Sarcoidosis differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

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Differential Diagnosis

Sarcoidosis has many differentials, which can be classified depending on the organ involved.

Lung

1.Tuberculosis 2.Atypical Mycobacteriosis 3.Cryptococcosis 4.Aspergillosis 5.Aspiration of foriegn materials 6.Blastomycosis 7.Pneumocystitis carinii 8.Pneumoconiosis 9.Drug reactions 10.Hypersensitivity pneumonitis 11.Drug reactions12..Histoplasmosis 13.Chronic interstitial pneumonia 14.Necrotizing sarcoid granulomatosis 15.Wegner's granulomatosis

Lymph Node

1.Tuberculosis 2.Atypical Mycobacteriosis 3.Brucellosis 4.GLUS syndrome 5.Cat scratch disease 6.Toxoplasmosis 7.Hodgkin disease 8.Non Hodgkin lymphoma 9.Sarcoid reaction in lymph nodes to carcinoma 10.Kikuchi disease(granulomatous histiocytic necrotizing lymphadenitis)

Skin

1.Tuberculosis 2.Atypical mycobacteriosis 3.Fungal infection 4.Rheumatoid nodules 6.Reaction to foreign bodies

Liver

1.Tuberculosis 2.Brucellosis 3.Schitosomiasis 4.Crohn's disease 5.Hodgkin's disease 6. Non hodgkin's lymphoma 7.GLUS syndrome 8.Primary biliary cirrhosis

Bone Marrow

1.Tuberculosis 2.Histoplasmosis 3.Cytomegalovirus 4.Drugs 5.Infectious Mononucleosis 6.GLUS syndrome 7.Hodgkin's disease 8.Non Hodgkin's lymphoma

Other biopsy sites

1.Tuberculosis 2.Brucellosis 3.Crohn's disease 4.GLUS Syndrome 5.Other infections 6.Giant cell myocarditis

Differential diagnosis

Causes of lung cavities	Differentiating Features	Differentiating radiological findings	Diagnosis confirmation
Malignancy (Primary lung cancer)	Elderly male or female Chronic smokers Presents with a low-grade fever, absence of leukocytosis, systemic complaints weight loss, fatigue Absence of factors that predispose to gastric content aspiration, no response to antibiotics within 10 days Hemoptysis is commonly associated with bronchogenic carcinoma	A coin-shaped lesion with thick wall(>15mm) is seen on CXR with less ground glass opacities Bronchoalveolar lavage cytology shows malignant cells	Biopsy of lung
Pulmonary Tuberculosis	Mostly in endemic areas Symptoms include productive cough,night sweats, fever and weight loss	CXR and CT demonstrates cavities in the upper lobe of the lung	Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
Necrotizing Pneumonia	Any age group Acute, fulminant life threating complication of prior infection >100.4F fever, with hemodynamic instability Worsening pneumonia-like symptoms	CXR demonstrates multiple cavitary lesions Pleural effusion and empyema are common findings	CBC is positive for causative organism
Loculated empyema	Children and elderly are at risk Pleuritic chest pain, dry cough, fever with chills Dullness to percussion decreased breath sounds, and reduced vocal resonance on examination	Empyema appears lenticular in shape and has a thin wall with smooth luminal margins	Thoracocentesis
Granulomatosis with polyangiitis (Wegener's)	Women are more commonly effected than man. Kidneys are also involved Upper respiratory tract symptoms , perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract symptoms, hemoptysis, cough, dyspnea. Renal symptoms, hematuria, red cell casts	Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR	Positive for P-ANCA Biopsy of the tissue involved shows necrotizing granulomas
Rheumatoid nodule	Elderly females of 40-50 age group Manifestation of rheumatoid arthritis Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations.	Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on Xray.	Positive for both rheumatoid factor and anticyclic citrullinated peptide antibody.
Sarcoidosis	More common in African-American females Often asymptomatic except for enlarged lymph nodes Associated with restrictive lung disease Erythema nodosum Lupus pernio (skin lesions on face resembling lupus) Bell palsy Epithelioid granulomas containing microscopic Schaumann and asteroid bodies	On CXR bilateral adenopathy and coarse reticular opacities are seen. CT of the chest demonstrates extensive hilar and mediastinal adenopathy Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.	Biopsy of lung shows non-caseating granuloma
Bronchiolitis obliterans (Cryptogenic organizing pneumonia)	Rare condition and mimics asthma, pneumonia and emphysema It is caused by drug or toxin exposure, autoimmune diseases, viral infections, or radiation injury People working in industries are at high risk Presents with fever, cough, wheezing and shortness of breath over weeks to months,	Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.	Biopsy of the lung Pulmonary function tests demonstrate low fev1/fvc
Langerhans cell Histiocytosis	Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years. Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats and weight loss. Skin is involved in 80% of the cases, scaly erythematous rash is typical.	Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.	Biopsy of the lung

Sarcoidosis must be differentiated from other diseases that cause bone pain, edema, and erythema.

Disease	Findings
Soft tissue infection (Commonly cellulitis)	History of skin warmness, swelling and erythema. Bone probing is the definite way to differentiate them.
Osteonecrosis (Avascular necrosis of bone)	Previous history of trauma, radiation, use of steroids or biphosphonates are suggestive to differentiate osteonecrosis from ostemyelitis. MRI is diagnostic.
Charcot joint	Patients with Charcot joint commonly develop skin ulcerations that can in turn lead to secondary osteomyelitis. Contrast-enhanced MRI may be diagnostically useful if it shows a sinus tract, replacement of soft tissue fat, a fluid collection, or extensive marrow abnormalities. Bone biopsy is the definitive diagnostic modality.
Bone tumors	May present with local pain and radiographic changes consistent with osteomyelitis. Tumors most likely to mimic osteomyelitis are osteoid osteomas and chondroblastomas that produce small, round, radiolucent lesions on radiographs.
Gout	Gout presents with joint pain and swelling. Joint aspiration and crystals in synovial fluid is diagnostic for gout.
SAPHO syndrome (Synovitis, acne, pustulosis, hyperostosis, and osteitis)	SAPHO syndrome consists of a wide spectrum of neutrophilic dermatosis associated with aseptic osteoarticular lesions. It can mimic osteomyelitis in patients who lack the characteristic findings of pustulosis and synovitis. The diagnosis is established via clinical manifestations; bone culture is sterile in the setting of osteitis.
Sarcoidosis	It involves most frequently the pulmonary parenchyma and mediastinal lymph nodes, but any organ system can be affected. Bone involvement is often bilateral and bones commonly affected include the middle and distal phalanges (producing “sausage finger”), wrist, skull, vertebral column, and long bones.
Langerhans' cell histiocytosis	The disease usually manifests in the skeleton and solitary bone lesions are encountered twice as often as multiple bone lesions. The tumours can develop in any bone, but most commonly originate in the skull and jaw, followed by vertebral bodies, ribs, pelvis, and long bones.

must be differentiated from other causes of hypercalcaemia

Differential diagnosis of hyperparathyroidism on the basis of hypercalcemia
Disorder		Mechanism of hypercalcemia	Clinical features	Laboratory findings				Imaging & diagnostic modalities
				PTH	Calcium	Phosphate	Other findings
Hyperparathyroidism	Primary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a primary process in parathyroid gland. Parathyroid hormone causes increase in serum calcium.	Usually asymptomatic Hypercalcemia detected on routine biochemical panel	↑	↑	↓/Normal	Normal/↑ calcitriol	Findings of bone resorption: X-ray Dual energy X-ray absorptiometry (DXA) Preoperative localization of hyperfunctioning parathyroid gland: Non-Invasive Tc-99m sestamibi scintigraphy Neck ultrasound 4D-CT SPECT(P-SPECT) PET MRI Invasive: Super sensitive venous sampling Selective arteriography Angiography Predicting post-operative success: Intraoperative parathyroid hormone monitoring
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods.	May present with history of: Chronic renal failure Vitamin D deficiency	↑	↓/Normal	↑	--
	Tertiary hyperparathyroidism	Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes increase in serum calcium.	Usually present with history of kidney transplant Usually hyperplasia of all four parathyroid glands	↑	↑	↑	--
Familial hypocalciuric hypercalcemia		This is a genetic disorder caused my mutation in calcium-sensing receptor gene.	A benign condition Does not require treatment	Normal/↑	Normal/↑	--	--	Urinary calcium/creatinine clearance ratio
Malignancy	Humoral hypercalcemia of malignancy	Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone.	Most common cause of malignancy related hypercalcemia Usually present with solid tumors	--	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol	Chest X-ray CT scan MRI
	Osteolytic tumors	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.	Commonly present in multiple myeloma and breast cancer	↓	↑	--	--	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	Production of calcitirol	Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia.	Commonly present in lymphomas and in some ovarian germ cell tumors	--	↑	--	↑ Calcitriol	CT scan MRI
	Ectopic parathyroid hormone	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process	↑	↑	↓/Normal	Normal/↑ calcitriol	Chest X-ray CT scan MRI
Medication induced	Lithium	Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormone and enlargement if parathyroid gland after weeks to months of therapy.	History of mood disorder	↑	↑	--	--	Lithium levels
	Thiazide diuretics	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia.	History of cardiac disorder Rarely causes hypercalcemia	--	↑	--	--	--
Nutritional	Milk-alkali syndrome	Hypercalcemia is be caused by high intake of calcium carbonate.	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.	--	↑	--	--	Renal function tests
	Vitamin D toxicity	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D Topical application of vitamin D analogue calcipotriol	--	↑	--	↑ Vitamin D (calcidiol and/or calcitriol)	--
Granulomatous disease	Sarcoidosis	Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	--	↑	--	↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy