Pulmonary Sarcoidosis

Description

Pulmonary sarcoidosis is the most common form of sarcoidosis (90% of patients with sarcoidosis), a multi-system granulomatous disorder of unknown cause. It affects the lungs and hilar lymph nodes and is characterised by the formation of non-caseating granulomas within these structures. Pulmonary sarcoidosis is a common cause of interstitial lung disease. The greatest morbidity and mortality from sarcoidosis is due to pulmonary involement.

Pathogenesis

The exact cause of pulmonary sarcoidosis remains unknown, but it is thought to result from an exaggerated immune response to an unidentified antigen within the lungs and lymph nodes. This leads to the formation of non-caseating granulomas, which are clusters of immune cells, predominantly macrophages and T-lymphocytes.

Epidemiology, Risk Factors & Associations

• More common in females than males (3:2)
• Prevalence is highest among people of Northern European and African descent
• Peak incidence between ages 20 and 40
• Association with certain HLA types (e.g. HLA-DRB1)
• Non-smoking status is associated with a higher risk
• HIV infection: Cases reported after initiation of antiretroviral therapy with rise in CD4 cell count suggesting possible relation to immune restoration

Clinical Features

• Respiratory symptoms including cough, dyspnoea, and chest pain
• Systemic symptoms such as fatigue, fever, and weight loss
• Lofgren’s syndrome: acute febrile illness with erythema nodosum, bilateral hilar lymphadenopathy, and large joint arthritis. May also have parotitis and uveitits.
• Heerfordt syndrome: fever, parotid enlargement, facial palsy, and anterior uveitis. Most commonly affects patients in second to fourth decades of life.
• Lupus pernio: violaceous raised skin lesions on the cheeks and nose. Poor progonosis.

Complications

• Progression to pulmonary fibrosis, resulting in chronic respiratory failure
• Bronchiectasis
• Pneumothorax and bullae in cases of advanced disease

Pathological Features

Histopathology

• Macroscopic: The lungs typically show multiple small white nodules scattered throughout the parenchyma.
• Microscopic: Characterised by non-caseating granulomas, which consist of a central area of macrophages and multinucleated giant cells, surrounded by a rim of lymphocytes.
• Schaumann and asteroid body inclusions are not specific or pathognomonic for sarcoidosis and can be seen in other conditions such as tuberculosis, tuberculoid leprosy and berylliosis.

Serology

• Elevated levels of serum angiotensin-converting enzyme (ACE) are often seen in active sarcoidosis, but are not specific.

Biochemistry

• Hypercalcemia and hypercalciuria due to increased vitamin D production by macrophages in the granulomas

Radiological Features

General Features

• Characteristically demonstrates bilateral hilar and mediastinal lymphadenopathy. Usually non-compressive even if bulky.
• Eggshell calcification of lymph nodes is seen in a minority of cases (~10%). Incidence increases with disease duration.
• Pulmonary infiltrates, nodules along bronchovascular bundles (perilymphatic distribution), and ground-glass opacities
• Reticular opacities representing fibrosis in advanced disease, usually upper zone.
• Pleural effusions are rare.

XR

• Reticulonodular opacities with a mid- to upper-zone distribution, bilateral and symmetric
  • Miliary nodularity may be present, resembling miliary sarcoidosis
• Garland triad, also known as the 1-2-3 sign refers to the lymph node enlargement pattern involving:
  1. Right paratracheal nodes
  2. Right hilar nodes
  3. Left hilar nodes
• Hilar lymphadenopathy is symmetrical and usually massive, sometimes termed potato nodes. They typically do not abut the cardiac border which distinguishes the nodal enlargement from lymphoma.
• Pleural effusion may be present, though uncommon.

HRCT

• Nodules in a perilymphatic distribution, with mid- to upper lung predominance.
  • Perilymphatic distribution: Peribronchovascular, subpleural interstitial and interlobular septal locations
  • Nodules are typically irregular in morphology.
• Ground-glass opacities and interstitial thickening.
• Bulky symmetric hilar and mediastinal lymphadenopathy. They typically do not cause mass effect such as vascular compression.
• Pulmonary fibrosis is seen in advanced (stage IV) disease
  • Central bronchial distortion, bronchiectasis, air trapping.
  • Peripheral honeycombing, mainly middle to upper zones.
  • Diffuse linear fibrotic pattern, typically radiating from hila
• Galaxy sign – Clustering of granulomas appearing as mass-like region composed of numerous smaller granulomas, similar to a galaxy (uncommon, also seen in tuberculosis)

NM

• Ga-67: Lambda sign – increased uptake in the bilateral hilar and right paratracheal lymph node (equivalent to the garland triad)

Grading and Staging

The Scadding system is a commonly used radiological staging system for pulmonary sarcoidosis, based on chest radiograph findings.

• Stage 0: Normal chest radiograph, no abnormalities detected.
• Stage 1: Bilateral hilar lymphadenopathy (BHL) only.
• Stage 2: BHL with pulmonary infiltrates.
• Stage 3: Pulmonary infiltrates only, with resolution of BHL.
• Stage 4: Pulmonary fibrosis, which may present as distortion of lung architecture, honeycombing, and fibrocystic changes.

Diagnosis

Diagnosis is typically based on clinical presentation, radiographic findings, and histological confirmation of non-caseating granulomas in lung or lymph node biopsies. Biopsy can be performed:

• Bronchial or transbronchial biopsy – sensitivity 90%
• Open lung biopsy – sensitivity 100%
• Lymph node, parotid gland, nasal mucosa biopsy – sensitivity 95%
• Mediastinoscopy – sensitvity 95%

Differential Diagnosis

• Pneumoconiosis: Silicosis or coal-worker pneumoconiosis appears as well-defined, rounded and coalescent nodules in a perilymphatic distribution in a patient with a relevant occupational exposure. This can progress to large fibrotic opacities termed progressive massive fibrosis causing respiratory impairment. Egg-shell calcifications may also be present (silicosis > CWP).
• Tuberculosis: Similar granulomas and clinical features, but the granulomas in tuberculosis are caseating. Epidemiology and exposure history can help differentiate. Calcified lymph nodes, but not usually rim/egg-shell.
• Lymphoma: Can also cause lymphadenopathy and systemic symptoms. Presence of a mass, B symptoms, and lymphocyte predominance on biopsy would suggest lymphoma. Enlarged lymph nodes may be continuous with the pericardial outline. Post-radiation Hodgkin’s lymphoma can also cause egg-shell calcification.
• Other causes of interstitial lung disease, such as idiopathic pulmonary fibrosis and hypersensitivity pneumonitis

Management

Management is usually overseen by a respiratory physician and may include observation for asymptomatic disease, corticosteroids for symptomatic disease, and other immunosuppressive therapy for refractory disease.