Diagnosing sarcoidosis.

REVIEW URRENT C OPINION

Diagnosing sarcoidosis Daniel A. Culver

Purpose of review The usual diagnostic criteria for sarcoidosis include the documentation of a compatible clinicoradiologic scenario, biopsy proof of granulomas, and exclusion of alternate causes for the findings. Establishing the presence of multisystem disease, and longitudinal assessment for the emergence of potential sarcoidosis mimics both strengthen the diagnosis. These principles have constituted a ‘diagnostic modus operandi’ for several decades, but the emergence of several new technologies has begun to transform their application. Recent findings The widespread availability of high-resolution chest computed tomography, endobronchial ultrasoundguided transbronchial needle aspiration, rapid on-site cytopathology and to a lesser degree, fluorodeoxyglucose positron emission tomography have facilitated more convenient diagnosis. They also have identified possibilities for biopsy-less diagnosis in appropriate clinical contexts, similar to idiopathic pulmonary fibrosis, and allowed for more comprehensive assessment of the extent and activity of disease. Nonetheless, these new technologies cannot replace the central role of the clinician, whose judgment and circumspection are keys to accurate diagnosis. Summary The diagnosis of sarcoidosis and the assessment of its extent should be tailored to the clinical situation. The application of new technologies may permit some evolution of the diagnostic approach in many patients. Keywords diagnosis, endobronchial ultrasound-guided transbronchial needle aspiration, fluorodeoxyglucose positron emission tomography scan, heuristic, high-resolution chest computed tomography

INTRODUCTION The general approach for establishing a diagnosis of sarcoidosis has not changed substantially since the advent of flexible bronchoscopy nearly 50 years ago. In the past decade, however, new diagnostic technologies have emerged, been evaluated, and then incorporated widely into clinical practice. The current standard approach for diagnosis and assessment of sarcoidosis makes use of the newer modalities, but the general architecture of how the diagnosis and assessment is performed has not evolved substantially to date [1,2]. The process generally relies on documenting compatible clinical, radiologic, and pathologic data, and reasonably excluding the likelihood of alternate explanations for the findings. Establishing the presence of multisystem disease, and longitudinal assessment for the emergence of potential sarcoidosis mimics both strengthen diagnostic confidence. However, since sarcoidosis often presents as a syndrome with nonspecific symptoms, and may resemble several other maladies, the challenge of making a diagnosis commonly leads to delays [3]. The determination of whether organs are affected by sarcoidosis, or whether patient

symptoms are related to sarcoidosis, can be even more challenging than the diagnosis itself. This review will focus on the general approach to the diagnosis of sarcoidosis, primarily for pulmonary disease, which is the most commonly affected organ and the most frequently available site for biopsy [4,5]. The emergence of the newer technologies is leading to more individualized approaches to the diagnosis and assessment of sarcoidosis; however, astute clinical judgment remains crucial at present.

DIAGNOSTIC HEURISTIC The diagnosis of sarcoidosis and the diagnosis of its extent are not uniform exercises, identical in all Department of Pulmonary Medicine, Respiratory Institute, Cleveland, Ohio, USA Correspondence to Daniel A. Culver, DO, Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel: +1 216 444 6508; fax: +1 216 636 5384; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:499–509 DOI:10.1097/MCP.0000000000000201

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Sarcoidosis

investigations’ [6], the definition of ‘too small’ is not invariable. The clinician’s diagnostic aggressiveness should be tailored to the clinical situation [7]. For example, a patient with classic-appearing pulmonary disease that does not require treatment may warrant only very basic testing to survey major organ involvement, perhaps forgoing a biopsy diagnosis altogether. In contradistinction, a patient with a high chance of alternative diagnoses and severe organ impact may require very aggressive testing (e.g., brain biopsy in the setting of atypical brain imaging findings, or suspected isolated neurosarcoidosis) to arrive at a level of sufficient diagnostic certainty for confident decision-making. Figure 1 depicts some considerations for tailoring the pace, scope, and intensity of diagnostic testing. The same general construct can be applied for the attribution to sarcoidosis of symptoms, signs, or test results in patients with previously established diagnoses of sarcoidosis in other organs. The morbidity, expense, and anxiety provoked by subjecting the patient to a long series of tests may be unnecessary or even punitive. Two factors that should additionally be considered in this diagnostic heuristic are some reasonable estimation about the

KEY POINTS Diagnosis of sarcoidosis requires an integrated assessment of clinical, radiologic, and pathologic information. The aggressiveness of diagnostic testing depends on the clinician’s confidence and the stakes involved. The strategy is tempered by patient input, clinician comfort, and local capabilities. EBUS-TBNA is becoming the diagnostic procedure of choice in many centers, because of high sensitivity and low complication rate. Specific radiologic patterns on HRCT may allow confident diagnosis despite biopsy. FDG-PET scanning permits the visualization of unsuspected biopsy targets, as well as documentation of occult disease activity in persistently symptomatic patients.

patients. Although a presumed diagnosis may be reached when ‘the statistical likelihood of alternative diagnoses is too small to warrant further

Patient needs and preferences

Aggressive

Stakes

testing

Predicted treatment intensity

Less

Severity of organ involvement

testing

Uncertain

Confident Summative pre-test probability assessment

Clinicoepidemiologic features

Likelihood of mimics

Radiologic serologic data

FIGURE 1. Schema for theoretical decision-making when planning the pace, scope, and intensity of testing to diagnose sarcoidosis. Similar considerations apply to the use of testing to define organ involvement or to determine whether a symptom or sign could be because of sarcoidosis. ‘Stakes’ refers to the impact of missing or delaying a diagnosis. For example, in a situation with high stakes and low diagnostic confidence, testing should be aggressive. In the opposite scenario, low stakes and high pretest confidence, it may be unnecessary to perform any testing. Some patients who have traditionally required biopsies to confirm sarcoidosis fall in the latter category. The exact location of the line dividing testing from no testing also depends on patient input, local capabilities, and the clinician’s comfort. 500


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Diagnosing sarcoidosis Culver

future clinical course, and the opinion of the patient. Establishing a diagnosis as confidently as possible at the outset of therapy is typically more straightforward than after the waters are muddied by immunosuppressive medications. In situations where it is likely that the illness will persist or be difficult to manage, relatively more precedence should be placed on diagnostic confidence prior to the initiation of therapy. However, there may also be patients for whom prebiopsy diagnostic confidence is very high, and the likely treatment course relatively brief, for whom tissue diagnosis has a very low chance of altering treatment strategy or the course. Similarly, the opinion of the patient should be solicited and carefully considered at each step of the process when determining how avidly a diagnosis will be sought. Establishing a diagnosis of sarcoidosis has traditionally involved a three-step process: a clinical scenario resembling sarcoidosis should be present; biopsy proof of granulomas consistent with sarcoidosis should be obtained; and alternative explanations of granulomatous inflammation should be excluded [1,8]. However, this broad strategy was formulated prior to the advent of high-resolution computed tomography (HRCT) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans, and the widespread use of a less invasive highly sensitive technique for documenting granulomas endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). These new technologies have challenged the principles of sarcoidosis diagnosis, paradoxically rendering the pathologic documentation of granulomatous inflammation more accessible and diminishing its importance simultaneously by elevating the necessity to weigh clinic-radiologic data even more carefully than in the past. The availability of newer tools has instead perhaps elevated the responsibility of the clinician, who ultimately is the individual responsible for conferring a sarcoidosis diagnosis [9].

CLINICAL PRESENTATION OF SARCOIDOSIS Sarcoidosis involves the lungs in approximately 90% of patients [5], but causes pulmonary symptoms at presentation in only slightly more than half [10]. The most common thoracic symptoms include exertional dyspnea, nonproductive cough, wheezing, and chest pressure. The chest examination is usually unremarkable; a finding of clubbing or rales should suggest the possibility of an alternative diagnosis. In patients with airflow obstruction, wheezing may be heard; sometimes, the wheezing is focal, representing large airways obstruction from

extrinsic compression, architectural distortion, or endobronchial sarcoidosis. However, the presence of inspiratory squeaks is more typical of a sarcoidosis mimic hypersensitivity pneumonitis [11]. Systemic symptoms are common as well, including fatigue, arthralgias, weight loss, fever, peripheral neuropathy, and depression [12,13]. When the salient major organ involvement is extrapulmonary, the symptoms depend on the location and extent of the granulomas or fibrosis. However, it is often illuminating in the initial diagnostic interview to inquire about a history of suggestive features such as red eyes, blurry vision, floaters, renal lithiasis, unusual rashes, palpitations, and unexplained cranial neuropathies. Combinations of symptoms and historical clues may be helpful to establish a priori–diagnostic suspicion that can inform the interpretation of subsequent tests. Medical conditions or exposures that can cause granulomatous reactions, or that can mimic sarcoidosis radiologically, should be explored in the history. The presence of confounding clinical features does not exclude the possibility of sarcoidosis but will decrease its likelihood. Table 1 lists several clinical and laboratory features that may be helpful to build a case for or against the diagnosis of sarcoidosis. A careful occupational and avocational history may reveal unsuspected exposures that could cause granulomatous reactions. For example, in surveys of two sarcoidosis referral clinics in Germany and Israel, 6% of patients had evidence of chronic beryllium disease [14,15]. More recently, a syndrome of granulomatous inflammatory infiltration has been recognized in patients with immunodeficiency syndromes such as common variable immunodeficiency [16 ]. Biochemical data are nonspecific but may also provide support for the diagnosis of sarcoidosis. Serum angiotensin converting enzyme is elevated in approximately 57–66% of sarcoidosis patients, with an overall specificity of approximately 84–90% [17–19]. Increased soluble interleukin 2 receptor, a marker of lymphocyte activation, is increased in approximately 47–70% of patients, but also suffers from poor specificity [20–22]. Several other commonly available features may be found in the peripheral blood, including hypergammaglobulinemia (especially in blacks), lymphopenia, and elevated liver function tests [23,24]. Obviously, none of the serologic data are specific enough to serve as the main basis for a diagnosis. &

RADIOLOGIC EVIDENCE OF SARCOIDOSIS As far back as 1991, Grenier et al. [25] established that a diagnosis of sarcoidosis could be made in up




501

Sarcoidosis Table 1. Clinical features that may be helpful for assessing the likelihood of sarcoidosis More confident

Less confident

African-American or Northern European

Age < 18

Female

Smoking history

Asymptomatic presentation

Exposure to metal dusts, bioaerosols, and organic antigens

Hypergammaglobulinemia

History of exposure to tuberculosis

Peripheral blood lymphopenia

History of recurrent infections

Age > 60 in males

Elevation of liver enzymes or serum calcium

Hypogammaglobulinemia

Family history of sarcoidosis

Systemic disease capable of inducing granulomatous reactions Malignancy Inflammatory bowel disease Immunodeficiency

Elevated biomarkers (ACE, sIL2R, or 1,25-(OH)2-Vitamin D

Rales Clubbing

Multiorgan disease

Single organ disease

ACE, angiotensin-converting enzyme; sIL2R, soluble interleukin 2 receptor.

to 92% of cases using specific features of the HRCT scan, and that a highly confident diagnosis could be reached in 72% of sarcoidosis patients among a cohort of patients with parenchymal infiltration on chest radiograph. This line of reasoning is an extension of the argument first proposed by Winterbauer et al. [26] and later promulgated by Reich et al. [27], who demonstrated that asymptomatic patients with bilateral hilar lymphadenopathy (BHL) on plain chest radiograph, and who had no overt alternate explanation or sign, could be diagnosed with sarcoidosis with a high degree of confidence. In a cardinal analysis, Reich et al. [27] estimated that over 1800 patients with BHL would require invasive procedures to obtain one patient with an alternate cause. A key aspect of this approach, however, is that astuteness and circumspection by the diagnostician is central to interpretation and to diagnosis proposed in the absence of biopsy. In an era of widespread availability of chest computed tomography scanning, there are surely additional clinicoradiologic scenarios that do not mandate a biopsy [28,29]. This point is evidenced by the ability of multiple investigators to cherry-pick sarcoidosis cases in some of the EBUS-TBNA trials, prior to bronchoscopy, such that 92–98% of the cohorts had a final diagnosis of sarcoidosis [30,31 ]. The same line of reasoning has led to the use of specific HRCT features to make an accurate diagnosis of idiopathic pulmonary fibrosis in approximately 30–40% of individuals [32]. As an initial demonstration of the concept, a group of French investigators constructed a data algorithm for the analysis of CT characteristics, which combined with simple &&

502


clinical features, was able to diagnosis sarcoidosis with 97% accuracy [33]. Plain chest radiography has traditionally been deemed sufficient to guide diagnostic testing and stage sarcoidosis, but with widespread availability of CT scanners and the need to plan EBUS-TBNA for diagnosis, most patients with suspected sarcoidosis now have at least one chest CT scan prior to biopsy. Intravenous contrast is usually unnecessary, but the scan should be performed with thin section (1–2 mm) collimation to facilitate the detection of subtle abnormalities. Several CT features are relatively specific for sarcoidosis, and when more than one is present in a patient with the correct clinical features, the diagnosis of sarcoidosis may be confidently made without biopsy [28]. CT features of sarcoidosis are listed in Table 2.

FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY SCAN FDG-PET scan can reveal unsuspected sites of inflammation, guiding the selection of potential biopsy sites [34,35 ]. In a Dutch cohort, FDG-PET/CT revealed evidence of persistent inflammation in the thorax (58%) and extrathoracic locations (46%) despite unremarkable findings with routine testing, including serologic markers of sarcoidosis activity [35 ]. FDG-PET/CT scanning is also useful to assess response to therapy [36,37]. Perhaps the most interesting recent advance in PET scanning, however, is to aid the diagnosis and prognostication for cardiac sarcoidosis. In a study evaluating 118 consecutive patients with suspected cardiac sarcoidosis, the presence of &

&



Diagnosing sarcoidosis Culver Table 2. Selected chest computed tomography features suggesting sarcoidosis Relative frequency in sarcoidosis

Major differential considerations

Perilymphatic nodules predominating in the mid-to upper lung zones

þþþ

Granulomatous infection (usually unilateral)

Nodular thickening of the bronchovascular bundles, interlobular septae, fissures and/or pleura Bilateral hilar lymph node enlargement

þþþ

Lymphangitic tumor spread

þþþþ

Lymphoma, granulomatous infection, heart failure, reactive lymphadenopathy

‘Frosted’ calcification pattern of lymph nodes

þ

Early phase of fungal infection

‘Conglomerate’ bilateral perihilar masses

þ

Silicosis/coal workers pneumoconiosis

Symmetric peribronchial upper lobe predominant architectural distortion

þþ

Silicosis/coal workers pneumoconiosis, chronic hypersensitivity pneumonitis

Curvilinear upper lobe bronchial distortion

þ

Feature

Other features may be seen in sarcoidosis, including larger nodules, ground glass opacities, cavitary lesions, effusions, or clustered nodules (so-called galaxy sign).

inflammation or perfusion defects was associated with a hazard ratio of 3.9 for death or ventricular tachycardia, and remained significant even after adjusting for ejection fraction and other clinical evidence of cardiac disease [38 ]. Other groups have confirmed the prognostic implications of active FDG uptake [39 ,40]. Novel radiotracers, such as 68-Gasomatostatin receptor constructs, are not only gaining acceptance in neuroendocrine tumors, but also image activated lymphocytes avidly [41]. Used in combination with PET/CT scanning, these tracers may generate further advances for localizing and quantifying inflammation [41]. &&

&

ENDOBRONCHIAL ULTRASOUND-GUIDED TRANSBRONCHIAL NEEDLE ASPIRATION AND OTHER BRONCHOSCOPIC TECHNIQUES EBUS-TBNA improves the diagnostic yield of bronchoscopy. In a meta-analysis of 15 trials performed mainly in populations with high pretest likelihoods of sarcoidosis, the pooled diagnostic yield of EBUSTBNA for sarcoidosis was 79% (range 54–93%)[42]. It has been estimated that 87% of sarcoidosis patients with isolated mediastinal lymphadenopathy could be spared from mediastinoscopy [43]. However, much of the initial EBUS-TBNA data suffered from doubts about external validity because of highly selected study populations [30,44]. This limitation has been addressed recently in several publications. In a randomized trial of Indian patients with suspected sarcoidosis, the sensitivity of EBUS-TBNA for demonstration of granulomas was 75%, compared with 48% for conventional TBNA [45 ]. In Indian and Chinese populations of patients with high endemic rates of tuberculosis &&

who presented with unselected mediastinal lymphadenopathy, EBUS-TBNA had sensitivity values of 52–81% for sarcoidosis [46,47]. For overall diagnosis, the sensitivity and specificity were 82–92%, and 100%, respectively. A recent meta-analysis of 14 reports in clinically unselected populations (2097 total patients; sarcoidosis prevalence 1–37%) confirmed the usefulness of EBUS-TBNA for establishing the diagnosis [48 ]. In that analysis, the overall sensitivity was 84%; prevalence of sarcoidosis in the studied population did not influence the diagnostic accuracy of EBUS-TBNA. The more recent reports suggest that EBUS-TBNA can be applied broadly in practice, dependent on availability and the development of operator expertise. The safety of EBUS-TBNA is excellent, with 0.04% mortality for intrathoracic sampling [49]. Serious adverse events occurred in 23 of 16181 patients in a large systematic review (0.14%) [50]. The most common complication appears to be mediastinal or pulmonary infection [50]. As a result of the excellent diagnostic accuracy and low complication rate, EBUS-TBNA is rapidly becoming the diagnostic procedure of choice when a tissue diagnosis in the lungs is sought. On the other hand, the ascendancy of EBUSTBNA results has caused an unanticipated pitfall equating the presence of granulomas with a diagnosis of sarcoidosis, perhaps in part because of the relative ease of documenting granulomas. Instead of a diagnosis requiring a synthesis of all the available data, many patients may be labeled with sarcoidosis without the requisite consideration of alternative explanations for granulomatous inflammation. To illustrate this issue, we assessed the final clinical diagnosis after careful assessment and additional testing in 234 consecutive patients referred to our


&&



503

Sarcoidosis

center for the management of presumably established sarcoidosis over a period of 18 months. Of the referred patients, 39 (17%) were found not to have sarcoidosis after careful assessment including additional history, imaging, and serologic testing. Among the erroneous diagnoses, 51% had biopsies documenting granulomatous inflammation, including one-third with granulomata indistinguishable from sarcoidosis (3% of the total group). This experience demonstrates the crucial role of careful clinical assessment; the implication of these data is that clinical and radiologic features may be more important than biopsy information in some patients with possible sarcoidosis, and that the granuloma may not be the crucial data point necessary to obtain the requisite diagnostic confidence about the presence or absence of sarcoidosis. Other bronchoscopic techniques add to the diagnostic accuracy of EBUS. Transbronchoscopic lung biopsy (TBBx) yields granulomas in an additional 8–16% of patients when performed in conjunction with EBUS-TBNA [45 ,51–53]. However, the routine use of TBBx increases the length of the bronchoscopic procedure and may unnecessarily risk complications such as pneumothorax and bleeding. Endobronchial biopsies may also be helpful, especially in patients with visible mucosal abnormalities, but does not appear to increase the sensitivity of bronchoscopy sufficiently to warrant routine use when combined with EBUS-TBNA [45 ,51,53]. One advantage of tissue biopsies in difficult cases is that the anatomic location of the granulomas may be helpful sarcoidosis granulomas are generally located in the bronchial submucosa, whereas infectious granulomas typically erode into the luminal surface or the air sacs. Rapid on-site cytologic evaluation (ROSE) of specimens allows the determination of which patients should proceed to additional biopsy procedures, and which ones require only the EBUSTBNA as a biopsy technique. In a prospective Australian study of 60 patients, ROSE of TBNA specimens confirmed the diagnosis in 88% of patients, with a specificity of 91% and positive predictive value of 98%, obviating the need for additional biopsy procedures [54]. Sonographic characteristics may also be useful to gauge the likelihood that sarcoidosis is present, thereby informing decisions about aggressiveness of the bronchoscopic evaluation. For example, sarcoidosis is favored compared with infection when there is a granular rather than smooth appearance, distinct nodal margins, and absence of necrosis [55,56]. Homogeneous low echogenicity and the presence of a germinal center structure are observed in sarcoidosis more frequently than in cancer [57]. However, the use of sonographic characteristics should be considered &&

&&

504


adjunctive to all the other available data, and will likely depend on the experience of the bronchoscopist. Bronchoalveolar lavage (BAL) should be performed in all patients who have bronchoscopy, as the added time and risk of the procedure are minimal. The technique for BAL has been reviewed previously [58]. In centers with experience assessing cell counts, a differential count should be obtained. The BAL can bolster diagnostic confidence, especially in situations where biopsies were unrevealing, and it may also yield prognostic data. Greater than 15% lymphocytes in BAL fluid has a sensitivity of 90% for the diagnosis of sarcoidosis, although the specificity is low [59]. In one study, a lymphocyte CD4/CD8 ratio of greater than 3.5 had a sensitivity of 53%, specificity of 94%, a positive predictive value of 76%, and a negative predictive value of 85% for the diagnosis of sarcoidosis [59]. A grouping of features, such as an elevated total cell count, predominantly lymphocytes, together with a nearly normal percentage of eosinophils and neutrophils and the absence of plasma cells, distinguishes the most likely diagnosis of sarcoidosis from the most common interstitial lung diseases [60]. A finding of more than 3% neutrophils in the BAL fluid suggests a worse prognosis [61,62]. Finally, BAL is important in some cases for excluding infection that may cause granulomatous reactions in the mediastinal lymph nodes without obvious pathogens. For example, for discriminating smear-negative tuberculosis from sarcoidosis, BAL is especially important, with 72% of patients diagnosed using that technique versus 15–30% for other bronchoscopic modalities including TBNA [63].

GRANULOMAS Typically, sarcoidosis granulomas are well-formed clusters of epithelioid histiocytes, together with a few multinucleated giant cells, surrounded by an outer margin of T-lymphocytes. A variable rim of collagen and fibroblasts surrounds the granuloma. Pathologic assessment of sarcoidosis should include stains and cultures for mycobacteria and fungi, which can occasionally cause non-necrotizing granulomas. Sarcoidosis granulomas frequently exhibit focal necrosis [64], but it is rarely widespread or suppurative. The granulomas in sarcoidosis tend to be found in the airway’s submucosa, along the bronchovascular bundle, and in the lymphatics that run along the intralobular septae and pleural surfaces [65–67]. Apart from necrosis, features that suggest alternate diagnoses include loose or poorly formed granulomas, the presence of polarizable material in Volume 21 Number 5 September 2015




Prurigo nodularis

Drug eruptions Foreign body reaction (debris, metals, and inflammation)

Infections (mycobacteria and fungi)

Lupus erythematosus Foreign body reactions


Skin

Medication reactions GLUS

IgG4-related disease

Castleman’s disease Granulomas associated with immune dysregulation syndromes

Histiocytic necrotizing lymphadenitis (Kikuchi’s disease)

Viral (mononucleosis, HIV, and HSV)

Lymphoma or other malignancies Granulomatous tumor reactions

Foreign body granulomas (inhaled particulates or aspiration)

Infection (mycobacteria, fungi, bartonella, toxoplasmosis, and brucella) Lymph node

Granulomatosis and polyangiitis (Wegener’s) Medication reactions

GL-ILD

Asthma

Malignancy (lymphoma, metastatic malignancy, adenocarcinoma) Granulomatous tumor reactions

Interstitial lung disease (RB-ILD and NSIP)

Hypersensitivity pneumonitis metal exposure (beryllium, aluminum, titanium, and zirconium)

Infection (mycobacteria, fungi, and pneumocystis)

Other mimics

Lunga

As sarcoidosis is a multisystem disease, whereas some mimickers of sarcoidosis such as localized foreign body reactions and granulomatous responses to inhaled antigens tend to involve a single organ only, it has been proposed that the diagnosis of sarcoidosis requires evidence of at least two involved organs [73]. However, in practice, multiorgan involvement is readily apparent in only about 50% of patients [5], so that a requirement for radiologic, clinical, or pathologic confirmation in a second organ entails either additional testing or prevents the patient from obtaining a definite diagnosis altogether. For pulmonary sarcoidosis, there is little evidence that patients with single organ involvement have a materially different presentation than those with extrapulmonary disease, so that differentiating these categories may not be tremendously helpful. However, isolated granulomatous inflammation in certain organs (skin, liver, and muscle) cannot be used to confidently diagnose sarcoidosis [65], and further evidence of other organ involvement should be sought if making a diagnosis is deemed clinically

Granulomatous histopathology

IS EVIDENCE OF MULTISYSTEM DISEASE MANDATORY?

Table 3. Common or significant major differential diagnosis of sarcoidosis by organ

the granulomas, organizing pneumonia, mononuclear cell infiltrates, and atypical distribution. Sarcoidosis is by far the most frequent cause of noninfectious granulomatous inflammation in lung biopsies, comprising 27 and 21% of all cases of granulomatous lung disease in two large series [68,69]. However, the specific cause of infectious granulomas is dependent on geography in the USA, endemic fungal disease (69% of cases) predominates, whereas mycobacterial disease (80% of cases) is the most common infectious cause elsewhere [68]. Table 3 [65] lists some pathologic and clinical mimics that can be confused with sarcoidosis. Although cytopathologic specimens yield less morphologic information, careful assessment of cytology granulomas may nonetheless be informative. The presence of significant necrosis should raise the possibility of infection. In comparison to histoplasmosis, sarcoidosis granulomas tend to be more numerous, rounded, well formed, and lack necrosis in or around the granuloma; the granulomas from histoplasmosis are fewer (i.e., less than 2/slide), exhibit ragged borders, and often contain yeast forms when necrosis is seen [70]. In cases with tuberculosis, necrosis is also often present, but the cytopathologic distinction of tuberculosis from sarcoidosis is difficult, and cultures should be obtained when it is suspected [71,72]. Stains for acid-fast bacilli are less sensitive than for fungi in pulmonary infections [68].

Organ


505

506


Eosinophilic myocarditis

Lymphoma

GLUS


Granulomas associated with immune dysregulation syndromes

GLUS

Infections (mycobacteria and fungi)

Inflammatory bowel disease

Granulomatous tumor reactions

Malignancy (lymphoma and glioblastoma)

CNS vasculitis

Infections(HIV and lyme disease)

Neuromyelitis optica (Devic’s disease)

Multiple sclerosis

GL-ILD, granulomatous lymphocytic interstitial lung disease; GLUS, granulomatous lesions of undetermined significance; HSV, herpes simplex virus; NSIP, nonspecific interstitial pneumonitis; RB-ILD, respiratory bronchiolitis interstitial lung disease. Reproduced with permission from [65]. a (including intrathoracic LNs).

Spleen

Granulomatous tumor reactions

Ischemic and nonischemic cardiomyopathy

Amyloidosis

Arrythmogenic right ventricular dysplasia

Giant cell myocarditis

Idiopathic uveitis

Vasculitis

Infections (mycobacterial and syphilis)

Autoimmune hepatitis

Foreign material (e.g., mineral oil)

Medications

Primary sclerosing cholangitis Medications

Inflammatory bowel disease

Viral hepatitis

Isolated hepatic granulomatosis

Steatohepatitis

Primary biliary cirrhosis

Vasculitis

Other mimics

Infections (tuberculosis, brucella, and schistosomiasis)

Lymphoma

Nodular vasculitis

Crohn’s disease

Elastolytic granuloma

Rheumatoid nodule/granuloma annulare

Granulomatous histopathology

Central nervous system Infections (tuberculosis, histoplasmosis, and cryptococcosis)

Heart

Eye

Liver

Organ

Table 3 (Continued)

Sarcoidosis



important. Recently, the World Association of Sarcoidosis and Other Granulomatous Disorders published a guideline for the diagnosis of organ involvement in sarcoidosis [74]. The instrument is useful for clinical trials or registries, and to survey the opinions of experts in the field about which testing is most conclusive, but it suffers from the limitation that it is unable to accommodate the complexity of clinical judgment. For example, assessment of organ involvement in clinical practice usually involves some combination of amalgamating all the available test results pertaining to the organ in question, consideration of the chronicity and severity of the findings, and some evaluation of the likelihood of alternate diagnoses. By their nature, static clinical instruments are unable to accommodate the complexity of clinician judgment in patient care.

demonstrating granulomas in thoracic lymph nodes, but it has not eliminated the requirement that the diagnosis of sarcoidosis includes careful consideration of alternate explanations for the presence of granulomas. With the proliferation of new technologies, the planning of the diagnostic strategy entails some integrated consideration of the pretest diagnostic confidence and the stakes involved in the decision. In some patients, biopsy may become a less relevant factor for establishing the diagnosis in the lungs or in other organs.

FUTURE DIAGNOSTIC TECHNIQUES

Conflicts of interest There are no conflicts of interest.

Although no single biomarker confers adequate accuracy to diagnose or assess sarcoidosis, combinations of large numbers of features may perform better. Peripheral blood genome-wide gene transcriptional profiling allowed good discrimination between granulomatous lung diseases including sarcoidosis and tuberculosis, compared with pneumonia and lung cancer [75]. The profiles also distinguished sarcoidosis phenotypes [75]. Preliminary reports demonstrated the feasibility of using the same technique for biopsy specimens from patients with orbital inflammatory diseases [76] and for distinguishing cardiac sarcoidosis, giant cell myocarditis, and inflammatory myocarditis [77]. Using a more limited gene expression profile, granulomas from sarcoidosis, fungi, and suture reactions could be differentiated [78]. A novel technique using quantitative phenotyping consisting of flow cytometry and multiparameter morphologic measurements on CD8þ T cells was recently used to discriminate uveitis from Behcet’s disease and sarcoidosis [79]. None of these molecular profiling techniques are mature enough for large-scale use, and any of them will require extensive validation. Nonetheless, they could well serve as the basis for sarcoidosis diagnosis in the future.

CONCLUSION Diagnosis of sarcoidosis continues to be challenging, despite the availability of updated technologies in the past decade. As the capabilities and limitations of HRCT and FDG-PET scan become defined, it is likely that they will have significant impact on the general strategy for diagnosis and assessment of sarcoidosis. EBUS-TBNA has improved the ease of

Acknowledgements None. Financial support and sponsorship None.

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Determining factors in diagnosing pulmonary sarcoidosis by endobronchial ultrasound-guided transbronchial needle aspiration.

The usefulness of step sectioning of transbronchial lung biopsy specimen in diagnosing sarcoidosis.

Sarcoidosis.

Diagnosing dementia.

On diagnosing.

[Endobronchial sarcoidosis].

Equine sarcoidosis.

Letter: Sarcoidosis.

Retroperitoneal sarcoidosis.

Hepatic Sarcoidosis.

Diagnosing dementia.

Diagnosing concussion.

Diagnosing death.

Diagnosing angioedema.

Diagnosing concussion.

Cardiac sarcoidosis.

Vertebral sarcoidosis.

Gastric sarcoidosis.

Epididymal sarcoidosis.

Cutaneous sarcoidosis.

Administering the Sarcoidosis Health Questionnaire to sarcoidosis patients in Serbia.

Intramedullary Cervical Sarcoidosis as the Initial Presentation of Systemic Sarcoidosis.

Comparison of cutaneous sarcoidosis with systemic sarcoidosis: a retrospective analysis.

Sarcoidosis-associated pulmonary hypertension and lung transplantation for sarcoidosis.