Pathophysiology of sarcoidosis
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Sarcoidosis is an idiopathic, systemic disease in which granuloma formation is pathologically triggered in a susceptible individual, presumably by inhalation of various environmental antigens (eg, mycobacteria, tree pollen, mold, inorganic particles)
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Symptoms are caused by organ dysfunction secondary to granuloma accumulation, which impinge on normal structures (eg, airways) or by cytokine elaboration (eg, TNF-α) and vitamin D metabolism
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Granuloma formation is designed to surround and contain organisms that cannot be opsonized:
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Antigen-presenting cells stimulate an oligoclonal population of CD4 + T cells
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Activated CD4 + T cells secrete IL-2, interferon-γ, and TNF-α, stimulating macrophages to differentiate to epithelioid cells
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Epithelioid cells gain secretory antibacterial activity (in lieu of phagocytic ability)
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Epithelioid cells fuse to form multinucleated giant cells
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Granulomas covert vitamin D, leading to hypercalciuria and occasionally hypercalcemia
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Epidemiology of sarcoidosis:
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Typically affects the young (20–40 years old)
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Females more than males
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African Americans are afflicted three times more than Caucasian Americans
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Often older onset (40–50 years old)
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Worse prognosis
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Low income and poor socioeconomic status correlate with more severe sarcoidosis
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Individuals with an affected family member/siblings are at higher risk
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Patterns of organ involvement (eg, ocular, hepatic) track with families
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Natural history:
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50% experience remission within 3 years of diagnosis, and 66% experience remission within 10 years of diagnosis
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Recurrence after a year of remission is rare (< 5%)
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33% experience unrelenting disease and organ injury
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Mortality is < 5% and is most often associated with pulmonary fibrosis, followed by cardiac and neurologic involvement
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Pulmonary fibrosis occurs in 20%–25% of individuals presenting with stage 2–3 disease
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May occur despite resolution of granulomas
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The stages of sarcoidosis are not progressive, but rather represent presentations
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Individuals typically maintain the same stage throughout the course of their disease
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The exception being the occasional progression form stage 2 to stage 3
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Diagnosis:
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Sarcoidosis is a diagnosis of exclusion because adenopathy, nodules, and granulomas occur commonly in many infectious, inflammatory, and malignant diseases
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Requires a compatible clinical radiographic scenario with a tissue biopsy showing well-circumscribed noncaseating granulomas (with negative stains and cultures for acid-fast bacilli, fungi, and foreign matter)
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Biopsy may not be required for acute sarcoidosis presentations (Löfgren’s and Heerfordt’s)
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The easiest biopsy target should be pursued first (eg, skin, conspicuous peripheral lymph node)
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Bronchoscopy is often required:
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Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of thoracic lymph nodes, followed by transbronchial biopsy if aspirate is nondiagnostic (or if rapid on-site evaluation [ROSE]) is not available
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This approach has a high sensitivity and specificity for both ruling out other entities (eg, malignancy) and making the diagnosis (> 90% yield)
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In the absence of adenopathy (stage 3), performing random transbronchial biopsies (eight samples, multiple segments, one side) also has a high diagnostic yield (~ 85%)
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Angiotensin-converting enzyme (ACE) is produced by granulomas, and levels are elevated in 60% of patients with sarcoidosis
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Limited diagnostic utility, given that the positive and negative predictive values are 84% and 74%, respectively
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Sarcoidosis Clinical Presentations (Acute, Stages 1–3, Stage 4, and Unique)
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Acute sarcoidosis (Löfgren’s and Heerfordt’s syndromes) represents ~ 20% of clinical presentations ( Fig. 14.1 )
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All have bilateral hilar adenopathy and fever with extrapulmonary manifestations
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Löfgren’s syndrome
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Bilateral, symmetric ankle or knee arthritis
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Lasts for weeks; treat pain with nonsteroidal antiinflammatory drugs (NSAIDs)
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More common in men
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Erythema nodosum
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More common in women
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Occurs in ~ 10% of acute sarcoid presentations
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Nonspecific, painful raised nodules on the lower extremities (shins)
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Caused by a nonspecific septal panniculitis such that biopsy is not useful for diagnosis of sarcoid
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Lasts for weeks; treat pain with NSAIDs
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90% spontaneous resolution of adenopathy (within 2 years)
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No biopsy or treatment required
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Heerfordt’s syndrome (a.k.a. uveoparotid fever)
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Uveitis and parotid gland swelling
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Unilateral facial nerve palsy
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Diagnosis confirmed by lacrimal gland biopsy or gallium scan showing the lambda panda sign
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Characteristic, symmetric uptake in the lacrimal, parotid, submandibular glands and thoracic lymph nodes
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Treat with prednisone
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Fig. 14.1
Clinical radiographic aspects of the two most common acute sarcoid presentations, Löfgren’s and Heerfordt’s. Both share the features of hilar adenopathy and fever. Löfgren’s features the extrapulmonary manifestations of symmetric knee/ankle arthritis and/or Erythema nodosum. Heerfordt’s (a.k.a. uveoparotid fever) is more serious, given that the cranial nerve VII (facial nerve) is commonly involved. Because of this, prednisone is indicated. Although the clinical syndrome of uveitis, parotitis coupled with the lambda panda sign, is sensitive and specific, lacrimal gland biopsy is a low-morbidity, high-yield procedure for the diagnosis of Heerfordt’s.
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Stage 1 sarcoidosis presentation: hilar and mediastinal adenopathy without parenchymal involvement on chest computed tomography (CT) scan ( Fig. 14.2 )
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Majority of cases are incidentally discovered by a chest x-ray obtained for another reason (eg, preoperatively)
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May have mild pulmonary symptoms (eg, dry cough, dyspnea, chest pain/tightness, wheezing)
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Systemic symptoms (eg, fatigue, night sweats, and weight loss) occur less commonly
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The differential diagnosis of stage 1 sarcoid is the same as the differential for isolated hilar and mediastinal adenopathy:
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Primary tuberculosis (TB), endemic fungal infection, lymphoma, small cell lung cancer, and metastatic adenocarcinoma (eg, breast, colon)
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Evaluation ( Fig. 14.3 )
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Immunologic workup:
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Quantiferon testing
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A positive quantiferon should prompt sputum sampling for mycobacterium tuberculosis (MTB)
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Complement fixation test for coccidioidomycosis and serum cryptococcal antigen (CrAg) in endemic areas or exposed individuals (sensitive and specific for active disease)
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A positive complement fixation titer (may take 6 weeks to occur) implies active disease and should prompt consideration for treatment
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One should not attempt to biopsy or process tissue specimens containing cocci because it is a hazard to laboratory workers (and diagnosis can be made serologically)
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Significant peripheral eosinophilia or the presence of a pleural effusion in the right patient (ie, young, no cancer risk factors) may increase the suspicion for cocci enough to warrant waiting 4–6 weeks to repeat complement fixation titer before lymph node biopsy
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A negative workup for active TB or coccidioidomycosis necessitates tissue sampling/biopsy:
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Any new raised or nodular skin lesions should be evaluated for biopsy (except erythema nodosum)
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Peripheral adenopathy is less helpful unless it is conspicuously pathologic
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If skin/peripheral targets are nonexistent, or nondiagnostic, a mediastinal/hilar lymph node biopsy is indicated
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The highest yield approach involves EBUS-TBNA of thoracic lymph nodes with flow cytometry to rule out lymphoma
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If cytology specimens are nondiagnostic (or not available in real time), additional endobronchial and transbronchial specimens should be considered when clinical suspicion is high (even in the absence of visualized disease)
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Fig. 14.3
Flow diagram outlining the workup of possible stage 1 sarcoidosis. Evaluation hinges on excluding infectious and/or malignant causes of hilar and mediastinal adenopathy. Tuberculosis (TB), coccidioidomycosis, and cryptococcosis can (and should) be screened for immunologically. The remainder of diseases are ruled out by lymph node aspirate/biopsy.
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