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adiología. 2011;53(5):434---448

www.elsevier.es/rx

PDATE IN RADIOLOGY

pdate thoracic sarcoidosis�

. Herráez Ortega ∗, L. López González

ervicio de Radiología, Complejo Asistencial Universitario de León, León, Spain

eceived 28 January 2011; accepted 22 March 2011

KEYWORDSSarcoidosis;Diffuse pulmonarydisease;High resolution chestcomputerizedtomography;Cardiac sarcoidosis

Abstract Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. It mainlyaffects the thoracic lymph nodes and the lungs. The staging of sarcoidosis, which classifiespatients according to their probability of spontaneous remission, is based on the plain chestfilm findings. Plain chest films are not as sensitive as high resolution computed tomography(HRCT) at detecting involvement of the lymph nodes, lungs, or bronchi. The high resolutionCT findings can be typical, practically pathognomic, or atypical. High resolution CT providesinformation about the activity of the disease and detects incipient signs of fibrosis and othercomplications. To reach the diagnosis, it is necessary to correlate the clinical and radiologicalfindings (and often the histological findings).

Cardiac involvement can cause sudden death. The diagnosis of cardiac involvement is diffi-cult; it is based on various imaging tests, such as magnetic resonance imaging, which is morespecific, and positron emission tomography. Diagnostic confirmation by endomyocardial biopsyis obtained in few patients.© 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVESarcoidosis;Enfermedadpulmonar difusa;Tomografía

La sarcoidosis torácica

Resumen La sarcoidosis es una enfermedad granulomatosa multisistémica de causa descono-cida, que afecta principalmente a los ganglios linfáticos torácicos y a los pulmones. Laestadificación, que agrupa a los pacientes con similar probabilidad de remisión espontánea, se

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computarizadade tórax de altaresolución;Sarcoidosis cardiaca

basa en los hallazgos de la radiografía de tórax, que tiene menor sensibilidad que la tomografíacomputarizada de alta resolución (TCAR) para detectar la afectación ganglionar, pulmonar ybronquial. Los hallazgos en TCAR pueden ser típicos, prácticamente patognomónicos, o atípi-cos. La TCAR aporta información sobre la actividad de la enfermedad y detecta incipientessignos de fibrosis y otras complicaciones. Para realizar el diagnóstico es precisa la correlación
clínica, radiológica, y en muchos casos anatomopatológica.
� Please cite this article as: Herráez Ortega I, López González L. La sarcoidosis torácica. Radiología. 2011;53:434---48.∗ Corresponding author.

E-mail address: [email protected] (I. Herráez Ortega).

173-5107/$ – see front matter © 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

dx.doi.org/10.1016/j.rxeng.2011.03.001

http://www.elsevier.es/rx

mailto:[email protected]

Update thoracic sarcoidosis 435

La afectación cardiaca puede provocar muerte súbita; el diagnóstico, difícil, se basa envarias pruebas de imagen, como la resonancia magnética, que tiene mayor especificidad, yla tomografía por emisión de positrones; la confirmación mediante biopsia endomiocárdica seobtiene en pocos pacientes.© 2011 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

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Document downloaded from http://http://zl.elsevier.es, day 22/10/2013. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Introduction

Sarcoidosis (from Greek ‘‘sark oid’’, meaning flesh-like) isalso called Besnier-Boeck’s disease after the Norwegian der-matologist Caesar Boeck, who in 1899 described the skinlesions of the disease and coined the term ‘‘benign sarcoid’’because of its histologic similarity to sarcoma. Later, hedescribed the involvement of the lungs, bone, lymph nodes,spleen, nasal mucosa and conjunctiva. In 1915, Kusnitski andBittorf described the chest radiographic features.1

Sarcoidosis is a systemic granulomatous disease whosecause is still unknown.2 However, infectious factors suchas viruses, mycobacteria (mycobacterial DNA has beendetected by the polymerase chain reaction [PCR]) and fungi,as well as environmental agents (after 9/11, increased ratesof sarcoidosis were described in fire-fighters who took partin the rescue work at the World Trade Center) or geneticfactors may induce the abnormal immune response seen inthe disease. It remains however unclear why this responseis triggered.1 Thoracic and pulmonary lymph nodes are themost common sites, and even though eyes, skin, salivaryglands, liver, spleen, heart, bone and the central nervoussystem can also be involved, pulmonary sarcoidosis accountsfor the highest rates of morbidity and mortality. Althoughthe prognosis of the disease is usually favorable, its coursecannot be predicted and in 10---30% of patients is chronic orprogressive.

Sarcoidosis is one of the most common diffuse infiltrativelung diseases (DILD). In a series of 500 consecutive patientswith suspected DILD, sarcoidosis was the most commondisease (19% of patients).3 Its incidence is heterogeneousamong different populations,4 and it seems to be rarelyreported in Ecuador and more common in Northern Europeancountries (60 cases/100 000 population) and among AfricanAmericans. There is a higher disease rate for women in their3rd and 4th decades.

Approximately 30% of patients are asymptomatic, whilethe most common clinical manifestations in symptomaticpatients are erythema nodosum and occasionally respira-tory symptoms, including dry irritating cough, chest pain anddyspnea, with dissociation between clinical and radiologicalfindings (with more radiological than clinical involvement).Some patients develop Löfgren’s syndrome, which maycause fever, erythema nodosum, arthralgia and bilateralhilar lymphadenopathy. Patients >70 years usually havesystemic symptoms and salivary gland involvement.5 Ele-
vated angiotensin-converting enzyme (ACE), hypercalciuria,decreased diffusion capacity and restrictive pattern on pul-monary function tests as well as increased CD4/CD8 ratio inthe bronchoalveolar lavage (BAL) fluid may also appear.
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The characteristic histologic lesion of sarcoidosis is well-formed, non-necrotizing granuloma with histio-ytes, epithelioid cells and multinucleated giant cellsurrounded by a rim of lymphocytes.6 Sarcoid granulomasay develop fibrotic changes and occasionally focal coagula-

ive necrosis.1 In the early stages of the pulmonary disease,efore the formation of granulomas, there is lymphocyteccumulation in the alveolar septa (lymphocyte alveoli-is). Subsequently, granulomas form in the perilymphaticnterstitium (with a peribronchovascular, centrilobular andubpleural distribution) and, less frequently, in the interlob-lar septa.7 Microscopic granulomas may coalesce to formacroscopic nodules.

ymph node, pulmonary and bronchialnvolvement

hest radiographic findings and staging

A and lateral chest radiographic (chest X-ray) examinationsre essential since sarcoidosis most commonly targets thehorax and thoracic sarcoidosis is seen in over 90% of patientst some stage of the disease.8 Nonetheless, patients withistologically proven lung parenchymal disease may haveormal chest X-ray. In asymptomatic patients, radiographicndings are often the first manifestation of the disease.

Five decades ago, Scadding9 described four stages of sar-oidosis based on X-ray findings. Stage 0 was later addedor those cases with normal chest X-ray. Patients are clas-ified according to the likelihood of spontaneous remission,hich occurs in 55---90% of patients with stage I and in 0% ofatients with stage IV disease.

Stage 0: absence of chest X-ray abnormalities.Stage I: bilateral hilar lymphadenopathy that may be

ccompanied by right paratracheal and aortopulmonary win-ow adenopathy.8 The differential diagnosis should includeungal and mycobacterial infections, malignancies such asymphoma, bronchogenic carcinoma, and extrathoracic car-inoma. However, in the absence of specific symptoms,he most common cause of bilateral hilar adenopathy isarcoidosis.10 Calcification of long-standing lymph nodess common,11 sometimes in an ‘‘eggshell pattern’’ similaro that of silicosis.

Stage II: bilateral hilar lymphadenopathy and parenchy-al infiltration with a bilateral symmetric micronodular or

eticulonodular pattern with predominant perihilar distribu-ion, in middle and upper lung fields. Atypical findings arearge nodules, masses, consolidations, atelectasis secondaryo bronchial obstruction, cavities, pleural involvement and

436 I. Herráez Ortega, L. López González

Figure 1 Typical pattern of sarcoidosis. (A and B) Axial HRCT: patchy lymphangitic nodular pattern with peribronchovascular(thick arrow), centrilobular (open arrow) and subpleural (thin arrows) small nodules. (C) Coronal MIP image: predominant perihi-l nsbrl bro

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ar distribution in the middle field. (D) Photomicrograph of traymphangitic distribution (interlobular septum---thick arrow---and

neumothorax. The differential diagnosis includes pneumo-oniosis and, if the X-ray shows masses and consolidations,uberculosis and lymphoma should also be ruled out.

Stage III: parenchymal infiltration without hilar adenopa-hy. The differential diagnosis should include pneumoco-iosis, lymphangitis carcinomatosis and, if the X-ray showsasses and consolidations, infections, cryptogenic organiz-

ng pneumonia, vasculitis, adenocarcinoma and lymphomahould also be ruled out.

Stage IV: fibrosis with evidence of reticular pattern withraction bronchiectasis, masses causing architectural distor-ion or honeycomb cysts, predominantly in the upper fields.he differential diagnosis includes complicated pneumoco-iosis and other causes of fibrosis such as chronic extrinsicllergic alveolitis and idiopathic pulmonary fibrosis (IPF).

Staging has prognostic and therapeutic implications ands still done using the same criteria, based on imagingndings.10

igh resolution computed tomography findings

RCT, either sequential or volumetric with IV contrast, can
etect lesions that are not visible on chest X-ray, provinghat lung and lymph node involvement is more common thathe involvement seen on radiographic images. Chest radio-raphs only detect 50---60% of lymph nodes and 30---40% of
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onchial biopsy specimen: well-formed granulomas (stars) in anchovascular bundle---open arrow) (Masson’s trichrome).

arenchymal abnormalities found with HRCT. Only in a fewases, patients with sarcoidosis confirmed by transbronchialiopsy (TBB) have normal HRCT scans.10

HRCT scans of most patients with pulmonary disease shownvolvement of multiple lymph node chains, usually theight paratracheal and bilateral symmetric hilar chainsccompanied by prevascular, left paratracheal, aortopul-onary window, paraaortic and subcarinal lymph nodes.

solated unilateral enlargement and involvement of thenternal mammary and posterior mediastinal nodes (par-vertebral and retrocrural) is less common.12

Perilymphatic distribution of pulmonary granulomas iseadily detected on HRCT.13 The most common findings andhose that represent the characteristic appearance of theisease are well-defined, small nodules <1 cm (most fre-uently between 2 and 5 mm), smooth or irregular, withymphangitic distribution (lymphangitic nodular pattern):eribronchovascular, centrilobular, subpleural and, to aesser extent, in the interlobular septa14,15 (Fig. 1). Althoughhe lesions can be seen in the central lung, usually in aeribronchovascular and centrilobular distribution, they areore commonly seen in the peripheral lung, usually in a

entrilobular and subpleural distribution and along the fis-ures. Moreover, the involvement is commonly symmetricnd patchy, and the lung zones most often involved are thepper and middle fields16 (Table 1).


Table 1 Typical HRTC findings of sarcoidosis.

Adenopathy: symmetric hilar and right paratracheal as wellas medial and anterior mediastinal

Lymphangitic nodular patternNodule type: <10 mm, usually between 2 and 5 mm,

well-defined, smooth or irregularType of distribution: lymphangitic, patchy, more common

in central or peripheral (more frequent) lung and in upperand middle fields

‘‘Fairy ring’’ and ‘‘sarcoid cluster’’ signs*

Bronchiolar involvement: air trapping on expiratory HRCT**

Fibrosis: traction bronchiectasis in UL, honeycombing inmiddle fields

* Described in sarcoidosis. Only one case of ‘‘sarcoid cluster’’described in tuberculosis.

** Nonspecific finding, but it is the second most common after

Table 2 Atypical HRCT findings of sarcoidosis.

Adenopathy: unilateral, internal mammary, posteriormediastinal

Pulmonary patterns: centrilobular nodular, miliary, largenodules and masses, ground-glass, consolidations, paving,interlobular septal and calcified micronodules

Pulmonary fibrosis: similar to IPFBronchial, pleural, cardiac, mediastinal and vascular

involvement

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lymphangitic nodular pattern.

Other nodular patterns have been described in patientswith sarcoidosis including the centrilobular distribution, due
to isolated or predominant involvement of the centrilobularinterstitium,17 and the random or miliary pattern18; bothatypical and uncommon findings of the disease.
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Figure 2 Atypical pattern of sarcoidosis. (A) Axial HRCT: large spolylobulated peribronchovascular large nodules in RUL (white arrowand subpleural small nodules. (C and D) Axial HRCT: cavitating mass

IPF: idiopathic pulmonary fibrosis.

Other atypical pulmonary lesions, secondary to coales-ent granulomas,19 are large nodules, masses, ground-glasspacities and consolidations12 (Table 2). Large nodules,---3 cm in diameter, and masses >3 cm may cavitate and veryeldom calcify.20 These nodules may appear as a single find-ng or associated with other lesions (Fig. 2). Ground-glassppearance always accompanies other pulmonary abnormal-ties and sometimes superimposes the nodular pattern. Theresence of consolidations (‘‘alveolar sarcoidosis’’), usuallyeribronchovascular and with aerial bronchogram, is usually
ssociated with a nodular pattern (Fig. 3). Both the ground-lass attenuation and consolidations are due to interstitialccumulation of granulomas, with or without microscopic
piculated nodules in RUL (open arrow). (B) Axial HRCT axial:) and subpleural in LUL (black arrow) as well as centrilobular

es in a different patient.


Figure 3 Atypical pattern of sarcoidosis. (A) Axial HRCT: ground-glass areas with ‘‘black bronchus’’ sign and superimposed smallnodules; some thickened interlobular septa (arrow). (B) Sagittal MIP image in the same patient shows centrilobular and supleuralsmall nodules predominantly in the posterior part of the lower lobes; nodules in minor fissure (arrow). (C and D) Axial HRCT in ap olidas und-

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atient with ‘‘alveolar’’ sarcoidosis: peribronchovascular consubpleural small nodules, some of them clustered together. Gro

brosis. This accumulation leads to partial (ground-glass) orotal (consolidation) collapse of the alveolar spaces.

Other less common findings include the ‘‘paving’’attern,21 the septal pattern as dominant finding (Fig. 4),he calcified micronodular pattern simulating pulmonarylveolar microlithiasis, the halo sign22 and reversed halo signsmall nodules in the central ground-glass area and surround-ng the outer areas of consolidation).23

In some cases, the ‘‘sarcoid galaxy’’ sign appears as aesult of the particular distribution of granulomas: a largeodule that arises from the coalescence of granulomas sur-ounded by tiny satellite lesions.24 This finding may alsoe seen in tuberculosis and lung carcinoma. Other typi-al signs of sarcoidosis are the ‘‘fairy ring’’, where tinyodules organize in a circumferential fashion,25 and theecently described ‘‘sarcoid cluster’’ sign, where multipleiny centrilobular nodules, very close to each other butoncoalescing, cluster together in the peripheral regions ofhe lung.26 When the clusters are located in the subpleuraleripheral regions, the clusters contain tiny subpleural nod-
les (Fig. 5). Studies on the correlation between imagingnd histopathologic findings reveal that the small nodulesorrespond to noncaseating, noncoalescing granulomas with
predominance of CD4+ lymphocytes, without fibrosis and

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tions with aerial bronchogram, and multiple centrilobular andglass opacity superimposing many of the small nodule areas.

ith lymphangitic distribution. The ‘‘sarcoid cluster’’ signas also been found in one patient with tuberculosis.27

HRCT is more accurate than chest radiography for thessessment of pulmonary fibrosis8 (Fig. 6), which causesentral and peripheral bronchiectasis and significant lungistortion,28 linear opacities or irregular bands with trac-ion bronchiectasis and volume loss (Fig. 7) or masses withraction bronchiectasis and volume loss. In either case, thepper and middle lung fields are more commonly affectedypically resulting in a posterior displacement of the mainronchi and upper lobe bronchi. Sometimes a honeycombattern with peripheral distribution appears in the uppernd middle fields. Only in a very small number of cases,he honeycomb pattern appears predominantly in the lowerelds producing appearances similar to IPF29 (Fig. 8). Nod-les can be seen associated with other patterns of fibrosisut not with honeycombing.30

HRTC may demonstrate signs of bronchial involvement31

uch as bronchial wall thickening, stenosis and airwaybstruction leading to distal atelectasis. These findings
re secondary to intramural and endobronchial granulo-as. Compression of the bronchi by adjacent lymph nodesay also occur. However, signs of bronchiolar involvement
uch as air trapping on expiratory HRCT are more common


Figure 4 Atypical pattern of sarcoidosis. (A) Coronal HRCT: smooth thickened interlobular septa (arrow), predominantly in upperfields, and multiple subpleural and centrilobular small nodules. (B) Coronal MIP images detect better the lymphangitic nodularpattern and calcified mediastinal adenopathy some of them in an eggshell pattern (arrow).

Figure 5 Signs of sarcoidosis. (A) Axial HRCT: ‘‘sarcoid galaxy’’ sign, where the central cavitating nodule is surrounded by satellitetiny nodules. (B) ‘‘Sarcoid cluster’’ sign: multiple clusters of tiny centrilobular (thick white arrow) nodules and centrilobular and


subpleural (thin white arrow) tiny nodules. (C) ‘‘Sarcoid cluster’’ (thnodules in the right major fissure (open arrow).

ick arrow) and ‘‘fairy ring’’ sign (thin arrows). Subpleural small


Figure 6 Stage II sarcoidosis. Discrepancy with HRCT findings. (A) Chest radiograph: lymph node and lung involvement. (B and C)Axial HRCT: signs of fibrosis (peripheral subpleural basal honeycomb cysts---black arrows---and traction bronchiectasis---white arrow)not visible on chest radiograph; and nodular pattern. (D) Sagittal MIP image: centrilobular (white arrows) and subpleural (blacka half o

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rrows) small nodules with a slight predominance in the lower

Fig. 9). Air trapping is the second most common findingfter the lymphangitic nodular pattern. It can appear at anytage of the disease and sometimes is the only finding inhe lung fields. It is secondary to small airway obstructionaused by peribronchiolar or intraluminal granulomas.32,33

he morphology of air trapping on expiratory HRCT isobular, with patchy areas of decreased attenuation in com-arison with the rest of the parenchyma.34 Inspiratory HRCThows air trapping areas with decreased vascularizationaused by reflex vasoconstriction, and areas of decreasedttenuation (vascularization and mosaic attenuation pat-erns). Maximum and minimum intensity projections (MIPnd minIP) may also help in the visualization.35

HRCT is very useful in the assessment of theomplications of sarcoidosis such as chronic respiratoryailure secondary to fibrosis, pulmonary hypertension andemoptysis.36 The presence of a mycetoma in a cavitat-ng lesion is the main cause of hemoptysis in patientsith sarcoidosis (Fig. 8). Other causes are bronchiectasis,ecrotizing bronchial aspergillosis, semi-invasive pulmonary
spergillosis, erosion of a pulmonary artery due to an adja-ent necrotic lesion, and endobronchial lesions.
Bronchomalacia, or bronchial collapse at the end of expi-ation, also has been described as a complication of the

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ronchial involvement of sarcoidosis37 and it is associatedith greater air trapping.

igh resolution computed tomography diagnosis

he distinctive nodular pattern with lymphangitic distri-ution of sarcoidosis on HRCT is virtually pathognomonic.iagnostic accuracy increases when HRCT findings are inte-rated with clinical and chest radiographic data. A correctmaging diagnosis is almost always correct when based onhese findings.38,39

Despite the discrepancy between chest radiographic andRCT findings in a high number of patients due to the higherensitivity of HRCT in the detection of adenopathy, lungbnormalities and fibrosis, the prognostic value of HRCT hasot been sufficiently evaluated and staging is therefore stillased on chest radiographic findings.1,10

There are no imaging criteria indicative of reversibler irreversible disease or of progression to fibrosis (which
ppears in 20% of patients). Nonetheless, HRCT may pro-ide information about its potential reversibility38: nodulesre reversible in most cases, but not always; distor-ion of the lung architecture, traction bronchiectasis and


Figure 7 Stage IV sarcoidosis. (A and B) Axial HRCT: irregular dense bands (solid arrow) with traction bronchiectasis (open arrow)and distortion of lung architecture predominantly in the posterior segments of upper lobes and apical segments of inferior lobes.Multiple small nodules clustered together. (C) Coronal minIP image shows the predominant lesion distribution in middle fields,

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traction bronchiectasis and patchy areas of low attenuation sec

honeycombing are irreversible; ground-glass opacificationis unpredictable since it may remain stable, progress orresolve, depending on whether it corresponds to activedisease or macroscopic fibrosis (Fig. 10). A trial including40 patients in a 7-year follow-up period40 reported thatground-glass opacities and consolidations most frequentlyprogress to honeycomb cysts (5 and 3 patients, respec-tively), whereas abnormalities in nodular and large nodularpattern resolve or decrease in size. Fibrosis does not disap-pear and is associated with worse prognosis and increasedmorbidity and mortality.

The studies regarding the correlation of HRCT withother markers of activity such as 67Ga scintigraphy, lym-phocyte count and CD4/CD8 ratio in the BAL fluid andACE assay differ. However, the study by Leung et al.41

reported good correlation between these tests and theextent of nodules and consolidation. Correlation betweenHRCT and pulmonary function tests differs among studies,8

but the presence of fibrosis is associated with abnormaltests, especially in patients with honeycomb cysts. Func-tional impairment is relatively minor in patients with linearopacities or irregular bands

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ry to small airway involvement (star).

HRCT scanning should not be performed indiscriminatelyn all patients with suspected or proven sarcoidosis.42 Theoint statement of the ATS/ERS/WASOG (World Associationf Sarcoidosis and other Granulomatous Disorders) issuedn 19991 recommends lung CT scans in patients with atypi-al clinical and/or chest radiographic findings, when theres a normal chest radiograph but a clinical suspicion ofhe disease,43 and for the detection of complicationsf the disease such as bronchiectasis, aspergilloma, pul-onary fibrosis, traction emphysema, or superimposed

nfection or malignancy.

igh resolution computed tomography in theifferential diagnosis of sarcoidosis

he imaging differential diagnosis includes berylliosishistory of exposure to beryllium, with similar imaging
nd histologic findings), other pneumoconiosis (like sil-cosis and anthracosis), lymphangitis carcinomatosis andymphoma.44,45 In the ‘‘alveolar’’ variant of the disease,he differential diagnosis includes vasculitis, infections,


Figure 8 Stage IV sarcoidosis. (A and B) Axial HRCT: honeycomb cysts, some of them large in size, with predominant peripheraldistribution. Mycetomas in two of the honeycomb cysts (arrows) and hilar and mediastinal calcified adenopathy. (C) Sagittal HRCT:honeycombing predominantly in the middle fields. (D) Axial HRCT of a patient with predominant basal honeycombing, similar to IPF(lymph node biopsy by mediastinoscopy).

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ryptogenic organizing pneumonia, adenocarcinoma andymphoma.46 In patients with pulmonary fibrosis, the dif-erential diagnosis includes other causes of fibrosis suchs chronic extrinsic allergic alveolitis, IPF and lung fibro-is related to collagen diseases and to drug toxicity. Theresence of a nodular pattern helps in the diagnosis of theisease.47

racheal involvement

racheal involvement is rare and is either secondary toompression from adjacent lymph nodes or to the presencef granulomas within the airway mucosa and submu-osa resulting in luminal stenosis and wall thickening
hat can be smooth, irregular or nodular. Extensive tra-heal involvement may cause bronchomalacia.47 Differentialiagnosis includes tracheobronchopathy osteochondroplas-ica and relapsing polychondritis (which do not affecthe posterior tracheal wall), amyloidosis and Wegener’sranulomatosis.
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leural involvement

arcoid granulomatous involvement of the pleura is rare. Itauses pleural effusion that resolves in 2 or 3 months anday leave behind pachypleuritis.Spontaneous pneumothorax is a rare complication that

ccurs in 2---5% of patients with long-standing sarcoidosis,specially in those with fibrosis. Pneumothorax can be recur-ent, although it can also be the initial manifestation of theisease.48 Causes of pneumothorax include rupture of a sub-leural bleb or necrosis of a subpleural granuloma. Bilateralnd tension pneumothorax as well as hemopneumothoraxave also been described.49

ascular involvement

arcoid granulomatous involvement of the pulmonary arter-es and veins is noted in 42---89% of lung biopsies. However,linically significant pulmonary vascular involvement isncommon.


Figure 9 Airway involvement. (A) Axial HRCT and (B) coronal minIP image: complete bronchial obstruction of upper lobes (arrows),with distal atelectasis. Patchy areas of low attenuation secondary to small airway involvement. (C and D) Expiratory HRCT: patchy airtrapping areas (white stars) as the predominant manifestation of small airway involvement in a patient with lymph node involvement(black stars) (chest radiographic stage I disease).

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Pulmonary hypertension occurs in 1---5% of patients andis associated with higher mortality rates.10,50 The mech-anisms contributing to pulmonary hypertension includethe fibrous destruction of the pulmonary vascular bed,51

extrinsic compression of the central pulmonary arteries bylymphadenopathy, granulomatous mediastinitis52 and intrin-sic vasculopathy. Another cause of pulmonary hypertensionis left ventricular dysfunction.

Cardiac involvement

Cardiac sarcoidosis can be primary or secondary. Secondaryinvolvement corresponds to cor pulmonale secondary topulmonary disease-related hypertension. Primary cardiacsarcoidosis is caused by myocardial infiltration with gran-ulomas resulting in restrictive cardiomyopathy or heartfailure.53 Its incidence in autopsies of patients with sar-coidosis ranges between 20 and 60%. Nonetheless, cardiac
involvement is seldom recognized during the course of sar-coidosis since myocardial infiltration is usually silent andapproximately only 10% of the patients have symptoms.Given the fact that cardiac sarcoidosis can lead to sudden
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eath, early diagnosis and prompt treatment are essentialor these patients. However, there is not scientific evidenceupporting the screening for cardiac involvement in asymp-omatic patients with proven sarcoidosis.54

The most common manifestations include atrioventric-lar conduction defects and branch blocks, followed byustained and non-sustained ventricular tachycardia andtrial arrhythmia.54

Ventricular wall infiltration with granulomas may resultn decreased myocardial contractility (systolic failure) orecreased ventricular relaxation (diastolic failure), witheart failure in both cases. Heart failure may also resultrom mitral dysfunction secondary to infiltration or rupturef papillary muscles. When heart failure occurs, the diseases generally in the late stages.

Since none of the diagnostic modalities available com-ines high sensitivity and high specificity, the diagnosishould be based on a combination of ECG, morpho-ogic, functional and/or histologic findings. Magnetic
esonance imaging (MRI) is the most sensitive and specificon-invasive technique for the diagnosis of cardiac sar-oidosis and the most useful imaging technique for earlyiagnosis.


Figure 10 Progression of the disease, before (A) and after(B) treatment: resolution of peribronchovascular consolidationsand of many diffuse small nodules with randomly distributedpredominantly in the lower lobes. Bronchiectasis and loss ofvolume persist in RLL. An irregular line (arrow), visible beforet

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Table 3 Areas of cardiac involvement, listed from the mostto the least common.

Free wall of the left ventricleInterventricular septumFree right ventricular wallRight atrium

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reatment, has appeared in the site of the large nodule (star).

The most common MRI findings are morphologic andunctional abnormalities (areas of ventricular dilation, seg-ental contractility defects and areas of basal thinning

f the left ventricle), valve insufficiency and pericardialffusion. In addition, MRI provides additional informationuring T2-weighted and delayed gadolinium enhancementequences.55

Cardiac MRI helps identify the three stages in the diseaserocess: the initial phase of edema that is followed by gran-lomatous infiltration, and last phase of postinflammatorycarring. These stages may superimpose and findings of thehree stages may be found in the same patient.56

The administration of a contrast agent (0.1 mmol/kg) isssential for the diagnosis of cardiac sarcoidosis. First steperfusion and ‘‘black myocardium’’ sequences are analyzed;his way, the normal hypointense myocardium contrasts withbnormal areas, characteristically hyperintense. Myocar-ial scarring appears as patchy areas of hypokinesis andyocardial thinning, with enhancement in a predomi-

antly subpericardial distribution on ‘‘black myocardium’’
equences. Cases of subendocardial enhancement in areasf hypokinesis and thinning have been described although,nlike ischemic heart disease, cardiac sarcoidosis shows no
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ascular distribution. Steroid treatment reduces the areasf edema and of delayed enhancement57 (Fig. 11).

Myocardial abnormalities are more common than pericar-ial, with a special predilection for the basal segments andree left ventricular wall and less commonly for the rightentricle and atria58,59 (Table 3).

Other diagnostic techniques include ECG, echocardio-raphy, positron emission tomography (PET), gallium-67nd/or thallium-201 scintigraphy and endomyocardialiopsy.60

istologic diagnosis

he aim of histologic examination in patients with suspectedulmonary sarcoidosis is to provide evidence of well-formedon-necrotizing granulomas with a perilymphatic distribu-ion. This is achieved in most cases by transbrochial biopsyTBB), which has a sensitivity of 80---90%. TBB may detectulmonary disease in the absence of HRCT abnormalities.RCT increases the diagnostic accuracy of TBB by helping

n the selection of the sites with sarcoid activity and guidinghe biopsy.61 Given the fact that endobronchial involvements common in sarcoidosis, endobronchial biopsy can increasehe diagnostic value of bronchoscopy when added toBB.62

Surgical biopsy of mediastinal adenopathy, by medi-stinoscopy or mediastinotomy, and lung biopsy, by openiopsy or videoassisted thoracoscopic, are indicated only inase of clinical and radiological suspicion of sarcoidosis whenther types of biopsy are nondiagnostic.

Both TBB and lung biopsy should be performed at sitesf disease activity, identified by HRCT. Some studies haveeported that PET scanning help locate occult sites of activeisease and perform the biopsy.64

In addition to detecting sarcoid granulomas, theathologist should rule out bacterial, mycobacterial andungal infections, berylliosis, granulomatosis caused byntravenous injection of talc, extrinsic allergic alveolitis,nd drugs such as methotrexate, lymphoma and vasculitis.arcoidlike reactions in lymph nodes and lung parenchymaave also been described in patients with thoracic andxtrathoracic malignancies.65 Granulomas with a sarcoid-ike pattern are, by themselves and in the absence of andentifiable cause, nonspecific lesions and not diagnostic ofarcoidosis.66

In patients with suspected cardiac sarcoidosis, endomy-cardial biopsy can demonstrate edema, non-necrotizing

iopsy may frequently be negative in cardiac sarcoidosis.his is due to the patchy distribution of the cardiac lesionsnd to the fact that biopsy specimens are taken from the


Figure 11 Cardiac sarcoidosis. Patients with heart rate alterations, cardiac enzymes and normal cardiac catheterism. The patientrequired cardiac transplantation and the explanted specimen confirmed the diagnosis. (A) Four-chamber gradient echo sequence:apical thinning of left ventricle, which appears slightly dilated (black arrow). (B and C) Four-chamber and short-axis, respectively,‘‘black myocardium’’ sequences show and area of delayed transmural (arrow) and subendocardial enhancement in left ventri-cle that extends to the papillary muscle (arrow and white star). Courtesy of Dr Álvarez López, Center of Magnetic Resonance,León.

siaodwcbt


apical interventricular septum, at the side of the rightventricle.60 The sensitivity of endomyocardial biopsy is thuslow (20---63%) which, together with the invasive nature ofthe technique, makes other diagnostic approaches more rec-ommended. A positive biopsy is therefore not needed fordiagnosis.1

Consensus diagnosis based on clinical imaging
and pathologic findings
The final diagnosis of pulmonary sarcoidosis is establishedwhen compatible clinical and radiological findings are

s

ta

upported by histologic evidence of noncaseating, or min-mally caseating, granulomas in a lymphangitic distributionnd once other diseases with similar findings are ruledut.67,68 In cases of typical presentation of Löfgren’s syn-rome, biopsy is not needed. A diagnosis of high probabilityithout histologic confirmation is also accepted whenompatible clinical and radiological findings are supportedy a BAL CD4/CD8 ratio >3.5 (specificity 93---96%, and sensi-ivity 53---59%).63,69 In multidisciplinary teams, the diagnosis
hould be established by consensus.70
Although not widely accepted by the international scien-ific community, the Japanese Ministry of Health Guidelinesre very useful in the diagnosis of cardiac sarcoidosis

446

Table 4 Criteria issued by the Japanese Ministry of Healthfor the diagnosis of cardiac sarcoidosis.

Histologic diagnosis group: cardiac sarcoidosis is confirmedwhen endomyocardial biopsy demonstrates epithelioidcell granuloma and noncaseating granuloma.

Clinical diagnosis group: cardiac sarcoidosis is suspectedwhen extracardiac sarcoidosis has been histologicallyproven, when item (a) and one or more items (b---e) aresatisfied:(a) Complete right branch block, left axis deviation, AVblock, ventricular tachycardia, premature ventricularcontraction, pathologic Q wave or ST---T changes on ECG.(b) Motion abnormalities in left ventricular wall, focalthinning of the ventricular wall or left ventriculardilation.(c) Perfusion defects detected by thallium-201scintigraphy or abnormal enhancement on gallium-67or technetium-99m scintigraphy.(d) Abnormal intracardiac pressure, low cardiac output ormotion abnormalities in left ventricular wall or decreasedleft ventricular ejection fraction.

(as

A

1

C

T

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2


(e) Interstitial fibrosis or at least moderate cell infiltrationeven with nonspecific findings.

Table 4).54 New research studies are thus needed to develop diagnostic algorithm to assess the cardiac involvement ofarcoidosis.68

uthorship

1. Responsible for the integrity of the study: IHO.2. Conception of the study: IHO.3. Design: IHO.4. Data collection: IHO, LLG.5. Analysis and interpretation of data: IHO, LLG.6. Statistical analysis: N/A.7. Bibliographic search: IHO, LLG.8. Drafting of the manuscript: IHO, LLG.9. Critical review with intellectually relevant contribu-

tions: IHO, LLG.0. Approval of the final version of the manuscript: IHO,

LLG.

onflict of interest

he authors declare no conflicts of interests.

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