Definition/General
Introduction:
Sarcoidosis is a multisystem inflammatory disorder characterized by non-caseating granulomas in affected organs
Lymph node involvement occurs in 75-90% of sarcoidosis cases
FNAC shows characteristic epithelioid cell granulomas without caseous necrosis
The diagnosis requires clinical-radiological-pathological correlation and exclusion of other granulomatous diseases.
Origin:
Etiology remains unknown but likely involves immune system dysfunction in genetically susceptible individuals
Exposure to environmental antigens may trigger abnormal immune response
Results in Th1-mediated and Th17-mediated inflammatory response
Formation of non-caseating granulomas is the hallmark
T-cell activation and macrophage accumulation are key features.
Classification:
Clinical classification: Stage 0 (normal chest X-ray)
Stage I (bilateral hilar lymphadenopathy)
Stage II (hilar lymphadenopathy + pulmonary infiltrates)
Stage III (pulmonary infiltrates without hilar lymphadenopathy)
Stage IV (pulmonary fibrosis)
Histological pattern: non-caseating granulomas with epithelioid cells and giant cells.
Epidemiology:
Worldwide distribution with geographic and racial variations
Higher prevalence in Northern Europeans and African Americans
Bimodal age distribution: peaks at 25-35 years and >50 years
Female predominance (60%)
In India, prevalence is lower compared to Western countries
Familial clustering observed in some cases.
Clinical Features
Presentation:
Bilateral hilar lymphadenopathy (most common, 90% cases)
Peripheral lymphadenopathy (cervical, axillary, inguinal)
Mediastinal lymph node enlargement
Asymptomatic in early stages (50-60%)
Löfgren syndrome (acute sarcoidosis with fever, arthralgia, erythema nodosum)
Parotid gland enlargement (Heerfordt syndrome).
Symptoms:
Respiratory symptoms: dry cough (50-60%), shortness of breath (40-50%)
Constitutional symptoms: fatigue (70%), weight loss (30%), low-grade fever (15%)
Ocular symptoms: blurred vision, eye pain, photophobia
Skin lesions: erythema nodosum, lupus pernio
Arthralgia and myalgia (20-30%)
Neurological symptoms (5%).
Risk Factors:
Genetic predisposition (HLA associations)
Environmental factors (organic/inorganic dusts, infectious agents)
Age (20-40 years most common)
Gender (female predominance)
Race (higher in certain ethnic groups)
Geographic location
Occupational exposure to dusts
Family history of sarcoidosis.
Screening:
No specific screening tests available
Chest X-ray shows bilateral hilar lymphadenopathy
High-resolution CT of chest for pulmonary involvement
Serum ACE levels elevated in 50-80% cases
Serum calcium may be elevated
24-hour urine calcium
PET scan for disease activity assessment.
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Gross Description
Appearance:
Enlarged lymph nodes (typically 1-4 cm)
Nodes are firm but not hard
Multiple node groups often involved
Bilateral symmetrical hilar lymphadenopathy characteristic
Cut surface shows gray-white appearance with fish-flesh consistency
No necrosis or caseation visible grossly.
Characteristics:
FNAC yields moderate to abundant cellular material
Aspirate appears grayish-white
Granular consistency due to epithelioid cells
Clean background without necrotic debris
May contain multinucleated giant cells
Calcium oxalate crystals occasionally seen
No caseous material.
Size Location:
Hilar lymph nodes most commonly affected (bilateral)
Mediastinal nodes (paratracheal, subcarinal)
Peripheral nodes: cervical (30%), axillary (20%), inguinal (15%)
Supraclavicular nodes less commonly involved
Node size usually 1-5 cm
Generalized lymphadenopathy in systemic disease.
Multifocality:
Bilateral hilar involvement is characteristic (90% of cases)
Mediastinal nodes frequently involved
Multiple peripheral node groups may be affected
Symmetrical involvement typical
Generalized lymphadenopathy in advanced cases
Regression may occur spontaneously in some cases.
Microscopic Description
Histological Features:
FNAC shows well-formed epithelioid cell granulomas
Multinucleated giant cells (Langhans type and foreign body type)
Absence of caseous necrosis (key feature)
Peripheral lymphocytes around granulomas
Plasma cells may be present
Background lymphoid cells from residual lymph node tissue.
Cellular Characteristics:
Epithelioid cells: Large, elongated cells with oval vesicular nuclei, abundant eosinophilic cytoplasm
Multinucleated giant cells: Langhans-type (peripheral nuclei), foreign body-type (random nuclei)
Lymphocytes: Small, mature lymphocytes around granulomas
Plasma cells and histiocytes may be seen
Asteroid bodies and Schaumann bodies in giant cells.
Architectural Patterns:
Discrete granulomas with well-defined borders
Compact epithelioid cell aggregates
Giant cells centrally located within granulomas
Lymphoid tissue in background
No central necrosis or caseation
Fibroblasts may be present at periphery of granulomas.
Grading Criteria:
No formal grading system for sarcoid granulomas
Assessment based on granuloma maturity: Well-formed vs loose aggregates
Presence/absence of giant cells
Inflammatory background assessment
Fibrosis in chronic cases
Disease activity correlates with granuloma density and cellular composition.
Immunohistochemistry
Positive Markers:
CD68 positive in epithelioid cells and giant cells
CD163 positive in macrophages
Lysozyme positive in epithelioid cells
CD3 positive in T-lymphocytes around granulomas
CD20 positive in B-lymphocytes (fewer)
S-100 positive in dendritic cells
CD1a may be positive in some epithelioid cells.
Negative Markers:
Cytokeratin negative (excludes carcinoma)
CD30 and CD15 negative (excludes Hodgkin lymphoma)
Melanoma markers negative
CD1a and Langerin usually negative (excludes Langerhans cell histiocytosis)
S-100 negative in epithelioid cells (unlike nerve sheath tumors)
ALK negative (excludes ALCL).
Diagnostic Utility:
IHC has limited utility in typical sarcoid granulomas
Useful to exclude malignancy in atypical cases
CD68 positivity confirms histiocytic nature
Helps differentiate from infectious granulomas
T-cell predominance around granulomas supports sarcoidosis
Useful in differential diagnosis with other granulomatous conditions.
Molecular Subtypes:
Sarcoidosis shows Th1 and Th17 immune response
High levels of TNF-alpha, interferon-gamma, and IL-17
Elevated ACE levels due to epithelioid cell production
Calcium metabolism abnormalities
Oxidative stress markers elevated
Complement activation may occur.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations for sarcoidosis
HLA associations: HLA-B8, HLA-DR3 (in Europeans), HLA-B35 (in Japanese)
BTNL2 gene polymorphisms
TNF-alpha gene polymorphisms
ACE gene polymorphisms
ANXA11 gene variants
FAM177B gene associations
ADAMTS19 gene polymorphisms.
Molecular Markers:
Elevated serum ACE (50-80% of cases)
Increased lysozyme levels
Elevated soluble IL-2 receptor
High neopterin levels
Increased chitotriosidase activity
Elevated KL-6 levels
YKL-40 elevation
VEGF elevation in active disease.
Prognostic Significance:
Spontaneous remission in 50-60% of cases within 2-5 years
Chronic progressive disease in 10-20% of cases
Stage I disease has excellent prognosis (>90% resolution)
Pulmonary fibrosis (Stage IV) has poor prognosis
Extrapulmonary involvement may affect prognosis
Age of onset influences outcome (younger patients have better prognosis).
Therapeutic Targets:
Corticosteroids: First-line therapy for symptomatic disease
Methotrexate: Steroid-sparing agent
TNF-alpha inhibitors: Infliximab for refractory cases
Antimalarials: Hydroxychloroquine for skin and joint involvement
Immunosuppressants: Azathioprine, mycophenolate
Rituximab: For refractory neurosarcoidosis.
Differential Diagnosis
Similar Entities:
Tuberculosis (caseating granulomas)
Atypical mycobacterial infections
Fungal infections (histoplasmosis, coccidioidomycosis)
Berylliosis
Hypersensitivity pneumonitis
Foreign body granulomas
Hodgkin lymphoma with granulomatous reaction
Primary biliary cirrhosis (in liver involvement).
Distinguishing Features:
Tuberculosis: Caseous necrosis, AFB positive, PCR positive
Atypical mycobacteria: Special stains positive, different clinical context
Fungal infections: Organisms visible on special stains, different geographic distribution
Berylliosis: Occupational history, beryllium lymphocyte proliferation test positive
Hodgkin lymphoma: Reed-Sternberg cells present.
Diagnostic Challenges:
Distinguishing from tuberculosis in endemic areas
Absence of organisms on special stains crucial
Non-caseating nature of granulomas important
Clinical presentation and radiological pattern help
Response to anti-TB treatment (absent in sarcoidosis)
Molecular tests for TB should be negative.
Rare Variants:
Necrotizing sarcoid granulomatosis (rare variant with necrosis)
Nodular sarcoidosis
Fibrosing sarcoidosis
Cardiac sarcoidosis
Neurosarcoidosis
Osseous sarcoidosis
Hepatic sarcoidosis
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
Fine needle aspiration cytology of [site] lymph node
Clinical History
Clinical presentation: [symptoms]. Imaging findings: [chest X-ray/CT findings]. Duration: [duration]
Adequacy
Adequate for evaluation - cellular smears with adequate inflammatory tissue
Morphological Features
Cellular smears showing well-formed epithelioid cell granulomas with multinucleated giant cells (Langhans and foreign body types). No caseous necrosis identified. Background shows lymphoid tissue
Special Stains
Ziehl-Neelsen stain for AFB: Negative. PAS stain: Negative. GMS stain: Negative. [Other stains as indicated]
Molecular Studies
PCR for Mycobacterium tuberculosis: [Negative if performed]. Other molecular tests: [as indicated]
Cytological Diagnosis
Non-caseating granulomatous inflammation, consistent with sarcoidosis (clinical correlation required)
Recommendations
Clinical-radiological correlation advised. Serum ACE levels. Exclusion of infectious causes. Multisystem evaluation for sarcoidosis. Follow-up as clinically indicated
Comments
The presence of non-caseating granulomas in the appropriate clinical setting is consistent with sarcoidosis. Diagnosis requires exclusion of infectious and other granulomatous diseases