SARCOIDOSIS

Dr.Md.Mizanur Rahman Chowdhury

SARCOIDOSISDefinition :Sarcoidosis is a multisystem disorder of unknown etiology characterized by non caseating granuloma which affects mainly lung but can also any other organs .

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

More predominant in women with an incidence of 6.3 vs 5.9 cases per 100,000 person-years.

Lifetime risk for US whites is 0.85 percent compared with 2.4 percent in US blacks.

More prevalent in Swedes, Danes, and US blacks.

EPIDEMIOLOGYAnnual incidence in the U.S. is 10/100,000

among whites and 36/100,000 among African Americans.

Most commonly seen in the mid-Atlantic and Southern Atlantic states but rare in the Southwest.

Affects siblings of first- or second- degree relatives in 15% of patients with sarcoidosis.

Familial cases described in 17% of African Americans, but only 6% of whites.

ETIOLOGY AND PATHOGENESISEtiology of sarcoidosis is remain unknown, but

several lines of evidence suggest that it is a disease of disordered immune regulation in genetically predispose individual.

Immunological FactorThere are several immunological abnormalities

in the granuloma of sarcoidosis that suggest the development of cell mediated response to an unidentified antigen. These process are driven by CD4+T Cell.

ETIOLOGY AND PATHOGENESISIntra-alveolar and interstitial

accumulation of CD4+T cell ,resulting CD4/CD8 T cell ratio ranging from 5:1 to 15:1.There is oligoclonal expansion of T-cell subsets as determined by analysis of T cell receptor rearrangement, suggesting an antigen driven proliferation.

Increase levels of T-cell derived TH 1 cytokines such as IL-2 and IFN-у resulting in T-cell expansion and macrophage activation respectively.

ETIOLOGY AND PATHOGENESISIncrease levels of cytokines in the local envirment (IL-8,Macrophage inflammatory protein 1 α ) that favour recruitment of additional T cell and Macrophage and contribution to the formation of granulomas. TNF in particular release of high levels by activated alveolar macrophage and the TNF concentration in the broncho alveolar fluid is a disease activity.

T cells, Macrophages

Chemoattractants Growth Factors

Cellular proliferation Granuloma

Fibrosis

Overall Pathogenesis

PATHOGENESIS

PATHOGENESIS

PATHOGENESOS

PATHOGENESIS

PATHOGENESIS

ETIOLOGY AND PATHOGENESIS

Genetic FactorEvidence of genetic influences are the familial and racial clustering of cases and the association with certain HLA genotypes

(eg:HLA-A1and HLA-B8)

ETIOLOGY AND PATHOGENESIS Envirment factorThese are possibly the most tenuous of all the associations in the pathogenesis of sarcoidosis. As with many other diseases of unknown etiology, suspicion fall on microbes. Indeed several putative microbes have been proposed as the inciting agent for sarcoidosis (eg-mycobacteria, propionobacterium acnes, Rickettsia species)

MORPHOLOGY

Histologically all involved tissues show the classic well formed noncaseating granuloma, each composed of an aggregates of tightly clustered epithelioid cell, often with langhans 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.

MORPHOLOGYlaminated concentration composed of calcium and proteins known as schaumann bodies and stellate inclusion as asteroid bodies enclosed with in giant cells are formed in approximately 60% of granulomas.though characteristic these microscopic features are not pathognomic of sarcoidosis because asteroid and schaumann bodies may be encounteered in other granulomatous disease

LANGHANS' GIANT CELL LANGHANS' GIANT CELL IN CENTER OF GRANULOMA IS SURROUNDED BY EPITHELIOID CELLS

ADVANCED COLLAGENOUS FIBROSIS ELONGATED FIBROBLASTS (FB) WITH EXTENSIVE COLLAGENOUS TISSUE (C). GIANT CELLS (ARROWS)

CYTOPLASMIC INCLUSION BODY SCHAUMANN BODY (ARROW) IS COMMON IN SARCOIDOSIS BUT IS NONSPECIFIC.

CYTOPLASMIC INCLUSION BODY SCHAUMANN BODY (ARROW)

ASTEROID BODIES

ASTEROID BODIES

ASTEROID BODIES

SYSTEMS AFFECTED BY SARCOIDOSIS

Systems Percentage

Pulmonary 90%

Lymph nodes 70%

Hepatic 50-80%

Cardiac 30%

Cuteneous 25%

Ocular 20%

Spleen 18%

Bones 14%

Neurogenic 5%

PULM0NARY SARCOIDOSIS

PULMONARY SARCOIDOSISFirst side of involvement

Begain with alveolitis involving small bronchi and small blood vessels

Alvveolitis either clear up spontaneously or lead to granuloma or fibrosis

PULMONARY SARCOIDOSIS

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

PULMONARY SARCOIDOSISHistologically. The lesion are distributed primarily along the lymphatic's, 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

NONCASEATING GRANULOMA IN LUNG IS THE CHARACTERISTIC LESION OF SARCOIDOSIS.

CASEOUS NECROSISCELLULAR DESTRUCTION IN TB GRANULOMA APPEARS AS CLUMPED DEBRIS (ARROWS). THIS NECROSIS DOES NOT OCCUR IN SARCOIDOSIS.

M. TUBERCULOSIS BACILLI CASEOUS NECROSIS IS MOST COMMON IN TB, BUT GRAM NEGATIVE, ACID FAST BACILLI MUST BE IDENTIFIED TO MAKE THE DIAGNOSIS.

SUBPLEURAL GRANULOMA IN LUNG

STAGE I THORACIC LYMPHADNOPATY. NORMAL LUNG PARENCHYMA. (50%)

STAGE II HILAR AND MEDIASTINAL LYMPHADNOPATY. ABNORMAL LUNG PARENCHYMA. ( 30% )

STAGE III ABNORMAL LUNG PARENCHYMA. NO LYMPHADNOPATY. ( 15% )

STAGE IV EXTENSIVE PULMONARY FIBROSIS IS TYPICALLY WORST IN THE UPPER LOBES.

STAGE IV BROAD BANDS OF FIBROSIS IN THE UPPER LOBES

MILIARY SARCOIDOSIS CT SHOWS WELL DEFINED LUNG NODULES LESS THAN 5MM IN DIAMETER. THIS PATTERN IS RARE

ALVEOLAR SARCOIDOSIS MULTIPLE LUNG MASSES ARE AN UNUSUAL FORM OF SARCOIDOSIS, RESEMBLES LUNG METASTASES.

ALVEOLAR SARCOIDOSIS COMPUTED TOMOGRAPHY SHOWS A MASS WHICH HAS AIR CONTAINING BRONCHI (ARROWS) WITHIN IT.

CAVITARY SARCOIDOSIS RARE PATTERN OF MULTIPLE CAVITARY SARCOID LUNG LESIONS. NOTE LYMPHADNOPATY.

RETICULONODULAR PATTERN COMMON APPEARANCE OF SARCOIDOSIS INVOLVING THE LUNG PARENCHYMA.

RETICULONODULAR PATTERN CLOSEUP WELL DEFINED LINEAR AND NODULAR DENSITIES CHARACTERISTIC OF LUNG INTERSTITIAL DISEASE.

ACINAR PATTERN POORLY DEFINED NODULAR OPACITIES ARE THE SIZE OF PULMONARY ACINI (6MM).

PNEUMONIC APPEARANCE CONFLUENT ACINAR OPACITIES LOOK SIMILAR TO PNEUMONIC CONSOLIDATION.

NODULAR PATTERN SMALL 5MM NODULES ARE SUBPLEURAL, ALONG FISSURES AND BRONCHOVASCULAR BUNDLES. GIVE THE VESSELS (ARROW) AND FISSURES A BEADED APPEARANCE.

LYMPH NODES WITH RIM (EGGSHELL) CALCIFICATION (ARROW) ARE RARE IN SARCOIDOSIS BUT COMMON IN SILICOSIS.

MOST COMMON PATTERN BILATERAL SYMMETRIC HILAR AND RIGHT PARATRACHEAL MEDIASTINAL ADENOPATHY.

STAGE IV PERMANENT LUNG FIBROSIS. (20%)

DIFFERENTIAL DIAGNOSIS OF NONCASEATING GRANULOMAS

TBFungal infectionsLymphomaEpithelioid tumors of the breastLung cancer

DIFFERENTIAL DIAGNOSIS OF BHL

Granulomatous infectionsTBHistoplasmosisCoccidiomycosisAutoimmune disordersMalignancy (Lymphoma)

CLINICAL PRESENTATION

Most patients have the pulmonary manifestations, most commonly presenting with incidental findings on CXR.

Interstitial diseaseSymptoms include dry cough, dyspnea, and chest discomfort

Unpredictable course

PROGNOSIS OF PULMONARY SARCOIDOSIS

LYMPH NODES sarcoidosis

SARCOIDOSIS OF LYMPH NODESLymphadnopathyLymph nodes are involved in almost all cases particularly the hilar and medistinal nodes, but any other nodes may be involved .nodes are characteristically enlarge discrete and sometimes calcified

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

LYMPHADENOPATHY Typical

1.Bilateral hilar & right paratracheal LN, 2.Middle mediastinal LN occur in 50% of

cases.

3.Left paratracheal, aorto-pulmonary & subcarinal LN.

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

LYMPHADENOPATHY

Atypical

1.Unilateral hilar LN.

2.Anterior or posterior mediastinal LN.

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

LYMPHADENOPATHY

LYMPHADENOPATHY

LYMPHADENOPATHY

LYMPHADENOPATHY

LYMPHADENOPATHY

ENLARGED BILATERAL HILAR, RIGHT PARATRACHEAL (ARROW), AND AORTOPULMONARY WINDOW (ARROWHEAD) NODES.

CALCIFIED LYMPH NODES LATE MANIFESTATION IN 5% OF PATIENTS.

PARACARDIAC LYMPH NODE

ABDOMINAL LYMPHADENOPATHY MULTIPLE ENLARGED PARAAORTIC, PARACAVAL, AND PORTA HEPATIS LYMPH NODES (ARROWS).

CUTENEOUS sarcoidosis

SKIN 33% have skin lesions

Cutaneous anergy is common.

LOFGREN'S SYNDROME; acute triad of erythema nodosum, joint pains, and bilateral hilar adenopathy

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

SKIN Lupus pernio- 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

LUPUS PERNIO

RAISED PLAQUESTHESE RAISED PLAQUES ARE THE RESULT OF COALESCENCE OF NODULES.

PSORIASIS LIKE LESIONS THESE SMALL WHITE LESIONS CLOSELY RESEMBLE PSORIASIS.

SARCOID SKIN LESION

OCCULAR sarcoidosis

EYES25% have eye lesions

Blurred vision, pain, photophobia and dry eyes

Chronic uveitis leads to glaucoma, cataracts and blindness

Keratoconjunctivitis sicca

Papilledema

CONJUNCTIVITIS

PAPILLEDEMA OFTEN ASSOCIATED WITH 7TH NERVE FACIAL PALSY.

SARCOID CHOREORETINITIS

SA

RC

OID

UV

EIT

IS

Hypopion

posterior synechiae :Iris deformity

cataract

LIVER sarcoidosis

LIVER33% 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.

EARLY COLLAGEN FORMATION EXTRACELLULAR COLLAGEN (C) IS BEING PRODUCED BY FIBROBLASTS

MUSCULOSKELETAL

SARCOIDOSIS

MUSCULOSKELETAL Acute polyarthritis with fever is common

Arthritis is self limited

Chronic destructive bone disease with deformity is rare

Polymyositis and chronic myopathy

Muscle disease is rare

PUNCHED OUT LYTIC LESIONS FOCAL OSTEOLYTIC LESIONS IN THE FINGERS ARE MOST COMMON ABNORMALITY.

LACY TRABECULAR PATTERN OSTEOLYSIS HAS LEFT A LACY TRABECULAR PATTERN IN THIS PHALANX (ARROW)

SCLEROTIC LESION RARE AND OFTEN IN THE AXIAL SKELETON.

NASAL BONE LESION NASAL SARCOIDOSIS CAN LEAD TO OSTEOLYSIS OF THE NASAL BONE (ARROWS).

NERVOUS SYSTEM 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

HEREFORDT'S SYNDROME; facial palsy accompanied by fever, uveitis, and enlargement of the parotid gland

T1-W POST GADOLINIUM MR IMAGE POST CONTRAST IMAGE OF HIGH SIGNAL INTENSITY TEMPORAL LOBE SARCOID LESION (ARROW)

T2-W MR IMAGE HIGH SIGNAL INTENSITY EDEMA SURROUNDING BIOPSY PROVEN SARCOID LESION.

NERVOUS SYSTEM Optic nerve dysfunction

Papilledema

Palate dysfunction

Hearing abnormalities

Paresthesias

Meningeal granulomas

Encephalopathy

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

NEPHROCALCINOSIS THERE ARE MULTIPLE CALCIFICATIONS OF THE KIDNEYS. ENLARGED RETROPERITONEAL LYMPH NODES (ARROWS)

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

Hyperglobulenemia

LAB ABNORMALITIESElevated level of angiotensin

converting enzyme

Gallium 67 lung scan showing a pattern of diffused uptake.

Bronchiole alveolar lavage shows increased lymphocytes

LUNG FUNCTION TESTLung function abnormalities for interstitial

lung disease with decreased lung volumes and diffusing capacities

RADIOGRAPHY “Egg shell” calcification of hilar nodesPlural effusionsCavitationsAtelectasisPulmonary hypertensionPneumothorax Cardiomegaly

DIAGNOSISIdentify noncaseating granulomasVariety of infectionsTransbronchial biopsies positive in 65-

95%, even if no lung parenchymal abnormalities imaged.

Tissue from mediastinoscopy positive in 95%

Scalene node biopsy positive in 80%

DIAGNOSISDifficult to differentiate from chronic

infections, fungal diseases, T.B. and lymphoma.

Based on combined clinical, radiologic and histologic findings.

Laboratory tests seldom importantAsymptomatic

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.

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.

THE KVEIM-SILTZBACH TEST

The Kveim-Siltzbach skin test  is based upon studies conducted by Dr. Morten Ansgar Kveim, a Norwegian dermatologist,  and published in 1941. The test was later studied extensively and popularized by Dr. Louis Siltzbach at the Mt. Sinai Medical Center in New York City. It  is the only test that, if positive, is considered to be diagnostic of sarcoidosis. The test material, a suspension of granuloma-containing spleen, lymph node, or other tissue  from a confirmed case of sarcoidosis, is injected intradermally. A positive test is characterized by the formation of a papule at the site of injection within 4-6 weeks  which, on microscopic examination, exhibits non-necrotizing granulomas and the absence of foreign material.

THE KVEIM-SILTZBACH TESTThe Kveim test has been reported to be positive in a

mean of 78% of patients with sarcoidosis worldwide (range 54%-92%). A satisfactory test suspension will identify at least 60% of patients with active sarcoidosis and will yield no more than 1% of false positive results in individuals without sarcoidosis.  A  positive Kveim test assures a diagnosis of sarcoidosis in 97%-98% of responsive individuals.  The test material must be validated by comparison with a previously validated suspension in patients with and without sarcoidosis.

THE KVEIM-SILTZBACH TESTBecause of the difficulties involved in

preparation, standardization and validation of the test material as well as significant variation in the sensitivity and specificity of  test suspensions obtained from different sources, the need for a biopsy procedure and the wait of 4-6 weeks for a diagnosis,  the Kveim test has been largely replaced by transbronchial biopsy for the diagnosis of sarcoidosis. At the present time validated Kveim test suspensions are available for diagnostic use at very few institutions worldwide.

KVEIM TEST - SKIN BIOPSYNON-NECROTIZING GRANULOMAS

KVEIM TEST - SKIN BIOPSYNON-NECROTIZING GRANULOMAS

KVEIM TEST - SKIN BIOPSYNON-NECROTIZING GRANULOMAS

DIAGNOSISTest not always positive

Not used often in US

Test material not approved for sale by FDA.

PROGNOSISGood

50% have some permanent organ dysfunction

In 15-20% remains active or recurs intermittently.

TH

AN

K

YO

U