TB drugs: isoniazid, rifampin, ethambutol, pyrazinamide
Second-line drugs for resistant cases: fluoroquinolones, aminoglycosides, ethionamide
Newer drugs: bedaquiline, delamanid, pretomanid
Treatment duration: 6 months for drug-sensitive, 18-24 months for MDR-TB
Directly observed therapy (DOTS)
Contact tracing and infection control.
Differential Diagnosis
Similar Entities:
Sarcoidosis (non-caseating granulomas)
Cat scratch disease (stellate abscesses)
Atypical mycobacterial infection
Hodgkin lymphoma (epithelioid cell-rich variant)
Metastatic carcinoma with necrosis
Kikuchi disease (necrotizing lymphadenitis)
Fungal infections (histoplasmosis, cryptococcosis)
Foreign body reaction.
Distinguishing Features:
Tuberculosis: caseating granulomas, Langhans giant cells, AFB positive, caseous necrosis
Sarcoidosis: non-caseating granulomas, asteroid bodies, hilar lymphadenopathy, negative AFB
Cat scratch: stellate abscesses, neutrophils, Warthin-Starry positive
Hodgkin: Reed-Sternberg cells, CD30+, CD15+
Atypical mycobacteria: different AFB morphology, culture differences
Fungi: specific organism morphology, fungal stains positive.
Diagnostic Challenges:
Paucibacillary disease may have negative AFB stains
Early granulomas may lack caseous necrosis
Immunocompromised patients may show atypical histology
Coexistent malignancy can complicate diagnosis
Atypical mycobacteria require culture differentiation
Molecular methods increasingly important
Clinical correlation essential.
Rare Variants:
Miliary tuberculosis (widespread dissemination)
Scrofula (cervical TB in children)
Tuberculous lymphadenitis in HIV (atypical presentation)
Post-primary TB (adult-type)
Primary TB (childhood)
Paradoxical reaction (worsening during treatment)
Immune reconstitution syndrome (in HIV patients)
Calcified tuberculous lymph nodes (healed disease).
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 [cervical/mediastinal/axillary] region, measuring [X.X] cm, with [caseous/firm/calcified] consistency
Diagnosis
Tuberculous lymphadenitis with caseating epithelioid granulomas
Stage Classification
Stage: [granulomatous/necrotizing/fibrocaseous], activity: [active/chronic/healing]
Histological Features
Shows [caseating epithelioid granulomas] with [central caseous necrosis] and [Langhans giant cells]
Size and Necrosis
Size: [X.X] cm, necrosis: [extensive caseous/focal/minimal], granulomas: [well-formed/coalescent]
Organism Detection
AFB stain: [positive/negative], morphology: [acid-fast bacilli identified/not identified]
Special Studies
AFB stain (Ziehl-Neelsen): [positive/negative for acid-fast bacilli]
PCR/GeneXpert: [positive/negative for M. tuberculosis complex]
Culture: [if available] [positive/negative/pending for M. tuberculosis]
Drug sensitivity: [if available] [sensitive/resistant pattern]
Final Diagnosis
Tuberculous lymphadenitis, [drug-sensitive/drug-resistant if known], consistent with mycobacterial infection