Sarcoidosis Dr. Sagar A Gandhi

Resident Department of pulmonary medicine

GMCH , Nagpur

Introduction

• Jonathan Hutchinson was the first to describe a case of sarcoidosis in 1887;

• He called it Mortimer’s malady, after one of his patients who presented with face and limb skin lesions.

Sarcoidosis is a multisystem disorder of unknown

etiology characterized by non caseating granuloma

which affects mainly lungs but can also occur in other

organs .

Caseating granulomasTB

Non caseating granulomasSarcoidosis

Epidemiology • It occurs mainly in 3rd or 4th decade of life

• > 80 % cases in age group 20 – 50 yrs

• Prevalence is 10 to 40 cases / 100000.

• Persistent disease with greater mortality found in blacks and women .

• Mortality is 1 to 5 %

Etiology and Pathogenesis• Remains unknown, but several lines of evidence suggest that it is a

disease of disordered immune regulation in genetically predisposed individual.

• The mycobacterial catalase-peroxidase protein (mKatG) is a pathogenic antigen.

• Other mycobacterial antigens including . mKatG, . Mycobacterium tuberculosis ESAT-6, . Ag85, . superoxide dismutase

Etiology and Pathogenesis

Also suspected of having a causative role are Borrelia burgdorferriChlymadia pneumoniaRickettsia

VirusesEBV,CMV, HHV-6, HTLV 1 :::::> B cell activation

Etiology and Pathogenesis

Genetic factorsAssociated with HLA class I, HLA B8, HLA-DR3,HLA-DR B1-1101, HLA-DRB1-1501

Not associated withNon HLA, ACE , Vit D, HLA DR1 , HLA DR4, HLA DR17

T cells, Macrophages

Chemoattractants Growth Factors

Cellular proliferation Granuloma

Fibrosis

Overall Pathogenesis

Pathogenesis• These process are driven by CD4+T Cell.• Increase levels of T-cell derived TH 1 cytokines.

• The antigenic triggering agents cause activation of the Helper T-cell and Macrophages.

• Activated Helper T-cell and Macrophages produce IL-2, IFN and TNF.

• complex interaction of cytokines cause Inflammatory response leading to granuloma.

Pathogenesis

Pathophysiology• Granulomas are Pathologic hall mark of sarcoidosis.

• Giant cells are collection of fused Macrophages-Langerhans giant cells found in the central part of the granuloma

• The central epithelioid and giant cells are surrounded by a rim of lymphocytes,

mostly T-helper cells

Histologically

• All involved tissues show the classic well formed non-caseating granuloma.

• composed of an aggregates of tightly clustered epithelioid cell with langerhans or foreign body giant cell.

• central necrosis is unusual.

• With chronicity the granulomas may become enclosed within fibrous rimes or may be eventually be replaced by hyaline fibrous scars.

LANGHANS' GIANT CELL

Langhans' giant cell in center of granuloma is surrounded by epithelioid cells

Asteroid bodiesstellate inclusion enclosed with in giant cells are formed in

approximately 60% of granulomas

Asteroid bodies

Asteroid bodies

CYTOPLASMIC INCLUSION BODY Schaumann body (arrow)

laminated concentration composed of calcium and proteins

ADVANCED COLLAGENOUS FIBROSIS Elongated fibroblasts (FB) with extensive collagenous tissue

(C). Giant cells (arrows)

Systems affected by sarcoidosisSystems Percentage

Pulmonary 90%Lymph nodes 70%Hepatic 50-80%Cardiac 30%Cutaneous 25%Ocular 20%Spleen 18%Bones 14%Neurogenic 5%

C.PSarcoidosis

Asymptomatic 50%

Respiratory symptoms

Cough

Dyspnea

expectoration

Constitutionalsymptoms

Fatigue

Weight loss

Night sweats

Erythema nodosum

Pulmonary sarcoidosis

Pulmonary Sarcoidosis• It is the First site of involvement.

• Begin with alveolitis involving small bronchi and small blood vessels.

• Alveolitis either clear up spontaneously or lead to granuloma or fibrosis.

Pulmonary Sarcoidosis

Microscopically..

There is usually no demonstrable alteration , although in advanced cases granuloma produce small nodule that are palpable or visible as 1 to 2 cm noncaseating, noncavitary consolidation.

Pulmonary Sarcoidosis

Histologically.• The lesion are distributed primarily along the lymphatics,

around the bronchi and blood vessels.Although alveolar lesion are also seen in relative frequency.• The granulomas in the bronchial sub mucosa account for

the high diagnostic yield of bronchoscopic biopsy.• There seems to be a strong tendency for lesion to heals in

the lungs, so varying stages of fibrosis, hyalinization are not found.

CASEOUS NECROSISCellular destruction in TB granuloma appears as clumped debris

(arrows). This necrosis does not occur in sarcoidosis.

Noncaseating granuloma in lung is the characteristic lesion of sarcoidosis.

SUBPLEURAL GRANULOMA IN LUNG

Paradoxical response

One of the distinguishing features of sarcoidosis.As the lung disease worsens, the nodal enlargement usually regresses.

Nodal enlargementLung disease

Parenchymal sarcoidosisTypical

Interstitial micro-nodules

Fibrosis

Atypical Pulmonary nodules &

masses

Consolidation

Ground glass opacification

Linear reticular opacities

Fibrocystic changes

Miliary opacities

Airway involvement

Pleural disease

InterstitiumCentral

Peribronchovascular

PeripheralInterlobu

larSubpleur

al

Bilateral perihilar predominance

Atypical parenchymal sarcoidosisMilliary opacities

CT shows well defined lung nodules less than 5mm in diameter.

Rare 1%

ALVEOLAR SARCOIDOSIS Multiple lung masses are an unusual form of

Sarcoidosis, resembles lung metastases.

Atypical parenchymal sarcoidosisLinear reticular opacities

15-20%

Atypical sarcoidosisPulmonary consolidation

10-20%

PNEUMONIC APPEARANCE Confluent acinar opacities look similar to pneumonic

consolidation.

Atypical parenchymal sarcoidosisPulmonary nodules or masses

15-25 %

Sarcoid Galaxy sign

NODULAR PATTERN Small 5mm nodules are subpleural, along fissures and bronchovascular bundles. Give the vessels (arrow) and

fissures a beaded appearance.

Nodular thickening of the peri-broncho-vascular interstitium

Sub-pleural nodules

Fissure nodules

Lymph nodes with rim (eggshell) calcification are rare in sarcoidosis but common in silicosis.

Atypical parenchymal sarcoidosisPatchy ground glass opacities

40%

Pleural disease

Rare < 1%• Pleural effusion.• Hemothorax.• Chylothorax (due to involvement of the mediastinal LN or thoracic duct).

Air way involvement

• May occur at any level• Bronchial wall thickening• Luminal abnormalities• Obstruction of lobular or

segmental bronchi• Mosaic perfusion• Air-trapping on

expiration

Air trapping seen on expiration

I II

III IV

STAGE I Thoracic Lymphadenopathy.

Normal lung parenchyma. (50%)

STAGE II Hilar and mediastinal Lymphadenopathy.

Abnormal lung parenchyma. ( 30% )

STAGE III pulmonary infiltrates with No Lymphadenopathy.

STAGE IV Extensive pulmonary fibrosis is typically worst in the

upper lobes.

Upper lobe predominance

STAGE IV Broad bands of fibrosis in the upper lobes

STAGE IV Permanent lung fibrosis. (20%)

MOST COMMON PATTERN Bilateral symmetric hilar and right paratracheal

mediastinal adenopathy.

Differential Diagnosis of Noncaseating Granulomas

TBFungal infectionsLymphomaEpithelioid tumors of the breastLung cancer

Clinical Presentation– Most patients have the pulmonary manifestations, most commonly presenting with incidental findings on

CXR.

– Interstitial disease

– Symptoms include dry cough, dyspnea, and chest discomfort

– Unpredictable course

PROGNOSIS OF PULMONARY SARCOIDOSIS

Prognosis of pulmonary sarcoidosis

3/4

Complete resolution of

hilar lymphadenopathy

1/3

Complete resolutionof

parenchymaldisease

1/5

Irreversiblepulmonary

fibrosis

LYMPH NODES sarcoidosis

Sarcoidosis of Lymph nodesLymph nodes are involved in almost all cases

particularly the hilar and medistinal nodes.

Any other nodes may be involved.

Nodes are characteristically enlarged discrete and sometimes calcified.

Tonsil may affected in about quarter to one third of the cases

Lymphadenopathy

Lymphadenopathy Typical

Bilateral hilar & right paratracheal LN. Middle mediastinal LN occur in 50% of cases.

Left paratracheal, aorto-pulmonary & subcarinal LN.

1-2-3 sign present in 95% of cases. This is called Garland triad

Differential Diagnosis ofbilateral hilar LN

Granulomatous infectionsTBHistoplasmosisCoccidiomycosisAutoimmune disordersMalignancy (Lymphoma)

Lymphadenopathy

Lymphadenopathy

Lymphadenopathy

Lymphadenopathy

Enlarged bilateral hilar, right paratracheal (arrow), and aortopulmonary window (arrowhead) nodes.

Lymphadenopathy Atypical

Unilateral hilar LN.

Anterior or posterior mediastinal LN.

LN calcification (amorphus, punctate, popcorn or eggshell calcification).

DD of calcified hilar or mediastinal LN

• Silicosis• Sarcoidosis.• TB.• Treated lymphoma.

Calcified hilar & mediastinal LN

Calcified hilar & mediastinal LN

PARACARDIAC LYMPH NODE

ABDOMINAL LYMPHADENOPATHY Multiple enlarged paraaortic, paracaval, and porta

hepatis lymph nodes (arrows).

CUTANEOUS sarcoidosis

Skin 33% have skin lesions

Cutaneous anergy is common.

NAKED GRANULOMA Young granulomas (arrows) in the skin with no

surrounding rim of mononuclear cells.

ERYTHEMA NODOSUM These reddish raised lesions

Erythema Nodosum

Erythema nodosum

Lofgren syndrome• Acute sarcoidosis characterized by triad • Also lupus pernio is never present in lofgren syndrome

Lofgren syndrome

Bilateral hilar

lymphadenopathyArthritis Erythema

nodosum

Skin Lupus pernio- by besnier

• indurated blue purple swollen shiny lesions on nose, cheeks, lips, ears and fingers.

• Papules, nodules, and plaques

• Psoriatic like lesions

• Lesions in scars and tattoos

LUPUS PERNIO Facial lesions are most common, but the extremities

and buttocks can be involved.

LUPUS PERNIO Indurated and violaceous range from a few small lesions to large

lesions

PSORIASIS LIKE LESIONS These small white lesions closely resemble psoriasis.

OCCULAR sarcoidosis

Eyes25% have eye lesions

Blurred vision, pain, photophobia and dry eyes

Chronic uveitis leads to glaucoma, cataracts and blindness

Keratoconjunctivitis sicca

Papilloedema

CONJUNCTIVITIS

PAPILLEDEMA Often associated with 7th nerve facial palsy.

Sarcoid Choreoretinitis

Heerfordt’s syndrome

• Acute sarcoidosis characterized by uveoparotitis

Heerfordt’s syndrome

Uveitis Parotitis Facial palsy

Heerfordt’s syndrome

Bilateral parotitis

Panda sign

• Bilateral lacirmal gland, parotid gland & normal nasopharyngelal uptake on

Ga-67 scintigraphy.

LIVER sarcoidosis

Liver• 33% have hepatomegaly or biochemical

evidence of disease

• Symptoms usually absent

• Cholestasis, fibrosis, cirrhosis, portal hypertension, and the Budd-Chiari syndrome have been seen

SPLEEN & LIVER GRANULOMAS The small low attenuation lesions in the liver and spleen

in sarcoidosis.

MUSCULOSKELETAL SARCOIDOSIS

Musculoskeletal sarcoidosis

•Arthralgia (Lofgren syndrome).Joints•Myopathic type•Nodular type.Muscles• Lace like lytic lesion +

(tendosynovitis).• Cytic lesions.• Sclerotic lesions.

Osseous sarcoidosis

Arthritis Acute polyarthritis with fever is common

Arthritis is self limited

Polymyositis and chronic myopathy

Chronic destructive bone disease with deformity is rare

Musclar nodular sarcoidosis

Low signal intensity centre due to fibrosis.

Sarcoid dacytilits

• Tenosynovitis + lace like lytic lesion

LACY TRABECULAR PATTERN Osteolysis has left a lacy trabecular pattern in this

phalanx (arrow)

PUNCHED OUT LYTIC LESIONS Focal osteolytic lesions in the fingers are most

common abnormality.

SCLEROTIC LESION Rare and often in the axial skeleton.

NERVOUS SYSTEM

SARCOIDOSIS

Neurosarcoidosis• Periventricular white matter lesions• Enhancing nodules or massesParenchymal S

• Dural masses.• Diffuse dural thickeningPachymeningeal S

• Basal cisterns.• Cerebral sulci or cerebellar fissures.• Virchow Robin perivascular spaces.

Leptomeningeal S

• Thickening & enhancement.Pituitary / hypothalamic S

• Optic nerves.• Facial nerves.Cranial nerve S

• Osteolytic lesion with well defined non sclerotic margin.Calvarial sarcoidosis

Nervous SystemCranial nerves, and peripheral nerves can be

involved

7th nerve facial palsy is most common

Acute, transient, and can be unilateral or bilateral

KIDNEY SARCOIDOSIS

KidneyGranulomatous interstitial nephritis produces

renal failure

Develops over a period of weeks to months

Rapid response to steroid therapy

Kidney stones (nephrolithiasis) and nephrocalcinosis are very unusual

secondary to hypercalcemia and hypercalciuria

KidneyIncreased calcium absorption in the gut

Related to high levels of circulating 1,25-dihydroxy vitamin D produced by

mononuclear phagocytes in granulomas

GASTRIC SARCOID Granuloma involves the gastric antrum leading to

irregular nonspecific narrowing.

COLONIC SARCOID Irregular narrowing of the rectosigmoid has the

appearance of inflammatory disease or malignancy.

Lab Abnormalities Lymphocytopenia

Mild eosinphilia

Increased E.S.R

Hyperglobulinemia

Lab AbnormalitiesElevated level of angiotensin converting enzyme(ACE)

Bronchioalveolar lavage shows increased lymphocytes

Lab Abnormalities• ACE levels elevated 60- 80%.

• Activated macrophages produce ACE.

• Non Specific- Also in Hodgkins,histoplasma,leprosy • ACE levels tested regularly to check the severity of

the disease and to monitor the response to therapy.

Lung Function TestMay be normal

Restrictive pattern DLCO, FEV1, FVC

Obstructive impairment in advanced fibrocystic disease Bronchial hyperresponsiveness responding to

bronchodilator therapy

DiagnosisIdentify noncaseating granulomas.

Variety of infections.

Difficult to differentiate from chronic infections, fungal diseases, T.B. and lymphoma.

Based on combined Clinical + radiological + histological findings.

DiagnosisTransbronchial biopsies positive in 65-95%, even if no lung parenchymal abnormalities imaged.

Tissue from mediastinoscopy positive in 95%

Scalene node biopsy positive in 80%

DiagnosisKVEIM TEST

Involves injecting standardized preparation of sarcoid tissue material into the skin.

Unique lump formed at the point of injection is considered positive for sarcoidosis.

Kveim test - skin biopsyNon-necrotizing granulomas

Prognosis

• Good• In 15-20% remains active or reccurs

intermittently. • 50% have some permanent organ

dysfunction

ADENOPATHY AT TIME OF DIAGNOSIS Marked enlarged hilar and mediastinal lymph nodes.

ADENOPATHY DECREASED 2 YRS LATER Lymph nodes are smaller and there is parenchymal

lung disease.

Treatment• No known cure• Corticosteroids, primary treatment for

inflammation and granuloma formation.• Prednisolone, 1 mg/kg for 4-6 weeks

followed by slow taper over 2-3 months.• Mostly given for 6 to 24 months• Early taper results in relapse• Inhaled steroid limited effect• 20 % reccurance

Treatment

Cutaneous Sarcoidosis-

Topical steriods/Hydroxychloroquine.

Chloroquine in lupus pernio

IMMUNOSUPPRESANTS• Methotrexate - Prednisolone not

tolerated/not effective/steriod sparing agent.

• MTX –Start with 10mg/week and maintain with 2.5 to 15mg/week.

• CBC,KFT,LFT/2months.

Treatment

ANTI-TNF • Infliximab• Etanercept• Adalimumab

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