Definition/General
Introduction:
Non-caseating lymphadenitis is characterized by epithelioid granulomas without central necrosis, representing a chronic immune response to various stimuli
Sarcoidosis is the prototype condition but multiple other causes exist
The absence of caseous necrosis distinguishes it from tuberculous lymphadenitis and represents different pathophysiological mechanisms of granuloma formation.
Origin:
Results from chronic antigenic stimulation with contained immune response
Sarcoidosis (most common cause, unknown etiology)
Berylliosis (occupational exposure to beryllium)
Hypersensitivity pneumonitis (organic dust exposure)
Drug-induced granulomatous reactions
Autoimmune conditions (Crohn disease, primary biliary cirrhosis)
Foreign body reactions (silica, tattoo pigments).
Classification:
Classified by underlying etiology: Sarcoidosis (systemic granulomatous disease)
Occupational lung diseases (berylliosis, silicosis)
Drug-induced (methotrexate, TNF-α inhibitors)
Autoimmune-associated
Infectious (brucellosis, some fungal infections)
Malignancy-associated (sarcoid-like reactions)
Idiopathic non-caseating granulomatous lymphadenitis.
Epidemiology:
Variable epidemiology depending on underlying cause
Sarcoidosis: peak in 3rd-4th decades, higher in Scandinavians and African Americans
Berylliosis: occupational exposure history
Drug-induced: related to specific medications
Geographic clustering for some causes
Lower prevalence in Indian population compared to Western countries.
Clinical Features
Presentation:
Bilateral hilar lymphadenopathy (classic sarcoidosis presentation)
Asymptomatic lymphadenopathy common (incidental finding)
Peripheral lymphadenopathy in 25-30% of cases
Löfgren syndrome (acute sarcoidosis with erythema nodosum, arthritis)
Systemic symptoms variable
Multi-organ involvement possible
Symmetric, bilateral distribution.
Symptoms:
Asymptomatic in 30-50% of patients
Respiratory symptoms: dry cough, dyspnea, chest pain
Constitutional symptoms: fever, weight loss, fatigue
Skin manifestations: erythema nodosum, lupus pernio, plaques
Ocular symptoms: uveitis, conjunctival nodules
Neurological symptoms: cranial nerve palsies
Cardiac symptoms: arrhythmias (rare but serious).
Risk Factors:
Genetic predisposition (HLA-DRB1, HLA-DQB1 associations)
Environmental exposures (organic dusts, metals)
Occupational exposures (beryllium, silica)
Geographic location (higher prevalence areas)
Family history of sarcoidosis
Female gender (slight predominance)
Healthcare worker (some studies suggest increased risk).
Screening:
Chest X-ray (bilateral hilar lymphadenopathy pathognomonic)
High-resolution CT for detailed assessment
Serum ACE levels (elevated in 60% of active sarcoidosis)
Serum calcium and 24-hour urine calcium
Pulmonary function tests
Ophthalmologic examination
Tissue biopsy for histological confirmation
Exclusion of infections (TB, fungi).
Master Non-Caseating Lymphadenitis Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Enlarged lymph nodes with firm, rubbery consistency
Cut surface shows gray-white homogeneous appearance
Multiple small nodules corresponding to granulomas
No necrosis or caseation
Preserved capsule without adherence
Bilateral involvement common
Fibrotic changes in chronic cases.
Characteristics:
Firm consistency due to granulomatous infiltration
Homogeneous gray-white cut surface
No softening or fluctuation
Discrete nodular pattern may be visible
No calcification typically
Preserved architecture grossly
Multiple lymph nodes similarly affected.
Size Location:
Hilar lymph nodes most commonly affected (90% in sarcoidosis)
Bilateral symmetric involvement characteristic
Mediastinal lymph nodes (paratracheal, subcarinal)
Peripheral lymph nodes in 25-30% of cases
Size ranges from 1-5 cm typically
Retroperitoneal involvement less common.
Multifocality:
Bilateral hilar involvement pathognomonic (potato nodes)
Symmetric distribution pattern
Multiple lymph node stations involved
Systemic disease with multi-organ involvement
Peripheral lymphadenopathy may accompany hilar disease
Spontaneous regression possible.
Microscopic Description
Histological Features:
Well-formed epithelioid granulomas without central necrosis
Epithelioid cells with abundant eosinophilic cytoplasm
Multinucleated giant cells (Langhans and foreign body types)
Schaumann bodies and asteroid bodies in giant cells
Lymphocytes and plasma cells at periphery
Preserved lymph node architecture
Fibrosis in chronic cases.
Cellular Characteristics:
Epithelioid cells (activated macrophages) predominant
Multinucleated giant cells with inclusion bodies
Schaumann bodies (laminated, basophilic inclusions)
Asteroid bodies (star-shaped, eosinophilic inclusions)
Chronic inflammatory cells at granuloma margins
Absence of neutrophils
No necrosis or caseation.
Architectural Patterns:
Discrete, well-circumscribed granulomas
Interfollicular and paracortical location
Preserved follicular structures between granulomas
No architectural effacement in early stages
Granulomas may coalesce in advanced cases
Capsular involvement possible
Fibrotic replacement in chronic stages.
Grading Criteria:
No standard grading system for non-caseating granulomas
Granuloma density and distribution
Degree of giant cell formation
Inclusion body content (Schaumann, asteroid bodies)
Associated fibrosis extent
Activity assessment (epithelioid cell morphology)
Architectural preservation vs distortion.
Immunohistochemistry
Positive Markers:
CD68 positive in epithelioid cells and giant cells
CD163 positive in M2 macrophages
Lysozyme positive in epithelioid cells
CD3 highlights T-lymphocytes around granulomas
CD20 shows preserved B-cell follicles
S-100 may be positive in some giant cells
Smooth muscle actin may be positive in epithelioid cells.
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
Mycobacterial markers negative.
Diagnostic Utility:
Limited utility for determining specific etiology
CD68 confirmation of histiocytic nature
Negative infectious stains (AFB, GMS, PAS) essential
Polarized light examination for foreign material
ACE levels and calcium metabolism more helpful for sarcoidosis
Beryllium lymphocyte proliferation test for berylliosis.
Molecular Subtypes:
No molecular subtypes but genetic associations recognized
HLA-DRB1*03, HLA-DQB1*02 (Löfgren syndrome)
BTNL2 gene variants (sarcoidosis susceptibility)
ANXA11 gene polymorphisms
Environmental trigger variations may influence presentation
Familial clustering suggests genetic component.
Molecular/Genetic
Genetic Mutations:
No specific mutations but genetic susceptibility loci identified
HLA associations (multiple alleles)
BTNL2, ANXA11, FAM177B gene variants
NOTCH4, TNF-α promoter polymorphisms
Complement component variants
Vitamin D pathway gene polymorphisms
No oncogene activation or tumor suppressor loss.
Molecular Markers:
Elevated serum ACE (angiotensin-converting enzyme)
Hypercalciuria and hypercalcemia
Elevated 1,25-dihydroxyvitamin D3
Soluble IL-2 receptor (sIL-2R)
Th1 cytokines (IFN-γ, IL-2, TNF-α)
Lysozyme levels increased
Complement activation products.
Prognostic Significance:
Variable prognosis depending on underlying cause and presentation
Löfgren syndrome: excellent prognosis (90% spontaneous remission)
Chronic progressive sarcoidosis: may lead to organ dysfunction
Pulmonary fibrosis: serious complication
Cardiac sarcoidosis: potentially fatal arrhythmias
Neurosarcoidosis: significant morbidity
Overall mortality: 1-5% of sarcoidosis cases.
Therapeutic Targets:
Corticosteroids (first-line for symptomatic disease)
Methotrexate as steroid-sparing agent
Azathioprine, mycophenolate for maintenance
Hydroxychloroquine (skin involvement, hypercalcemia)
TNF-α inhibitors (refractory cases)
Rituximab for severe cases
Observation for asymptomatic disease.
Differential Diagnosis
Similar Entities:
Tuberculosis (caseating granulomas)
Histoplasmosis (organisms in macrophages)
Berylliosis (occupational exposure)
Hypersensitivity pneumonitis (poorly formed granulomas)
Crohn disease (GI involvement)
Primary biliary cirrhosis (liver involvement)
Foreign body reaction (polarizable material).
Distinguishing Features:
Non-caseating lymphadenitis: well-formed granulomas without necrosis, bilateral hilar lymphadenopathy, elevated ACE
Tuberculosis: caseating granulomas, asymmetric involvement, positive AFB
Histoplasmosis: organisms visible, endemic areas, GMS positive
Berylliosis: occupational history, beryllium test positive
Hypersensitivity pneumonitis: poorly formed granulomas, exposure history.
Diagnostic Challenges:
Exclusion diagnosis requiring negative infectious workup
Sarcoid-like reactions in malignancy
Drug-induced granulomas require medication history
Occupational causes need exposure assessment
Overlap with other autoimmune conditions
Atypical presentations in different organs
Clinical correlation essential.
Rare Variants:
Löfgren syndrome (acute sarcoidosis with excellent prognosis)
Heerfordt syndrome (parotid enlargement, uveitis, fever, facial palsy)
Blau syndrome (familial granulomatous disease)
Cardiac sarcoidosis (isolated cardiac involvement)
Neurosarcoidosis (CNS granulomas)
Osseous sarcoidosis (bone involvement)
Cutaneous sarcoidosis variants.
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 [hilar/peripheral] location, measuring [X.X] cm in greatest dimension
Diagnosis
Non-caseating granulomatous lymphadenitis, consistent with sarcoidosis
Pattern Classification
Pattern: [well-formed non-caseating granulomas], distribution: [interfollicular/diffuse], activity: [active/chronic]
Histological Features
Shows [well-formed epithelioid granulomas] with [giant cells and inclusion bodies] without necrosis
Size and Distribution
Size: [X.X] cm, granulomas: [discrete/coalescent], architecture: [preserved/minimally distorted]
Granuloma Characteristics
Granulomas contain [epithelioid cells/Langhans giants/Schaumann bodies/asteroid bodies] without [necrosis/caseation]
Special Studies
Special stains: AFB [negative], GMS [negative], PAS [negative for organisms]
Polarized light: [negative for foreign material]
Clinical correlation: [bilateral hilar lymphadenopathy/ACE levels/calcium studies]
Final Diagnosis
Non-caseating granulomatous lymphadenitis, most consistent with sarcoidosis, clinical correlation recommended