SARCOIDOZA

DEFINIIE: - Granulomatoz multisistemic - Cauz necunoscut - Aduli tineri - Limfadenopatie hilar, infiltrat pulmonar i leziuni cutanate i oculare - Histologic - granulomul epitelioid necazeificat

EPIDEMIOLOGIE
Prevalena 1 - 40 / 100.000 locuitori Afecteaz n special vrsta 20-40 ani Heterogenitate epidemiologic prevalen i severitate Mai frecventa n nordul Europei i la negrii americani (1,15 % la suedezi i 2,4% la negrii americani) Afecteaz aproximatic egal ambele sexe

ETIOLOGIE
Susceptibilitate genetic a gazdei (genotipul sarcoidozei) Expunere la diferii ageni din mediu

Sarcoidoz Fenotip clinic

Etiologie factori de mediu

Ageni infecioi Virui (herpes, Epstein-Barr, retrovirus, coxsackie B, cytomegalovirus) Borrelia burgdorferi Propionibacterium acnes M. tuberculosis Mycoplasma Rickettsia Substane anorganice Aluminiu Zirconiu Talc Substane organice Polen de pin Rini

Etiologie factori genetici

Risc genetic poligenic predispoziie, clinic, evoluie, prognostic Evoluie favorabil sindrom Lofgren CW7 DR3 HLA-B8 Evoluie cronic HLA B13 Risc familial

FIZIOPATOLOGIE
Celule T, Macrofage

Factori de cretere Factori chemoatractani

Proliferare celular Granulom

Fibroz

Persistent stimulation of T-Cell by antigen (red oval) T-Cell releases chemokines causing more inflammation Via control by chemokines there is cell activation, proliferation and differentiation The granuloma forms from differentiated monocytes

MORFOPATOLOGIE
Alveolita - infiltraia peretelui alveolar predominant macrofage i limfocite T Secundar neutrofile, eozinofile, bazofile, mastocite etc. Granulom epitelioid necazeificat Aglomerare de celule epitelioide pe fondul unei reele de reticulin care la periferie prezint o coroan de limfocite. Prezena de celule gigante care conin incluziuni citoplasmatice (corpi Schauman): Corpi asteroizi Corpi conchoizi Corpi birefringenti Granulomul nespecific tuberculoz, lepr, sifilis, bruceloz Fibroza

Sarcoid Granuloma

Sarcoidosis Lung Gross

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.

CASEOUS NECROSIS Cellular 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

MECANISM IMUNOLOGIC
Deprimarea imunitii de tip celular IDR la PPD Exacerbarea imunitii de tip umoral Hipergammaglobulinemie, complexe imune circulante Limfopenie absolut

MANIFESTRI CLINICE
Simptomatologie de debut 50% asimptomatic Simptomatologie general nespecific Simptomatologie dependent de organ (polimorfism simptomatic) 30% debut acut - Sindrom Lofgren - Sindrom Heerfordt - Sindrom Miculicz-Sjogren

FORME CLINICE PARTICULARE

Sindrom Lofgren: adenopatie hilara bilaterala febra poliartralgii eritem nodos

Sindrom Heerfordt: febr uveita (iridociclita) parotidit paralizie nerv facial

- Sindrom Miculicz-Sjogren: - keratoconjunctivita uscat - hiposecreie salivar, gastric, pancreatic - poliartrit cronic - eczeme.

Simptomatologie

Afectare organic
Organ %

Adenopatii mediastinale
Plmni Ficat

95-98%
>90% 50-80%

Splin
Ochi Adenopatii periferice Cutanate

40-80%
20-80% 30% 25%

Sistem nervos
Cardiovascular

10%
5%

Simptomatologie
Pulmonar dispnea, tuse seac, dureri toracice difuze 90% Nefrit interstiial, insuficien renal, nefrocalcinoz Metabolism Hipercalcemie, hipercalciurie fosfocalcic Renal

Neurologic Paralizii de nervi cranieni, convulsii, meningit granulomatoas, leziuni hipotalamus sau hipofiz, 10% hidrocefalie, polineuropatie periferic i afectare psihiatric Ocular Uveit, chorioretinit, keratoconjunctivit, glaucom, cataract, orbire 20%

Cardiac 5%

Palpitaii, sincop, durere toracic, aritmii, moarte subit cardiac

Endocrine Hipo/hipertiroidism, insuficien adrenal Exocrin Tumefacia glandelor parotide, keratoconjunctivita sicca

Hepatic
Limfatic

Hepatalgii, hepatomegalie
Limfadenopatii, splenomegalie

Cutanate Eritem nodos, eritem polimorf sau vasculitic, lupus pernio, noduli subcutanai, erupie 25% maculopapular, alopecie, hiper/hipopigmentare

EN

Lupus Pernio

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

SMALL NODULES Papules and nodular lesions, can be found anywhere on the body. Papules are often multiple while nodules are often solitary.

RAISED PLAQUES These raised plaques are the result of coalescence of nodules.

PSORIASIS LIKE LESIONS These small white lesions closely resemble psoriasis.

EARLY COLLAGEN FORMATION Extracellular collagen (C) is being produced by fibroblasts

Adenopatii
Localizri adenopatii centrale: Mediastinal 100 % Hilar bilateral 75 % Adenopatii periferice: laterocervical i supraclavicular, epitrohleari, axilari, inghinali Ganglionii sunt mobili, nedureroi, cu diametru variabil, nu ulcereaz, nu fistulizeaz Splenomegalia rar, poate cauza hiperslenism

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

PARACARDIAC LYMPH NODE

ABDOMINAL LYMPHADENOPATHY Multiple enlarged paraaortic, paracaval, and porta hepatis lymph nodes (arrows).

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.

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)

DEFORMING LESIONS Advanced sarcoidosis with osteolytic lesions of the distal forearm, wrist, and bones of the hand

SCLEROTIC LESION Rare and often in the axial skeleton.

SCLEROTIC LESIONS, NONSPECIFIC Focal sclerosis (arrows) of distal phalanges is unusual

NASAL BONE LESION Nasal sarcoidosis can lead to osteolysis of the nasal bone (arrows).

T2-W MR IMAGE High signal intensity edema surrounding biopsy proven sarcoid lesion.

ASPECTE RADIOLOGICE
I
II

Adenopatie hilar bilateral i paratraheal

Adenopatie mediastinal cu leziuni ale parenchimului pulmonar Modificri parenchimul pulmonar fr adenopatii Fibroz pulmonar

55-90% remisie 40-70%

III IV

10-20% 0-5%

Limfadenopatii

+Infiltrate

infiltrate

Fibroz

Stadiile 14

Stages

Stadiu I

Stadiu II

Tip 1

Tip 1

Tip 2

Tip 2

Stadiu III

Stadiu IV

Tip 3

ASPECTE RADIOLOGICE
Atipice: - nodular-infiltrative - pseudotumorale - atelectazii

- caverne

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 lymphadenopathy.

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.

SUBPLEURAL NODULES Cluster of small nodules looks like a tumor on a radiograph.

MOST COMMON PATTERN Bilateral symmetric hilar and right paratracheal mediastinal adenopathy.

LYMPHADENOPATHY ON CT Para-aortic and retrocaval lymphadenopathy. CT shows enlarged lymph nodes not visible on radiographs.

POSTERIOR MEDIASTINAL LYMPH NODE next to the aorta (A). Bilateral hilar adenopathy was also shown.

STAGE IV Permanent lung fibrosis. (20%)

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.

Aspecte funcionale
Corelaie imperfect cu aspectul clinico-radiologic Anomalii predominant de tip restrictiv Tulburri ale transferului gazos Sindromul obstructiv distal 30-40 % din stadiile I si II Anomalii diverse la 74 % din pacieni n stadiul I

MODIFICARI BRONHOSCOPICE
ASPECT NORMAL LA 50 % DIN CAZURI !! (Discordan ntre modificrile bronhoscopice i aspectul radiologic)

ASPECTE PATOLOGICE:
capilaritate crescut proliferri de mucoas stenoze bronice granulaii sidefii-glbui compresii extrinseci

TEHNICI SUPLIMENTARE
Prelevri bioptice de mucoas Puncia-biopsie transbronic Lavajul bronho-alveolar

Lavaj bronhoalveolar
Alveolit limfocitar limfocitoz 80-90% din cazuri, nespecific pentru sarcoidoz Severitatea limfocitozei > 28% - debut acut - evoluie favorabil < 28% debut insidios evoluie cronic PMN>3% i eozinofile >1% markeri ai progresiei raport LTh/ LTS (CD4/CD8) > 3,5 Alveolita neutrofilic singurul element care indic necesitatea tratamentului

Transbronchial Needle Aspiration (TBNA) Cytology in Sarcoidosis

Multinucleated giant cell of Langhans type

Scattered epithelioid cells and lymphocytes

Smojver-Jezek S, et al. Cytopathology 2007; 18: 3

Linear Real-time Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Scope

(BF-UC160F-OL8; Olympus Medical Systems, Tokyo, Japan) Herth FJF. Eur Respir J

Endobronchial Ultrasound in Sarcoidosis

Right paratracheal LN

Vena cava superior

Wong M et al. Eur Respir J 2007; 29: 1182

Endobronchial Ultrasound in Sarcoidosis

Needle

Wong M et al. Eur Respir J 2007; 29: 1182

BIOCHIMIE
Cresc
.-VSH, PCR, globuline - Calcemia - Calciuria - Proteinemia - Lizozim - Angiotensin convertaza seric

Scad
- Limfocite. CD4

COMPUTER TOMOGRAFIE
Tomografia computerizat evaluare extindere leziuni i prognostic: - Micronoduli bronhovasculari i subpleurali reversibilitate crescut - Imagini n fagure de miere sau reticulare fibrozireversibil - Sticl mat cu evoluie variabil Confirm prezen adenopatii Nu este necesar de rutin, doar n cazuri atipice radiologic sau clinic.

Scintigrafia cu galiu
Extinderea i distribuia leziunilor inflamatorii Captare n celulele mononucleare Dou aspecte distincte: - captare n lambda gg limfatici intratoracici - captare n panda gl parotide i lacrimale

Examenul histologic
Test Kveim cel mai specific test pentru sarcoidoz

Biopsii

Ganglionar prin mediastinoscopie Pulmonar Bronic Ganglionii periferici Leziuni cutanate Leziuni hepatice Sediul leziunii

Investigaii specifice afectrii de organ

RMN afectare cerebral, muscular, osoas Angiografia cu fluorescen - vascular retinian Scintigrafia cu Thaliu, monitorizare Holter, angiografie coronarian afectare cardiac

Biopsie miocardic

Diagnostic
Diagnostic de excludere adenopatie hilar bilateral IDR negativ ACS crescut Observaie ndelungat Ansamblu concordant de semne Scopuri: - confirmare histologic, evaluare extindere i severitate, progresie i necesitate tratament Prezena granulomului epitelioid necazeificat

ETAPE DIAGNOSTIC
Anamnez i examen clinic Radiografie toracic CT Biopsie Diagnostic de certitudine biopsie pulmonar transbronic Explorri funcionale respiratorii, gaze arteriale Alte teste specifice: ecg, examen oftalmologic, etc

Kveim Test
Kveim test, or Kveim-Siltzbach test is a skin test used to detect sarcoidosis: Part of spleen of person with known sarcoidosis is injected in the skin of the patient being tested If granulomas are found, usually 4-6 weeks later test is positive It is named for the Norwegian pathologist Morten Ansgar Kveim, who first reported the test in 1941 using lymph node tissue from sarcoidosis patients

Diagnostic diferenial
Pulmonare
Tuberculoz Pneumonii atipice Criptococcoz Aspergiloz Histoplasmoz Coccidioidomicoz Blastomiocoz Pneumocistic carini Micoplasma Pneumonii de hipersensibilitate Pneumoconioz: berillium, titaniu, aluminiu

Adenopatii
Tuberculoz Micobacterii atipice Bruceloz Toxoplasmoz tumorale

Limfom Non-Hodgkin

Aspiraie de corp strin Granulomatoz Wegener Pneumonie interstiiale

PROGNOSTIC
Remisie 60% din cazuri Dificil de prezis Boal cronic progresiv 10-20% Mortalitate 1-5% Prognostic bun:
Stadiu I 80% remisie spontan sindrom Lofgren Asimptomatic Europeni

Prognostic nefavorabil:
Multisistemic (>3) Ras neagr Infiltrate pulmonare Neurologic, cardiac, uveit cronic Vrst > 40 ani Lupus pernio Hipercalcemie

DIAGNOSTIC: SARCOIDOZ
60%: rezoluie spontan!

TRATM PACIENTUL?

Tratament: motive s nu-l administrm!

Cauza bolii necunoscut Moment optim de iniiere a terapiei greu de stabilit Vindecare spontan frecvent Corticosteroizii prezint efecte secundare multiple Recidivele dup vindecarea spontan sunt rare Tratamentul nceput trebuie s fie de lung durat

TRATAMENT
Corticosteroizi sistemic manifestri cardiace, neurologice, afectare pulmonar progresiv sau n cazul hipercalcemiei Prednison = 20 - 40 mg/zi Indicaii absolute: afectarea organelor vitale tendina la fibroz Durata: aproximativ 1 an Monitorizare la 3 luni Corticosteroizi topici- afectare cutanat sau oftalmic

TRATAMENT

TRATAMENT

TRATAMENT

Monitorizare
Clinic Radiologic Adesea rezorbie lezional Uneori: imagine adenopatii inghetate Funcional Cretere ACS = puseu evolutiv Efecte adverse ale corticoterapiei

Alternative terapeutice la corticoterapie

Medicament, dozaj Utilizare n sarcoidoz Efecte adverse Greuri, neutropenie, toxicitate hepatic Greuri, neutropenie Metotrexat 10-25 mg/ Sarcoidoz sever, cronic sptmn, maxim 1-2 g/ Medicaie de linia II an Azatioprin 50-200 mg/zi Ciclofosfamid 50-150 mg/zi sau 500-2000 mg la 2 sptmni IV Hidroxiclorochin 200400 mg/zi Fibroz pulmonar Sarcoidoz sever, cronic Medicaie de linia II Sarcoidoz refractar la corticoterapie

Greuri, neutropenie

Manifestri cutanate,hipercalcemie, fibroz pulmonar

Retinopatie, depozite corneene.

Bilateral hilar lymphadenopathy : Judges wig appearance

A 30 - year - old man with
bilateral lymph node enlargement and fine reticulations in both lung fields

Deepak D and Shah A. Indian J Radiol Imag 2001 ; 11 : 191 198

Bilateral asymmetrical hilar nodes

A 50 - year - old man with bilateral asymmetrical hilar lymph nodes with lobulated

border on the right side .

Bilateral reticulonodular opacities are also visible

Deepak D and Shah A. Indian J Radiol Imag 2001 ; 11 : 191 198

Asymmetrical mediastinal lymphadenopathy in a 32 - year - old man with sarcoidosis

Radiograph shows striking asymmetric enlargement of mediastinal lymph nodes

HRCT of the same patient shows

bilateral multiple mediastinal lymphadenopathy

potato nodes

Deepak D and Shah A. Indian J Radiol Imag 2001 ; 11 : 191 198

1 - 2 - 3 sign or Garlands / pawnbrokers sign

Radiograph of 34 - year - old man shows bilateral hilar and right paratracheal lymph nodes

enlargement ( 1 - 2 - 3 sign ).
Also visible is bilateral parenchymal involvement with reduced lung volumes

Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

Unilateral hilar adenopathy

Postero - anterior chest radiograph in a 42 - year - old man with sarcoidosis shows

a left hilar lymph node and

consolidation in right upper and mid zones mistaken for tuberculosis
Deepak D and Shah A . Indian J Radiol Imag 2001 ; 11 : 191 - 198

Regression of lymphadenopathy and progression of pulmonary lesion

2 years later

Bilateral hilar lymph

nodes with prominent reticulonodular shadows

regression of the hilar lymph nodes with calcification ( arrow ) and honeycombing

Deepak D and Shah A. Indian J Radiol Imag 2001 ; 11 : 191 198

Unilateral disease
Radiograph of 49 - year - old

woman shows predominantly

unilateral disease involving left side with cavities ( arrows ) and features of parenchymal fibrosis in the left upper zone

as evidenced by the pulled - up

left hilum & tracheal deviation
Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

Parenchymal nodules

CECT of a 52 - year - old

woman through the level

of left upper lobe

bronchus shows bilateral

nodular opacities
Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

Reticulations

Chest radiograph in a
40 - year - old man shows bilateral reticulations. Pleural thickening ( arrow ) is also seen in the left upper zone

Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

Pulmonary sarcoidosis : alveolar pattern

areas of consolidation with

irregular borders preferentially involving central areas

HRCT showing bilateral consolidation with air

bronchogram ( arrow )

Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

Alveolar pattern : 11 years post treatment

Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

bilateral bullous areas pleural thickening clearing of consolidation

HRCT : bronchiectasis and bullae

Alveolar sarcoidosis with subpleural nodules

HRCT of a 30 year old man through the level of left lower lobe bronchus showing

alveolar pattern of
involvement on the left side. Also visible are bilateral sub - pleural nodules (arrows)
Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

Stage IV sarcoidosis : 50 - year - old woman

Deepak D and Shah A. Indian J Radiol Imag 2001; 11 : 191 198

- beaded appearance of bronchovascular bundles with - perihilar concentration of fibrosis and lobular distortion Left side : cystic spaces & fibrosis

Pulmonary sarcoidosis : simultaneous ground glass & honeycombing

HRCT through right lower lobe bronchus shows : - air bronchogram ( arrow ) - ground glass opacities

HRCT through apical region : - honeycombing on right side

Deepak D and Shah A. Indian J Radiol Imag 2001 ; 11 : 191 - 198

Pleura : a 35 - year - old man with a non - resolving pleural effusion

B / l mediastinal lymphadenopathy & thickening of both fissures

Mercilessly received second line antituberculous therapy
Panjabi C et al . Indian J Tuberc 2004 ; 51 ; 37 - 41

Well circumscribed noncaseating granuloma consisting of epitheloid cells and multinucleated giant cells ( H & E 100 )
Panjabi C et al . Indian J Tuberc 2004 ; 51 : 37 - 41

Spontaneous pneumothorax
Rare : 2-4 %
Mihailovic - Vucinic V and Jovanovic D . Clin Chest Med 2008 ; 29 : 459 - 473

Chest radiograph in a 45 - year - old woman with

sarcoidosis shows
pneumothorax ( arrows ) along with b / l hilar

prominence, reticular
opacities in lower zones
Deepak D and Shah A. Indian J Radiol Imag 2001 ; 11 : 191 198

Sarcoidosis : miliary pattern in a 40 - year - old man

Deepak D and Shah A . Indian J Radiol Imag 2001; 11 : 191 - 198

A 65 - year - old lady with cavitation

9 months prior to referral

Bilateral diffuse non - homogeneous opacities

A well - defined cavitary lesion

Bilateral hilar enlargement

Acinar pattern seen in the right mid and lower zones

in the anterior segment of the

right upper lobe

Panjabi C et al. Brazilian J Pulmonol 2009 ( in press )

Aspergilloma formation in a sarcoid cavity

1 - year after commencement of therapy for sarcoidosis

C T in supine position showing fungal ball within the cavity

C T in prone position

showing positional change

of the fungal ball

Panjabi C et al. Brazilian J Pulmonol 2009 ( in press )

Mediastinal lymphadenopathy in a 35 - year - old lady

A 35 - year - old lady

presented with a history

of dry cough , fever and weight loss for one month Chest X - ray showed bilateral symmetrical

hilar lymphadenopathy
FOB done elsewhere : inconclusive

On presentation : investigated for pulmonary sarcoidosis

Spirometry Serum ACE : mixed obstruction with restriction , diffusion per unit volume normal : 25.7 IU / ml ( 8 52 IU / ml )

Mantoux test : 20 mm x 22 mm ( 1 TU )

Bilateral extensive

mediastinal lymphadenopathy

Bilateral ground glass haze with right upper lobe consolidation and peri - bronchial cuffing

Six weeks later

Patient went out of town and reported later with persistent

fever and productive cough

Chest X - ray revealed a cavity in the right middle zone

All three consecutive samples for

AFB were positive
cavity

Sputum culture : positive Bronchial aspirate culture by BACTEC : positive

After six months of ATT

She complained of dyspnoea Chest X- ray : shrunken lung fields PFT : restrictive pattern with diffusion defect

Bilateral multiple mediastinal lymphadenopathy Ground glass haze Peribronchial cuffing and nodules