Definition/General
Introduction:
Sarcoidosis is a chronic, multisystem granulomatous disease of unknown etiology characterized by non-caseating epithelioid granulomas
It commonly involves lymph nodes and lungs but can affect any organ system
The disease shows variable clinical course from spontaneous remission to progressive organ dysfunction
It has complex immunopathogenesis involving aberrant immune response to unknown antigens.
Origin:
Etiology remains unknown but likely involves environmental triggers in genetically susceptible individuals
Infectious agents (mycobacteria, propionibacteria) proposed as triggers
Inorganic dust exposure (silica, metals) associated with some cases
Autoimmune mechanisms suggested by organ-specific involvement
Genetic predisposition evident from familial clustering
Th1-mediated immune response leads to granuloma formation.
Classification:
Clinical staging (Scadding stages): Stage 0 (normal chest X-ray)
Stage I (bilateral hilar lymphadenopathy)
Stage II (hilar lymphadenopathy + pulmonary infiltrates)
Stage III (pulmonary infiltrates only)
Stage IV (pulmonary fibrosis)
Löfgren syndrome: acute sarcoidosis with erythema nodosum, arthritis, hilar lymphadenopathy
Chronic progressive sarcoidosis.
Epidemiology:
Peak incidence in 3rd and 4th decades (20-40 years)
Bimodal age distribution with second peak after 50 years
Higher prevalence in Scandinavian and African populations
Female predominance (F:M = 2:1)
Geographic clustering suggests environmental factors
Familial cases in 5% of patients
Lower prevalence in Indian population compared to Western countries.
Clinical Features
Presentation:
Bilateral hilar lymphadenopathy (most common radiological finding - 90% of cases)
Asymptomatic presentation in 30-50% of patients
Constitutional symptoms: fever, weight loss, fatigue
Löfgren syndrome: acute onset with erythema nodosum, arthritis, bilateral hilar lymphadenopathy
Peripheral lymphadenopathy in 25-30% of cases
Hepatosplenomegaly in advanced cases.
Symptoms:
Respiratory symptoms: dry cough (50%), dyspnea (40%), chest pain
Skin manifestations: erythema nodosum (25%), lupus pernio, plaques
Ocular involvement: uveitis (25%), conjunctival nodules
Cardiac symptoms: arrhythmias, heart failure (5%)
Neurological symptoms: cranial nerve palsies, seizures (5%)
Hypercalcemia (10-15%) and hypercalciuria.
Risk Factors:
Genetic predisposition (HLA associations: HLA-DRB1, HLA-DQB1)
Environmental exposures (organic and inorganic dusts)
Infectious triggers (mycobacterial or bacterial antigens)
Geographic location (higher prevalence in certain regions)
Occupational exposures (healthcare workers, firefighters)
Family history (5-fold increased risk)
Female gender (2:1 female predominance).
Screening:
Chest X-ray (bilateral hilar lymphadenopathy pathognomonic)
High-resolution CT (HRCT) for detailed assessment
Pulmonary function tests
Serum ACE levels (elevated in 60% of active cases)
Serum calcium and 24-hour urinary calcium
Complete blood count (lymphopenia common)
Tissue biopsy for histological confirmation.
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Gross Description
Appearance:
Enlarged lymph nodes with smooth, intact capsule
Cut surface shows gray-white to tan coloration with firm consistency
Homogeneous appearance without necrosis or caseation
Multiple small nodules may be visible grossly
Preserved nodal architecture in early stages
Fibrosis and sclerosis in chronic cases
No calcification typically present.
Characteristics:
Firm, rubbery consistency due to granulomatous infiltration
No suppuration or abscess formation
Multinodular appearance with granuloma distribution
Capsular thickening in chronic cases
No adherence to surrounding structures typically
Variable size depending on stage and activity
Bilateral involvement common in hilar lymphadenopathy.
Size Location:
Hilar lymph nodes most commonly affected (90% of cases)
Bilateral symmetric involvement characteristic
Mediastinal lymph nodes (paratracheal, subcarinal)
Peripheral lymph nodes (cervical, axillary, inguinal) in 25-30%
Size ranges from 1-5 cm typically
Retroperitoneal lymph nodes less commonly involved.
Multifocality:
Bilateral hilar involvement pathognomonic (potato nodes appearance)
Symmetric distribution pattern characteristic
Multiple lymph node groups involved simultaneously
Systemic disease with multiple organ involvement
Progressive involvement over time
Spontaneous regression possible in some cases.
Microscopic Description
Histological Features:
Non-caseating epithelioid granulomas (hallmark feature)
Well-formed granulomas with epithelioid cells, lymphocytes, and giant cells
Langhans and foreign body giant cells
Absence of central necrosis (distinguishes from tuberculosis)
Schaumann bodies and asteroid bodies in giant cells
Preserved lymph node architecture in early stages
Fibrosis in chronic cases.
Cellular Characteristics:
Epithelioid cells (activated macrophages) with elongated nuclei and abundant cytoplasm
Multinucleated giant cells (Langhans and foreign body types)
Schaumann bodies (laminated, calcified inclusions)
Asteroid bodies (star-shaped inclusions)
Chronic inflammatory cells at periphery
Minimal necrosis or caseation
Fibroblasts and collagen in chronic lesions.
Architectural Patterns:
Interfollicular granulomatous pattern with preservation of nodal architecture
Discrete, well-circumscribed granulomas
Granulomas in paracortical and interfollicular areas
Compressed but preserved follicular structures
Capsular and pericapsular involvement
Sinus involvement uncommon
Progressive architectural effacement in advanced cases.
Grading Criteria:
No standard grading system for sarcoid granulomas
Activity assessment based on granuloma morphology and cellularity
Active granulomas: well-formed, cellular, epithelioid predominance
Chronic granulomas: fibrotic, sclerotic, fewer epithelioid cells
Granuloma density assessment
Degree of fibrosis indicates chronicity
Giant cell content and inclusion body presence.
Immunohistochemistry
Positive Markers:
CD68 positive in epithelioid cells and giant cells
CD3 highlights T-lymphocytes around granulomas
CD20 shows preserved B-cell follicles
Lysozyme positive in epithelioid cells
S-100 may be positive in some giant cells
Smooth muscle actin positive in fibroblasts
Ki-67 low in granulomatous areas.
Negative Markers:
CD1a and Langerin negative (excludes Langerhans cell histiocytosis)
CD30 negative (excludes lymphoma)
Cytokeratin negative in epithelioid cells
Mycobacterial markers negative
Fungal markers negative
Foreign body polarization negative
CD21 and CD23 highlight residual follicular dendritic cells.
Diagnostic Utility:
Limited utility of immunohistochemistry for sarcoidosis diagnosis
CD68 staining confirms histiocytic nature
Negative stains help exclude other conditions
AFB and GMS stains essential to exclude infections
Polarized light examination excludes foreign body reaction
ACE staining in tissue not routinely used
Diagnosis based on morphology and clinical correlation.
Molecular Subtypes:
No molecular subtypes recognized for sarcoidosis
Genetic associations with HLA alleles and other genes
Familial clustering suggests genetic component
Environmental trigger variations may influence presentation
Phenotypic variations based on organ involvement
Löfgren syndrome has better prognosis
Chronic progressive forms with worse outcome.
Molecular/Genetic
Genetic Mutations:
No specific mutations but genetic susceptibility loci identified
HLA associations: HLA-DRB1*03, HLA-DQB1*02 (Löfgren syndrome)
BTNL2 gene variants
ANXA11 gene polymorphisms
FAM177B gene associations
NOTCH4 gene variants
TNF-α promoter polymorphisms
ACE gene polymorphisms affect enzyme levels.
Molecular Markers:
Elevated serum ACE (angiotensin-converting enzyme) in 60% of active cases
Lysozyme levels increased
Th1 cytokines (IFN-γ, IL-2, TNF-α) elevated
IL-17 and Th17 response in some cases
Regulatory T-cell dysfunction
Calcium metabolism abnormalities (1,25-dihydroxyvitamin D3 elevation)
Soluble IL-2 receptor (sIL-2R) as activity marker.
Prognostic Significance:
Variable prognosis depending on presentation and organ involvement
Löfgren syndrome: excellent prognosis (90% spontaneous remission)
Chronic progressive disease: worse prognosis with organ dysfunction
Cardiac involvement: serious complications, arrhythmias
Neurosarcoidosis: significant morbidity
Pulmonary fibrosis: progressive respiratory failure
Overall mortality: 1-5% of cases.
Therapeutic Targets:
Corticosteroids (first-line therapy for symptomatic disease)
Methotrexate as steroid-sparing agent
Azathioprine for chronic cases
Hydroxychloroquine for skin and hypercalcemia
TNF-α inhibitors (infliximab, adalimumab) for refractory cases
Mycophenolate mofetil alternative immunosuppressant
Rituximab for refractory cases
Observation for asymptomatic cases.
Differential Diagnosis
Similar Entities:
Tuberculosis (caseating granulomas)
Histoplasmosis (fungal granulomas)
Berylliosis (occupational exposure)
Hypersensitivity pneumonitis (poorly formed granulomas)
Crohn disease (GI involvement)
Foreign body reaction (polarizable material)
Malignancy (sarcoid-like reaction)
Primary biliary cirrhosis (liver involvement).
Distinguishing Features:
Sarcoidosis: non-caseating granulomas, Schaumann/asteroid bodies, bilateral hilar lymphadenopathy, negative AFB
Tuberculosis: caseating granulomas, Langhans giants, positive AFB, asymmetric involvement
Histoplasmosis: organisms in giant cells, GMS positive, endemic areas
Berylliosis: occupational history, beryllium lymphocyte proliferation test positive
Foreign body: polarizable material, history of exposure.
Diagnostic Challenges:
Exclusion diagnosis requiring negative stains for organisms
Sarcoid-like reactions in malignancy can mimic true sarcoidosis
Early granulomas may be poorly formed
Chronic cases may show extensive fibrosis
Atypical presentations in different organ systems
Concurrent infections can complicate diagnosis
Clinical correlation essential for diagnosis.
Rare Variants:
Löfgren syndrome (acute form with excellent prognosis)
Heerfordt syndrome (parotid enlargement, uveitis, fever, facial palsy)
Blau syndrome (familial granulomatous disease)
Cardiac sarcoidosis (isolated cardiac involvement)
Neurosarcoidosis (CNS involvement)
Hepatic sarcoidosis
Cutaneous sarcoidosis
Osseous sarcoidosis (bone involvement).
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/mediastinal/peripheral] location, measuring [X.X] cm in greatest dimension
Diagnosis
Sarcoidosis with non-caseating epithelioid granulomas
Pattern Classification
Pattern: [interfollicular granulomatous], activity: [active/chronic], stage: [clinical correlation required]
Histological Features
Shows [well-formed non-caseating epithelioid granulomas] with [giant cells and inclusion bodies] without necrosis
Size and Distribution
Size: [X.X] cm, granulomas: [discrete/confluent], distribution: [interfollicular/diffuse]
Granuloma Characteristics
Granulomas show [epithelioid cells/giant cells/Schaumann bodies/asteroid bodies] without [caseation/necrosis]
Special Studies
Special stains: AFB [negative], GMS [negative], PAS [negative for organisms]
Polarized light: [negative for foreign material]
Clinical correlation: [ACE levels/calcium levels/imaging findings]
Final Diagnosis
Sarcoidosis (non-caseating granulomatous lymphadenitis), consistent with systemic granulomatous disease